阅读说明：本技术 新型拟甲状腺素药 (Novel thyromimetic agents ) 是由 托马斯·凡格尔德恩 布拉德利·贝克斯 于 2020-02-27 设计创作，主要内容包括：提供了具有以下式(I)结构的化合物或其药学上可接受的异构体、外消旋物、水合物、溶剂化物、同位素或盐,其中A、X～(1)、X～(2)、Q、R～(1)、R～(2)和n如本文所定义。此类化合物用作拟甲状腺素药并且具有用于治疗诸如神经变性疾病和纤维化疾病等疾病的效用。还提供了含有此类化合物的药物组合物,以及它们的使用和制备方法。(There is provided a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein A, X 1 、X 2 、Q、R 1 、R 2 And n is as defined herein. Such compounds are useful as thyromimetic agents and have utility for the treatment of diseases such as neurodegenerative and fibrotic diseases. Pharmaceutical compositions containing such compounds, as well as methods for their use and preparation, are also provided.)

1. A compound having the structure of formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halogenGeneration;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

q is a bond, -C (R)³R⁴) -or- { C (R)³R⁴)}₂-；

A is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

Wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR' substituted, whichWherein R 'and R' are each independently H, lower alkyl or lower haloalkyl; and is

Wherein when Q is-CH₂-, A is phenyl and n is 0, X¹Is lower haloalkyl or halo.

2. A compound having the structure of formula (I-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

q is a bond, -C (R)³R⁴) -or- { C (R)³R⁴)}₂-；

A is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR ^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbonCycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

3. A compound having the structure of formula (I-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

q is a bond, -C (R)³R⁴) -or- { C (R)³R⁴)}₂-；

A is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R ³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when Q is-CH₂-, A is phenyl and n is 0, X¹Is lower haloalkyl or halo.

4. The compound of claim 1, wherein Q is a bond, and which has the structure of formula (II):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR ^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

5. The compound of claim 1 or 2, having the structure of formula (II-a):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

Wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

6. The compound of claim 1 or 3, having the structure of formula (II-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

7. The compound of claim 1 or 4, wherein A is phenyl and has the structure of formula (III):

Or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTo which they are connectedThe nitrogen atoms together form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

8. The compound of any one of claims 1, 2, 4, 5, and 7, having the structure of formula (III-a):

Or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

9. The compound of any one of claims 1, 3, 4, 6, and 7, having the structure of formula (III-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹Is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1-5, and one R is²Is R substituted in ring A at the 3-position^2a。

11. The compound of any one of claims 1, 4, 7, and 10, having the structure of formula (IV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹Is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

12. The compound of any one of claims 1, 2, 4, 5, 7, 8, 10, and 11, having the structure of formula (IV-a):

Or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

a is aryl or heteroaryl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

13. The compound of any one of claims 1, 3, 4, 6, 7, 9, and 10, having the structure of formula (IV-B):

Or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

14. The compound of claim 1, wherein Q is-C (R)³R⁴) -, and which has the structure of formula (V):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹Is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, A is phenyl, and when n is 0, X ¹Is lower haloalkyl or halo.

15. The compound of claim 1 or 14, having the structure of formula (V-a):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl,Lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O) ₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

16. The compound of claim 1 or 14, having the structure of formula (V-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, A is phenyl, and when n is 0, X¹Is lower haloalkyl or halo.

17. The compound of claim 1 or 14, having the structure of formula (VI):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q¹、Q²、Q³、Q⁴and Q⁵Each independently is CH, CR²Or N;

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

Wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, and Q¹、Q²、Q³、Q⁴And Q⁵When each is CH, X¹Is lower haloalkyl or halo.

18. The compound of any one of claims 1, 14, 15, and 17, having the structure of formula (VI-a):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q¹、Q²、Q³、Q⁴and Q⁵Each independently is CH, CR²Or N;

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR ^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

19. The compound of any one of claims 1, 14, 16, and 17, having the structure of formula (VI-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q¹、Q²、Q³、Q⁴and Q⁵Each independently is CH, CR²Or N;

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R ³And R⁴Together form ═ O or ═ S; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, and Q¹、Q²、Q³、Q⁴And Q⁵When each is CH, X¹Is lower haloalkyl or halo.

20. The compound of any one of claims 1, 14, and 17, wherein ring a is phenyl and has the structure of formula (VII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1b、-OR^1cOr a heterocycle;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR ^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H and when n is 0, X¹Is lower haloalkyl or halo.

21. The compound of any one of claims 1, 14, 15, 17, 18, and 20, having the structure of formula (VII-a):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R ^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR ' wherein R ' and R 'Each independently is H, lower alkyl or lower haloalkyl.

22. The compound of any one of claims 1, 14, 16, 17, 19, and 20, having the structure of formula (VII-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

Each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H and when n is 0, X¹Is lower haloalkyl or halo.

23. The compound of any one of claims 1, 14, 17, and 20, wherein ring a is phenyl and has the structure of formula (VIII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR ^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lowerAlkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

24. The compound of any one of claims 1, 14, 15, 17, 18, 20, 21, and 23, having the structure of formula (VIII-a):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently of the otherIs H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

25. The compound of any one of claims 1, 14, 16, 17, 19, 20, 22, and 23, having the structure of formula (VIII-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR ^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

26. The compound of any one of claims 1-3 and 14-25, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R³Is H.

27. The compound of any one of claims 1-3 and 14-25, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R³Is carbocyclic.

28. The compound according to claim 27, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R³Is cyclopropyl or cyclobutyl.

29. The compound of any one of claims 1-3 and 14-25, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ³Is a lower alkyl group.

30. The compound of any one of claims 1-3 and 14-25, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R³is-OR^a。

31. The compound of claim 30, or a pharmaceutically acceptable thereofAn isomer, racemate, hydrate, solvate, isotope or salt of (a), wherein R^aIs H.

32. The compound according to any one of claims 1, 2, 4, 5, 7, 8, 10, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, and 26-31, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is^1aIs a lower alkyl group.

33. The compound according to any one of claims 1, 2, 4, 5, 7, 8, 10, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, and 26-32, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is^1aIs methyl.

34. The compound according to any one of claims 1, 2, 4, 5, 7, 8, 10, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, and 26-33, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is ^1bIs H.

35. The compound according to any one of claims 1, 3, 4, 6, 7, 9, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, and 26-31, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is^1cIs H.

36. The compound according to any one of claims 1, 3, 4, 6, 7, 9, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, and 26-31, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is^1cIs a lower alkyl group.

37. According to claims 1, 3, 4, 6, 7, 9, 10, 11, 13, 14, 16, 17,19. 20, 22, 23, 25, 26-31, and 36, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^1cIs methyl.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X¹Is a lower alkyl group.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ¹Is methyl.

40. The compound of any one of claims 1-37, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X¹Is halo.

41. The compound of any one of claims 1-37 and 40, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X¹Is Cl or Br.

42. The compound of any one of claims 1-37 and 40-41, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X¹Is Cl.

43. The compound of any one of claims 1-37 and 40-41, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X¹Is Br.

44. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereofBy an isomer, racemate, hydrate, solvate, isotope or salt, wherein X¹Is a lower haloalkyl group.

45. The compound of any one of claims 1-37 and 44, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ¹is-CF₃。

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X²Is a lower alkyl group.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X²Is methyl.

48. The compound of any one of claims 1-45, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X²Is halo.

49. The compound of any one of claims 1-45 and 48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X²Is Cl or Br.

50. The compound of any one of claims 1-45 and 48-49, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X²Is Cl.

51. The compound of any one of claims 1-45 and 48-49, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, thereof, Isotopes or salts of formula (I), wherein X²Is Br.

52. The compound of any one of claims 1-45, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X²Is a lower haloalkyl group.

53. The compound of any one of claims 1-45 and 52, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X²is-CF₃。

54. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²Is a lower alkyl group.

55. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²Is lower alkyl substituted by-OR'.

56. The compound of claim 55, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R' is H.

57. The compound of claim 55, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R' is lower alkyl.

58. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²Is a lower haloalkyl group.

59. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²is-OR^a。

60. The compound according to claim 59, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R^aIs a lower alkyl group.

61. The compound according to claim 59, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R^aIs a lower haloalkyl group.

62. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²is-C (O) R^a。

63. The compound according to claim 62, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R ^aIs a lower alkyl group.

64. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²is-NR^aC(O)R^b。

65. The compound of claim 64, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^aIs H and R^bIs a lower alkyl group.

66. The compound according to claim 65, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R^bIs methyl.

67. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²is-C (O) OR^a。

68. The compound of claim 67, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^aIs a lower alkyl group.

69. The compound according to claim 68, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R ^aIs methyl or ethyl.

70. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²is-S (O)₂R^a。

71. The compound according to claim 70, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R^aIs a lower alkyl group.

72. The compound according to claim 71, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R^aIs methyl.

73. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^2aOr at least one R²Is halo.

74. The compound according to claim 73, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R^2aOr at least one R²Is F.

75. The compound of any one of claims 1-53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^2aOr at least one R²Is cyano.

76. The compound according to claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, having the structure of any one of the compounds listed in table 1, or having the structure of any one of the compounds listed in table 2.

77. A pharmaceutical composition comprising a compound of any one of claims 1-76, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable excipient.

78. A method of treating a subject having a neurodegenerative disease, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

79. The method of claim 78, wherein the neurodegenerative disease is a demyelinating disease.

80. The method of claim 78 or 79, wherein the neurodegenerative disease is a chronic demyelinating disease.

81. The method of claim 78 or 79, wherein the neurodegenerative disease is an X-linked genetic disease, leukodystrophy, dementia, tauopathy, or ischemic stroke.

82. The method of claim 81, wherein the neurodegenerative disease is multiple sclerosis, MCT8 deficiency, X-linked Adrenoleukodystrophy (ALD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, or lacunar stroke.

83. The method of claim 78 or 79, wherein the neurodegenerative disease is adult Refsum disease, Alexander's disease, Alzheimer's disease, Barlow's concentric sclerosis, Canavan's disease, central pontine myelination, cerebral palsy, tendonoxanthomatosis, chronic inflammatory demyelinating polyneuropathy, Devic syndrome, diffuse demyelinating sclerosis, idiopathic inflammatory demyelinating disease, infant Refsum disease, Krabbe's disease, Leber hereditary optic neuropathy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal disease, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraplegia, van der Knaap disease, X-linked adrenoleukodystrophy or Zebra weger syndrome.

84. A method of treating a subject having a medical condition associated with TGF- β overexpression comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

85. The method of claim 84, wherein the medical condition associated with TGF- β overexpression is a fibrotic disease.

86. The method of claim 84 or 85, wherein the medical condition associated with TGF- β overexpression is non-alcoholic steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF), systemic scleroderma, or Alport syndrome.

87. A method of treating a patient suffering from adult Refsum disease, infant Refsum disease, Alexander disease, Alzheimer's disease, Barlow's concentric sclerosis, Carnawan disease, Central Pontine Myelination (CPM), cerebral palsy, tendonoxanthomatosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Idiopathic Inflammatory Demyelinating Disease (IIDD), Krabbe disease, Leber's hereditary optic neuropathy, leukodystrophy, Marburg's multiple sclerosis, Marchiafava-Bignam disease, Metachromatic Leukodystrophy (MLD), Multifocal Motor Neuropathy (MMN), Multiple Sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD), Progressive Multifocal Leukospasticity (PML), paraproteinemic paralysis (TSP), adrenodystrophy (ALX-linked Adrenodystrophy (ALD), HomexX-linked adrenodystrophy or HomexO, A method of treating a subject with Zellweger syndrome, MCT8 deficiency, Amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia, lacunar stroke, primary age-related tauopathy (PART), Pick disease, frontotemporal dementia linked to chromosome 17 and parkinson's disease (FTDP-17), Adrenomyeloneuropathy (AMN), cerebral adrenoleukodystrophy (cALD), non-alcoholic steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF), systemic scleroderma, or Alport syndrome, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

88. A method of treating a subject suffering from NASH, NAFLD associated with hyperlipidemia, alcoholic/alcoholic steatohepatitis, liver fibrosis associated with viral infection (HBV, HCV), fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, hereditary lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Willer's disease, Crigler-Najjar syndrome, lysosomal acid lipase deficiency, cystic fibrosis liver disease, the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

89. A method of treating a subject having Alport syndrome, diabetic nephropathy, FSGS, IgA nephropathy-associated fibrosis, Chronic Kidney Disease (CKD), post AKI, HIV-associated CKD, chemotherapy-induced CKD, nephrotoxic agent-associated CKD, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or Polycystic Kidney Disease (PKD), comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

90. A method of treating a patient suffering from IPF, ILD, pulmonary fibrosis associated with autoimmune diseases such as rheumatoid arthritis, scleroderma or sjogren's syndrome, asthma-associated pulmonary fibrosis, COPD, asbestos-or silica-induced pulmonary fibrosis, silicosis, respiratory bronchiolitis, Idiopathic Interstitial Pneumonia (IIP), idiopathic non-specific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, rare IIP: a method of treating a subject for idiopathic lymphoid interstitial pneumonia, idiopathic pleural parenchymal fibroelastosis, unclassified idiopathic interstitial pneumonia, hypersensitivity pneumonitis, radiation-induced lung injury, progressive massive fibrosis-pneumoconiosis, bronchiectasis, pneumoconiosis, chronic respiratory disease, Chronic Obstructive Pulmonary Disease (COPD), emphysema, Pulmonary Arterial Hypertension (PAH), or cystic fibrosis, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

91. A method of treating a subject having scleroderma/systemic sclerosis, graft versus host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, tardive skin porphyria, restrictive skin disease, Dupuytren's contracture, skin fibrosis, nephrogenic systemic fibrosis/nephrogenic fibrotic skin disease, mixed connective tissue disease, sclerosing mucoedema, eosinophilic fasciitis, fibrosis caused by exposure to chemical or physical substances, GvHD-induced fibrosis, adult scleroderma, liposcleroderma, or a premature aging disorder (premature aging, acromegaly, Werner syndrome), the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

92. A method of treating a subject having atrial fibrosis, endocardial myocardial fibrosis, atherosclerosis, restenosis, or joint fibrosis, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

93. A method of treating a subject having mediastinal fibrosis, myelofibrosis, post-polycythemia vera myelofibrosis, or essential thrombocythemia, comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

94. A method of treating a subject having crohn's disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, gastrointestinal fibrosis due to cystic fibrosis, or pancreatic fibrosis due to pancreatitis, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

95. A method of treating a subject having endometrial fibrosis, uterine fibroids, or Peyronie's disease, comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

96. A method of treating a subject having macular degeneration, diabetic retinopathy, retinal fibrovascular disease or vitreoretinopathy, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

97. A method of treating a subject having a scar associated with a wound, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof.

98. The method of claim 97, wherein the trauma-related scar is associated with a surgical complication, chemotherapy-induced fibrosis, or radiation-induced fibrosis.

99. A compound according to any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a neurodegenerative disease.

100. The compound of claim 99, wherein the neurodegenerative disease is a demyelinating disease.

101. The compound of claim 99 or 100, wherein the neurodegenerative disease is a chronic demyelinating disease.

102. The compound of claim 99 or 100, wherein the neurodegenerative disease is an X-linked genetic disease, leukodystrophy, dementia, tauopathy, or ischemic stroke.

103. The compound of claim 102, wherein the neurodegenerative disease is multiple sclerosis, MCT8 deficiency, X-linked Adrenoleukodystrophy (ALD), Amyotrophic Lateral Sclerosis (ALS), alzheimer's disease, frontotemporal dementia, or lacunar stroke.

104. The compound of claim 99 or 100, wherein the neurodegenerative disease is adult Refsum disease, alexander disease, alzheimer disease, barotrichosis, canavan disease, central pontine myelinolysis, cerebral palsy, tendonoxanthomatosis, chronic inflammatory demyelinating polyneuropathy, Devic syndrome, diffuse demyelinating sclerosis, idiopathic inflammatory demyelinating disease, infant Refsum disease, Krabbe disease, Leber's hereditary optic neuropathy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, gastrocnemius, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraplegia, van der Knaap disease, X-linked adrenoleukodystrophy, or zerewire syndrome.

105. A compound according to any one of claims 1 to 76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a medical condition associated with TGF- β overexpression.

106. The compound of claim 105, wherein the medical condition associated with TGF- β overexpression is a fibrotic disease.

107. The compound of claim 105 or 106, wherein the medical condition associated with TGF- β overexpression is non-alcoholic steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF), systemic scleroderma, or Alport syndrome.

108. A compound according to any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of adult Refsum disease, infant Refsum disease, alexander disease, alzheimer disease, barlow's concentric sclerosis, canavan disease, Central Pontine Myelination (CPM), cerebral palsy, tendonoxanthomatosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Idiopathic Inflammatory Demyelinating Disease (IIDD), Krabbe disease, Leber's hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic encephalodystrophy (MLD), polyneuropathy (MMN), Multiple Sclerosis (MS), paraproteinemia demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD), progressive leukoencephalopathy (PML), or white spot encephalopathy (PML), Tropical Spastic Paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO or X-linked ALO), Zellweger syndrome, MCT8 deficiency, Amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia, lacunar stroke, primary age-related tauopathies (PART), Pick disease, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Adrenomyeloneuropathy (AMN), cerebral adrenoleukodystrophy (cALD), nonalcoholic steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF), systemic scleroderma or Alport syndrome.

109. A compound according to any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of NASH, NAFLD with hyperlipidemia, alcoholic liver disease/alcoholic steatohepatitis, liver fibrosis associated with viral infections (HBV, HCV), fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, genetic lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogenosis, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, Crigler-Najjar syndrome, lysosomal acid lipase deficiency, cystic fibrosis liver disease.

110. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in treating Alport syndrome, diabetic nephropathy, FSGS, IgA nephropathy-associated fibrosis, Chronic Kidney Disease (CKD), post AKI, HIV-associated CKD, chemotherapy-induced CKD, nephrotoxic agent-associated CKD, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or Polycystic Kidney Disease (PKD).

111. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in treating IPF, ILD, pulmonary fibrosis associated with autoimmune diseases such as rheumatoid arthritis, scleroderma or sjogren's syndrome, asthma-associated pulmonary fibrosis, COPD, asbestos-or silica-induced pulmonary fibrosis, silicosis, respiratory bronchiolitis, Idiopathic Interstitial Pneumonia (IIP), idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, rare IIP: idiopathic lymphoid interstitial pneumonia, idiopathic pleural parenchymal fibroelastosis, unclassified idiopathic interstitial pneumonia, hypersensitivity pneumonia, radiation-induced lung injury, progressive massive fibrosis-pneumoconiosis, bronchiectasis, pneumoconiosis, chronic respiratory disease, Chronic Obstructive Pulmonary Disease (COPD), emphysema, Pulmonary Arterial Hypertension (PAH), or cystic fibrosis.

112. A compound according to any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of scleroderma/systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, delayed-onset porphyria cutanea, restrictive skin diseases, Dupuytren's contracture, skin fibrosis, nephrogenic systemic fibrosis/nephrogenic fibrotic skin diseases, mixed connective tissue disease, sclerosing mucoedema, eosinophilic fasciitis, fibrosis due to exposure to chemical or physical substances, GvHD-induced fibrosis, adult scleroderma, liposcleroderma, or a premature aging disorder (premature aging, acromegaly, Werner syndrome).

113. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in treating atrial fibrosis, endocardial myocardial fibrosis, atherosclerosis, restenosis, or joint fibrosis.

114. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in treating mediastinal fibrosis, myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia.

115. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of crohn's disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, gastrointestinal fibrosis due to cystic fibrosis, or pancreatic fibrosis due to pancreatitis.

116. A compound according to any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of endometrial fibrosis, uterine fibroids or Peyronie's disease.

117. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of macular degeneration, diabetic retinopathy, retinal fibrovascular disease, or vitreoretinopathy.

118. A compound according to any one of claims 1 to 76, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of scars associated with wounds.

119. The compound of claim 97, wherein the trauma-related scar is associated with a surgical complication, chemotherapy-drug-induced fibrosis, or radiation-induced fibrosis.

Technical Field

The present invention relates to thyromimetic compounds and products containing them, as well as methods for their use and preparation.

Description of the Related Art

Thyroid Hormone (TH) is a key signal for oligodendrocyte differentiation and myelination during development and also stimulates remyelination in an adult model of Multiple Sclerosis (MS) (Calz a et al, Brain Res Revs 48: 339-. However, TH is not an acceptable long-term therapy because of the limited therapeutic window over which remyelination can be achieved while avoiding cardiotoxicity and bone demineralization associated with chronic hyperthyroidism. Some thyroid hormone analogs can activate thyroid hormone responsive genes by exploiting the molecular and physiological characteristics of the thyroid hormone receptor, while avoiding the disadvantages associated with TH (Malm et al, Mini Rev Med Chem 7:79-86,2007). These receptors are expressed in two major forms with heterogeneous tissue distribution and overlapping but distinct sets of target genes (Yen, Physiol Rev 81:1097-1142, 2001). TR α is abundant in the heart, brain and bone, while TR β is abundant in the liver (O' Shea et al, Nuclear Recept Signal 4: e011,2006).

TH has also been reported to inhibit transforming growth factor beta (TGF-. beta.) signaling, thereby attenuating the fibrotic response (Alonso-Merino et al, Proc Natl Acad Sci U S A.113(24): E3451-60,2016). TGF-. beta.is a cytokine with pleiotropic effects in tissue homeostasis that plays a key role in pathological processes such as fibrosis (Massague, Nat Rev Mol Cell biol.13(10): 616-630,2012). By inhibiting TGF- β signaling, TR ligands or agonists may have the beneficial effect of blocking the progression of fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF) or systemic sclerosis (Varga et al, Curr Opin rheumatol.20(6): 720-.

Due to the high sequence homology of thyroid hormone receptor subtypes; that is, only one amino acid residue on the inner surface of the ligand binding domain cavity varies between the α 1 and β 1 forms, thus the development of selective thyromimetic drugs is challenging. Despite this challenge, several groups have reported TR β selective agonists. Scanlan et al determined that GC-1 (orbivirome) is one of the most potent analogs, which showed significant TR β selectivity in vitro (Chiellini et al, Chem Biol 5:299-306, 1998; Yoshihara et al, J Med Chem 46:3152 @, 2003) and in vivo (Trost et al, Endocrinology 141: 3057-. As used herein, the term "sapetipirole" refers to a synthetic diarylmethane derivative that is clinically investigated as a potential therapeutic agent for hypercholesterolemia (see U.S. patent 5,883,294, which is incorporated herein by reference). Other names for Subtilox found in the literature and regulatory documents include QRX-431 and GC-1. Metabasis used in MB07811 with a similar core and novel liver targeting prodrug strategy (Erion et al, PNAS 104(39), 15490-. Madrigal has reported the in vivo TR β -selective activity of MGL-3196 (Taub et al, Atheroscleosis 230(2):373-380, 2013). KaroBio has reported emperome (KB 2115; Berkenstar et al, PNAS 105(2): 663-. Further studies by this group highlighted other selective compounds (Hangeland et al, BMCL 14:3549-3553, 2004). Two TR β selective agonists identified as SKL-12846 and SKL-13784 were reported to accumulate in the liver and reduce cholesterol levels in rodents (Takahashi et al, BMC 22(1):488-498, 2014; Xenobiotica 2015, 1-9). Kissei also reported selective compounds (Shiohara et al, BMC 20(11), 3622-.

Although advances have been made in this area, there remains a need in the art for further selective thyromimetic compounds, as well as products containing them, and methods related to their use and preparation.

Disclosure of Invention

Disclosed herein are compounds according to formula I:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein A, X¹、X²、Q、R¹、R²And n is as defined below.

In an embodiment, there is provided a pharmaceutical composition comprising a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient. In embodiments, the pharmaceutical composition is for use in treating a neurodegenerative disorder, including a neurodegenerative disorder classified as a demyelinating disease, such as X-linked adrenoleukodystrophy or multiple sclerosis. In another embodiment, the pharmaceutical composition is used to treat a medical condition associated with increased TGF- β activity, such as a fibrotic disease.

In an embodiment, there is provided a method of treating a neurodegenerative disorder in a subject in need thereof comprising administering a compound having the structure of formula (I), or a pharmaceutically acceptable salt or a composition comprising the compound. In some aspects, the neurodegenerative disorder can be classified as a demyelinating disease, such as X-linked adrenoleukodystrophy or multiple sclerosis.

In another embodiment, a method is provided for treating a medical condition associated with TGF- β overexpression in a subject in need thereof, comprising administering a compound having the structure of formula (I), or a pharmaceutically acceptable salt or composition comprising the compound. In some aspects, the medical condition associated with TGF- β overexpression is a fibrotic disease.

Detailed Description

As noted above, the present invention relates to thyromimetic compounds, products containing the compounds, and methods of their use and synthesis.

In one embodiment, compounds having the structure of formula (I) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTo which they are connectedThe attached nitrogen atoms together form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

Q is a bond, -C (R)³R⁴) -or- { C (R)³R⁴)}₂-；

A is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R³And R⁴Independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when Q is-CH₂-, A is phenyl, R¹When n is 0, X is ═ OH¹Is lower haloalkyl or halo.

Acid Compound (R) of the present invention¹＝-OR^1cAnd R is^1cH) is an active agonist that selectively activates the TR β receptor. Amide Compound (R) of the present invention¹＝–NR^1aR^1b) Can act as a substrate for the specific hydrolase fatty acid-amide hydrolase (FAAH), which cleaves the amide, releasing the thyromimetic. Thus, the conversion of the prodrug to the drug is enhanced in tissues expressing high levels of FAAH, such as the central nervous system. Ester Compound (R) of the present invention ¹＝-OR^1cAnd R is^1cNot H) is also a prodrug, usually processed by the action of an esterase, which can be selectively present in specific tissues.

As used herein, "lower alkyl" refers to a straight or branched chain alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments, from 1 to 3 carbon atoms. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched lower alkyl include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2, 2-dimethylpropyl.

As used herein, "lower alkenyl" refers to straight or branched chain alkenyl groups having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments, from 2 to 3 carbon atoms. An alkenyl group is an unsaturated hydrocarbon chain containing at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

As used herein, "lower alkynyl" refers to straight or branched chain alkynyl groups having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments, from 2 to 3 carbon atoms. Alkynyl is an unsaturated hydrocarbon chain containing at least one carbon-carbon triple bond. Examples of lower alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

"halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

"hydroxy" means-OH.

"cyano" means-CN.

"lower haloalkyl" means a lower alkyl group as defined above wherein one or more hydrogen atoms are replaced by halogen. Examples of lower haloalkyl include, but are not limited to, -CF₃、-CHF₂And the like.

"lower alkoxy" means a lower alkyl group as defined above (i.e., -O- (lower alkyl)) attached through an oxygen atom. Examples of lower alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy and the like.

"lower haloalkoxy" means a lower haloalkyl group as defined above (i.e., -O- (lower haloalkyl)) attached through an oxygen atom. Examples of lower haloalkoxy include, but are not limited to, -OCF ₃And the like.

"cycloalkyl" refers to an alkyl group that forms a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or fully unsaturated, wherein if unsaturation is present, conjugation of pi electrons in the ring does not result in aromaticity. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphene (camphenyl), isobornene (isocamphenyl), and carenyl (carenyl), as well as fused rings such as, but not limited to, decahydronaphthyl and the like.

"cycloalkylalkyl" is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a cycloalkyl group as defined above.

An "aryl" group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptenylenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, tetracenyl, phenanthrenyl, and phenanthrenyl, Mesityl, biphenylene, anthracenyl and naphthyl. In some embodiments, the aryl group contains 6 to 14 carbons in the cyclic portion of the group. The terms "aryl" and "aryl group" include fused rings in which at least one, but not necessarily all, of the rings are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). In one embodiment aryl is phenyl or naphthyl, while in another embodiment aryl is phenyl.

"carbocyclyl", "carbocycle" or "carbocyclic" refers to an alkyl group that forms a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or fully unsaturated, wherein if unsaturation is present, conjugation of pi electrons in the ring may result in aromaticity. In one embodiment, carbocycle includes cycloalkyl as defined above. In another embodiment, carbocycle includes aryl as defined above.

"Carbocycloalkyl" is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a carbocyclic group as defined above.

"heterocyclyl", "heterocycle" or "heterocyclic" refer to aromatic and non-aromatic cyclic moieties containing 3 or more ring members, wherein one or more ring members is a heteroatom, such as but not limited to N, O, S or P. In some embodiments, heterocyclyl includes 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but each ring in a polycyclic ring system need not contain heteroatoms. For example, dioxolanyl rings and benzodioxolyl ring systems (methylenedioxyphenyl ring systems) are all heterocyclyl groups within the scope of what is referred to herein.

Heterocyclic groups also include fused ring species, including those having fused aromatic and non-aromatic groups. Heterocyclyl also includes polycyclic ring systems containing heteroatoms such as, but not limited to, quinuclidinyl, and also includes heterocyclyl groups having substituents including, but not limited to, alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy bonded to one of the ring members. A heterocyclyl group as defined herein may be a heteroaryl group or a partially or fully saturated cyclic group containing at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furyl, tetrahydrofuryl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl, benzofuranyl, dihydrobenzofuranyl, indolyl, indolinyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl (thianaphtalenyl), purinyl, xanthyl, adenyl, guanyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl.

"heterocycloalkyl" is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclic group as defined above.

"heteroaryl" refers to an aromatic ring moiety containing 5 or more ring members, wherein one or more ring members are heteroatoms such as, but not limited to N, O and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl (pyrazyl), pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthine, adenylyl, guanine, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinoxalyl, and quinazolinyl. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds, for example, wherein at least one, but not necessarily all, of the rings are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2, 3-dihydroindolyl.

In one embodiment, compounds having the structure of formula (I-A) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

q is a bond, -C (R)³R⁴) -or- { C (R)³R⁴)}₂-；

A is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R³And R⁴Independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O) ₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (I-B) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

q is a bond, -C (R)³R⁴) -or- { C (R)³R⁴)}₂-；

A is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R³And R⁴Independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Are formed togetherO or S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O) ₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when Q is-CH₂-, A is phenyl, R^1cIs H, and when n is 0, X¹Is lower haloalkyl or halo.

In one embodiment, compounds having the structure of formula (I-B) are provided, wherein A is heteroaryl, and in a more specific embodiment, is furyl or thienyl.

In one embodiment, compounds having the structure of formula (II) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkylCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR ^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (II-a) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

Wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (II-B) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (III) are provided:

Or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocydoalkylCycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (III-A) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹Is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (III-B) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

Each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In a more particular embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), or (III-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1 to 5 and one R is²Is R substituted in ring A at the 3-position^2a。

In one embodiment, compounds having the structure of formula (IV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (IV-A) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹Is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (IV-B) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹Is lower alkyl, lower haloalkyl or halo;

X²is a lower alkaneAlkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (V) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower halogenAlkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, A is phenyl, R¹is-OH, and when n is 0, X¹Is lower haloalkyl or halo.

In one embodiment, compounds having the structure of formula (V) are provided wherein a is heteroaryl, and in a more specific embodiment, is furyl or thienyl.

In one embodiment, compounds having the structure of formula (V-a) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (V-B) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

a is aryl or heteroaryl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Are formed togetherO or S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, A is phenyl, R^1cIs H, and when n is 0, X ¹Is lower haloalkyl or halo.

In one embodiment, compounds having the structure of formula (VI):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q¹、Q²、Q³、Q⁴and Q⁵Each independently is CH, CR²Or N;

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle,Carbocycloalkyl or heterocycloalkyl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is ^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, R¹is-OH, and Q¹、Q²、Q³、Q⁴And Q⁵When each is CH, X¹Is lower haloalkyl or halo.

In one embodiment, compounds having the structure of formula (VI-A) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q¹、Q²、Q³、Q⁴and Q⁵Each independently is CH, CR²Or N;

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR ^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (VI-B) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

Q¹、Q²、Q³、Q⁴and Q⁵Each independently is CH, CR²Or N;

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R ³And R⁴Together form ═ O or ═ S; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, R^1cIs H, and Q¹、Q²、Q³、Q⁴And Q⁵Each of which isWhen is CH, X¹Is lower haloalkyl or halo.

In one embodiment, compounds having the structure of formula (VII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1b、-OR^1cOr a heterocycle;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR ^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, R¹is-OH, and when n is 0, X¹Is lower haloalkyl or halo.

In one embodiment, compounds having the structure of formula (VII-a) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

Each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is HHalo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (VII-B) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

each R²Independently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR ^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkylLower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

n is 0 to 5; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R²、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl; and is

Wherein when R is³And R⁴Each is H, R¹is-OH, and when n is 0, X¹Is lower haloalkyl or halo.

In one embodiment, compounds having the structure of formula (VIII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R¹is-NR^1aR^1bOR-OR^1c；

R^1aAnd R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^1cIs H,Lower alkyl, carbocyclic ring, heterocyclic ring, carbocycloalkyl, or heterocycloalkyl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (VIII-A) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹Is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1aand R^1bEach independently is H, lower alkyl, lower alkenyl, lower alkynyl, -OR^a、-NR^aR^bCarbocyclic ring, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R^1aAnd R^1bTogether with the nitrogen atom to which they are attached form a heterocyclic ring;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloAn alkyl group;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O)₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In one embodiment, compounds having the structure of formula (VIII-B) are provided:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X¹is lower alkyl, lower haloalkyl or halo;

X²is lower alkyl, lower haloalkyl or halo;

R^1cis H, lower alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl;

R^2ais halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

Each R^2bIndependently is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycloalkyl, heterocycloalkyl, -OR^a、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)₂R^aor-S (O)₂OR^a；

R³And R⁴Each independently is H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR^a、-NR^aR^bCarbocyclic ring, heterocyclic ring, carbocycloalkyl or heterocycloalkyl, or R³And R⁴Together form ═ O or ═ S;

m is 0 to 4; and is

R^aAnd R^bEach independently is H, lower alkyl or lower haloalkyl;

wherein R is^1a、R^1b、R^1c、R^2a、R^2b、R³、R⁴、R^aAnd R^bEach independently optionally substituted with one OR more halo, cyano, -OR ', -NR' R ", -S (O) ₂R' or-S (O)₂OR 'wherein R' and R "are each independently H, lower alkyl OR lower haloalkyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is hydrogen, an alkyl group, an aryl group, or a substituted aryl group, or a pharmaceutically acceptable salt thereof³Is H.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is hydrogen, an alkyl group, an aryl group, or a substituted aryl group, or a pharmaceutically acceptable salt thereof³Is carbocyclic.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is hydrogen, an alkyl group, an aryl group, or a substituted aryl group, or a pharmaceutically acceptable salt thereof ³Is cyclopropyl or cyclobutyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is hydrogen, an alkyl group, an aryl group, or a substituted aryl group, or a pharmaceutically acceptable salt thereof³Is a lower alkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is hydrogen, an alkyl group, an aryl group, or a substituted aryl group, or a pharmaceutically acceptable salt thereof³Is a lower haloalkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is hydrogen, an alkyl group, an aryl group, or a substituted aryl group, or a pharmaceutically acceptable salt thereof ³is-OR^aAnd in further embodiments, R^aIs H.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (II-A), (III-A), (IV-A), (V-A), (VI-A), (VII-A), (VIII) or (VIII-A) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R is hydrogen, methyl, ethyl, propyl, or propyl^1aIs a lower alkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (II-A), (III-A), (IV-A), (V-A), (VI-A), (VII-A), (VIII) or (VIII-A) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R is hydrogen, methyl, ethyl, propyl, or propyl^1aIs methyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (II-A), (III-A), (IV-A), (V-A), (VI-A), (VII-A), (VIII) or (VIII-A) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R is hydrogen, methyl, ethyl, propyl, or propyl ^1bIs H.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-B), (II-B), (III-B), (IV-B), (V-B), (VI-B), (VII-B), (VIII) or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R is hydrogen, methyl, ethyl, propyl, or propyl^1cIs H.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-B), (II-B), (III-B), (IV-B), (V-B), (VI-B), (VII-B), (VIII) or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R is hydrogen, methyl, ethyl, propyl, or propyl^1cIs a lower alkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-B), (II-B), (III-B), (IV-B), (V-B), (VI-B), (VII-B), (VIII) or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R is hydrogen, methyl, ethyl, propyl, or propyl ^1cIs methyl or ethyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein¹Is a lower alkyl group.

In addition toIn a particular embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein¹Is methyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein ¹Is lower alkenyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein¹Is halo.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein¹Is Cl or Br.

In a more specific embodiment, there is provided a composition having the formula (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI), (V-A), (V-B), (V) and (V A compound of the structure of any one of VI-a), (VI-B), (VII-a), (VII-B), (VIII-a), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is¹Is Cl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein¹Is Br.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein ¹Is a lower haloalkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein¹is-CF₃。

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, or hydrate thereofSolvates, isotopes or salts thereof, wherein X²Is a lower alkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein ²Is methyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein²Is halo.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein²Is Cl or Br.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein ²Is Cl.

In more specific embodiments, there are provided compositions having the formula (I), (I-A), (I-B), (II) above) A compound of the structure of any one of (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A) or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein X is²Is Br.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein²Is a lower haloalkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X is X, wherein X is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and wherein ²is-CF₃。

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is a pharmaceutically acceptable salt thereof, hydrate, solvate, or hydrate thereof^2aOr at least one R²Is a lower alkyl group.

In a more specific embodiment, there is provided a composition having the formula (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII)A compound of the structure of any one of-a), (VII-B), (VIII-a) or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R is^2aOr at least one R²Is lower alkyl substituted by-OR ', and in further embodiments, R ' is H, OR R ' is lower alkyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is a pharmaceutically acceptable salt thereof, hydrate, solvate, or hydrate thereof ^2aOr at least one R²Is a lower haloalkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is a pharmaceutically acceptable salt thereof, hydrate, solvate, or hydrate thereof^2aOr at least one R²is-OR^aAnd in further embodiments, R^aIs lower alkyl, or R^aIs a lower haloalkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is a pharmaceutically acceptable salt thereof, hydrate, solvate, or hydrate thereof^2aOr at least one R²is-C (O) R^aAnd in further embodiments, R ^aIs a lower alkyl group.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is a pharmaceutically acceptable salt thereof, hydrate, solvate, or hydrate thereof^2aOr at least one R²is-NR^aC(O)R^bAnd in further embodiments, R^aIs H, and R^bIs lower alkyl, or R^bIs methyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is a pharmaceutically acceptable salt thereof, hydrate, solvate, or hydrate thereof^2aOr at least one R²is-C (O) OR^aAnd in further embodiments, R^aIs lower alkyl, or R ^aIs methyl or ethyl.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is a pharmaceutically acceptable salt thereof, hydrate, solvate, or hydrate thereof^2aOr at least one R²is-S (O)₂R^aAnd in further embodiments, R^aIs lower alkyl, or R^aIs methyl.

In a more specific embodiment, there is provided a composition having the formula (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A) above) (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A) or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, wherein R is a pharmaceutically acceptable salt, solvate, hydrate, or hydrate thereof^2aOr at least one R²Is halo, and in further embodiments, R^2aOr at least one R ²Is F.

In a more specific embodiment, there is provided a compound having the structure of any one of formulas (I), (I-A), (I-B), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A), (VI-B), (VII-A), (VII-B), (VIII-A), or (VIII-B) above, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R is a pharmaceutically acceptable salt thereof, hydrate, solvate, or hydrate thereof^2aOr at least one R²Is cyano.

Representative compounds of formula (I) and formulae (II) to (VIII) that are suitable for use include the compounds listed in table 1 below and pharmaceutically acceptable salts thereof. For this reason, representative compounds are identified herein by their respective "compound number," sometimes abbreviated as "compound No." or "number.

TABLE 1

Representative Compounds

"isomers" are used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless the specific stereochemistry or isomeric form is specifically indicated. Such compounds may be optical isomers at any or all asymmetric atoms (apparent from the description) enriched or resolved in any degree of enrichment. Both racemic and diastereomeric mixtures and individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric counterparts, and these are within the scope of certain embodiments of the invention. Isomers that arise due to the presence of chiral centers include a pair of non-superimposable isomers known as "enantiomers". The single enantiomers of the pure compounds are optically active (i.e., they are capable of rotating about the plane of plane polarized light and are referred to as R or S).

"isolated optical isomers" refers to compounds that have been substantially purified from the corresponding optical isomers of the same general formula. For example, an isolated isomer may be at least about 80%, at least 80%, or at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.

By "substantially enantiomerically or diastereomerically" pure, it is meant that the enantiomeric or diastereomeric enrichment level of one enantiomer relative to another is at least about 80%, more specifically greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. The racemate is labeled "(±)" because it is optically inactive (i.e., does not rotate plane polarized light in either direction because its constituent enantiomers cancel each other out). All compounds bearing an asterisk adjacent to a tertiary or quaternary carbon are optical isomers which can be purified from the respective racemate and/or synthesized by appropriate chiral synthesis.

A "hydrate" is a compound that exists in combination with a water molecule. The combination may include a stoichiometric amount of water, such as a monohydrate or dihydrate, or may include a random amount of water. As the term is used herein, "hydrate" refers to a solid form; that is, for a compound in aqueous solution, although it may be hydrated, it is not the hydrate to which the term is used herein.

"solvates" are analogous to hydrates except that a solvent other than water is present. For example, methanol or ethanol may form "alcoholates", which may also be stoichiometric or non-stoichiometric. As the term is used herein, "solvate" refers to a solid form; that is, for a compound in a solvent solution, although it may be solvated, it is not the solvate to which the term is used herein.

An "isotope" refers to an atom having the same number of protons but a different number of neutrons, and an isotope of a compound of formula (I) includes any such compound in which one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, while carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes: deuterium (one proton and one neutron) and tritium (one proton and two neutrons). Fluorine has many isotopes, with fluorine 19 having the longest half-life. Thus, isotopes of compounds having the structure of formula (I) include, but are not limited to, compounds of formula (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced by deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine-19.

"salt" generally refers to an organic compound in ionic form, such as a carboxylic acid or amine, in combination with a counterion. For example, the salt formed between an acid in its anionic form and a cation is referred to as an "acid addition salt". In contrast, salts formed between a base in cationic form and an anion are referred to as "base addition salts".

The term "pharmaceutically acceptable" refers to agents that have been approved for human administration and are generally non-toxic. For example, the term "pharmaceutically acceptable salts" refers to non-toxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al, Salt Selection for Basic Drugs, int.j. pharm.,33,201-217,1986), which are incorporated herein by reference.

Pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts, including salts of alkali, alkaline earth and transition metals, e.g., calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts formed from basic amines such as N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

Pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or from organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, methylenepamoic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylsulfamic, stearic, alginic, beta-hydroxybutyric, salicylic, galactaric and galacturonic.

Although pharmaceutically unacceptable salts are not generally useful as pharmaceuticals, such salts may be useful, for example, as intermediates in the synthesis of compounds having the structure of formula (I), for example, in their purification by recrystallization.

In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and at least one pharmaceutically acceptable carrier, diluent or excipient. For example, the active compound will generally be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet, paper or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material that serves as a vehicle, excipient, or medium for the active compound. The active compound may be adsorbed on a particulate solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono-and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

As used herein, the term "pharmaceutical composition" refers to a composition comprising one or more compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, formulated with a pharmaceutically acceptable carrier, which may also contain other additives, approved by a governmental regulatory agency, for manufacture or sale as part of a therapeutic regimen for the treatment of diseases in mammals. For example, the pharmaceutical composition can be formulated for oral administration in a unit dosage form (e.g., a tablet, capsule, caplet, softgel, or syrup); topical administration (e.g., as a cream, gel, lotion, or ointment); intravenous administration (e.g., as a sterile solution without particulate emboli and in a solvent system suitable for intravenous use); or any other formulation described herein. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st edition, eds Gennaro, Lippenkett Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36NF31), published in 2013.

As used herein, the term "pharmaceutically acceptable carrier" refers to any ingredient (e.g., a carrier capable of suspending or dissolving an active compound) other than the disclosed compound or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and which has non-toxic and non-inflammatory properties in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film formers or coatings, flavourings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners or water of hydration. Exemplary excipients include, but are not limited to: butylated Hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin a, vitamin E, vitamin C, and xylitol.

The formulations may be mixed with adjuvants which do not deleteriously react with the active compounds. Such additives may include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffers and/or coloring substances, preservatives, sweeteners or flavorings. The composition may also be sterilized, if desired.

The route of administration may be any route which is effective for transporting the active compounds of the invention to the appropriate or desired site of action, such as orally, nasally, pulmonarily, buccally, subcutaneously, intradermally, transdermally or parenterally, including intravenously, subcutaneously and/or intramuscularly. In one embodiment, the route of administration is oral.

The dosage form may be administered once daily or more than once daily, for example, twice or three times daily. Alternatively, the dosage form may be administered less frequently than once a day, for example every other day or once a week, if the prescribing physician deems it appropriate or if the prescribing information for the drug indicates that it is appropriate. Dosage regimens include, for example, titration of a dose to the extent necessary or useful for the indication being treated, to adapt the patient's body to therapy, to minimize or avoid adverse side effects associated with therapy, and/or to maximize the therapeutic effect of a compound of the invention. Other dosage forms include delayed or controlled release forms. Suitable dosage regimens and/or formats include, for example, those listed in the latest edition of the Physicians' Desk Reference, which is incorporated herein by Reference.

In another embodiment, there is provided a method of preparing a composition of the compounds described herein, comprising formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may further comprise the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further comprises the step of lyophilizing the composition to form a lyophilized article.

In another embodiment, there is provided a method of treating a subject having a neurodegenerative disease, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the neurodegenerative disease is a demyelinating disease. In another embodiment, the demyelinating disease is a chronic demyelinating disease. In yet another embodiment, the demyelinating disease is or is associated with an X-linked genetic disease, leukodystrophy, dementia, tauopathy, or ischemic stroke. In another embodiment, the demyelinating disease is or is associated with: adult Refsum disease, alexander disease, alzheimer disease, Barlow's concentric sclerosis, Canavan disease, Central Pontine Myelination (CPM), cerebral palsy, tendonopheliosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Idiopathic Inflammatory Demyelinating Disease (IIDD), infant Refsum disease, Krabbe disease, Leber's hereditary optic neuropathy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, amyotrophic, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraplegia, van der krapp disease, or Zeweger syndrome. In another embodiment, the demyelinating disease is or is associated with: multiple sclerosis, MCT8 deficiency, X-linked Adrenoleukodystrophy (ALD), Amyotrophic Lateral Sclerosis (ALS), alzheimer's disease, frontotemporal dementia, or lacunar stroke.

As used herein, the term "neurodegenerative disease" refers to any type of disease characterized by progressive deterioration of the nervous system.

As used herein, the term "demyelinating disease" refers to any disease or medical condition of the nervous system in which myelin sheaths are damaged or lost, or in which myelin sheath growth or development is impaired. Demyelination inhibits the conduction of signals in the affected nerves, resulting in impairment of sensory, motor, cognitive, or other nerve-related functions. Demyelinating diseases have many different causes, either genetic or acquired. In some cases, the demyelinating disease is caused by an infectious agent, an autoimmune response, a toxic agent, or traumatic injury. In other cases, the cause of the demyelinating disease is unknown ("idiopathic") or developed from a combination of factors.

As used herein, the term "leukodystrophy" refers to a group of diseases that affect myelin growth or development.

As used herein, the term "leukoencephalopathy" refers to any of a group of diseases that affect white matter of the brain; several diseases may be specifically identified, including, for example, "leukocytic white matter disappearance" and "toxic white matter disease". Leukoencephalopathy is a disease similar to leukodystrophy.

As used herein, the term "tauopathy" refers to a condition or disorder associated with tau, such as Alzheimer's Disease (AD), Progressive Supranuclear Palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), argentional particle disease (AGD)), frontotemporal dementia and parkinson's disease (FTDP-17) linked to chromosome 17, parkinson's disease, stroke, traumatic brain injury, mild cognitive impairment, and the like.

As used herein, the terms "multiple sclerosis" and "MS" refer to a slowly progressing central nervous system disease characterized by diffuse demyelinating plaques in the brain and spinal cord, resulting in a variety of different neurological symptoms and signs, usually with remission and worsening. The cause of MS is unknown but suspected to be associated with immune abnormalities. Increased familial morbidity indicates genetic susceptibility, while women are slightly more susceptible than men. Symptoms of MS include weakness, lack of coordination, paresthesia, speech and visual disturbances, most commonly double vision. More specific signs and symptoms depend on the location of the lesion and the severity and destructive nature of the inflammatory and sclerosing processes. Relapsing-remitting multiple sclerosis (RRMS) is the clinical course of MS characterized by well-defined acute attacks with complete or partial recovery with no disease progression between attacks. Secondary Progressive Multiple Sclerosis (SPMS) is a clinical course of MS that is initially relapsing-remitting and then progresses at different rates, with occasional relapses and mild remissions. Primary Progressive Multiple Sclerosis (PPMS) initially occurs in a progressive form. Clinically isolated syndrome is the first neurological episode, which is caused by inflammation/demyelination at one or more sites in the central nervous system. Progressive Relapsing Multiple Sclerosis (PRMS) is a rare form of MS (about 5%) characterized by a steady worsening of the disease state from onset, with acute relapses but no remissions.

In yet another embodiment, there is provided a method of treating a subject having an X-linked genetic disorder, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the X-linked genetic disease is MCT8 deficiency or X-linked Adrenoleukodystrophy (ALD).

In another embodiment, there is provided a method of treating a subject having a white matter dystrophy, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the leukodystrophy is Adrenoleukodystrophy (ALD), Adrenomyeloneuropathy (AMN), cerebral adrenoleukodystrophy (cALD), Metachromatic Leukodystrophy (MLD), canavan disease, or Krabbe disease (globuloid cell leukodystrophy). As used herein, the term "adrenomyeloneuropathy" or "AMN" refers to an adult variant of X-linked adrenoleukodystrophy characterized by a mutation in the ABCD1 gene that results in impaired peroxisome function with the accumulation and demyelination of Very Long Chain Fatty Acids (VLCFA).

In one embodiment, there is provided a method of treating a subject having a tauopathy comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the tauopathy is alzheimer's disease, frontotemporal dementia, primary age-related tauopathy (PART), Pick's disease, or frontotemporal dementia linked to chromosome 17 and parkinson's disease (FTDP-17).

In yet another embodiment, there is provided a method of treating a subject having ischemic stroke comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the ischemic stroke is a lacunar stroke (also referred to as "lacunar infarction"). In another embodiment, the method is used to treat a subject having lacunar stroke syndrome (LACS).

In another embodiment, a method of treating a patient having adult Refsum disease, infant Refsum disease, alexander disease, alzheimer disease, Barlow's concentric sclerosis, canavan disease, Central Pontine Myelination (CPM), cerebral palsy, tendonosis cerebri, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Idiopathic Inflammatory Demyelinating Disease (IIDD), krabe disease, Leber's hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, marchiaffava-bigna disease, Metachromatic Leukodystrophy (MLD), Multifocal Motor Neuropathy (MMN), Multiple Sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Pelizaeus-merzcherer disease (PMD), Progressive Multifocal Leukoleukodystrophy (PML), adrenal paraprotection X (TSP X), and focal-linked hypophysectopathy (TSP-X), is provided, A method of a subject of ALO or X-linked ALO) or Zellweger syndrome, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In one embodiment, the demyelinating disease is multiple sclerosis. In another embodiment, the demyelinating disease is X-linked Adrenoleukodystrophy (ALD).

In another embodiment, there is provided a method of treating a subject having Amyotrophic Lateral Sclerosis (ALS) disease, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the ALS is a sporadic or familial ALS, or an ALS with a superoxide dismutase-1 mutation.

In one embodiment, a method is provided for treating a subject having a medical condition associated with increased TGF- β activity, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the medical condition associated with increased TGF- β activity is a fibrotic disease. In another embodiment, the fibrotic disease is non-alcoholic steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF), systemic scleroderma, or Alport syndrome, or is associated with the disease. As used herein, the term "Alport syndrome" refers to an inherited disorder caused by mutations in the collagen network gene of a3a4a5(IV), which result in structural defects in Glomerular Basement Membrane (GBM) early in development, followed by the development of filter barrier disruption, renal fibrosis, and renal failure.

As used herein, the term "fibrotic disease" refers to a condition, disease or disorder susceptible to treatment by administration of a compound having anti-fibrotic activity. Fibrotic diseases include, but are not limited to, pulmonary fibrosis, including Idiopathic Pulmonary Fibrosis (IPF) and pulmonary fibrosis of known etiology, liver fibrosis and kidney fibrosis. Other exemplary fibrotic diseases include musculoskeletal fibrosis, myocardial fibrosis, post-operative adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

In another embodiment, there is provided a method of treating a subject suffering from NASH, NAFLD associated with hyperlipidemia, alcoholic liver disease/alcoholic steatohepatitis, liver fibrosis associated with viral infection (HBV, HCV), fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, hereditary lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson disease, Crigler-Najjar syndrome, lysosomal acid lipase deficiency, cystic fibrosis liver disease comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, or pharmaceutically acceptable salt thereof, A hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating a subject having Alport syndrome, diabetic nephropathy, FSGS, IgA nephropathy-associated fibrosis, Chronic Kidney Disease (CKD), post AKI, HIV-associated CKD, chemotherapy-induced CKD, nephrotoxic agent-associated CKD, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or Polycystic Kidney Disease (PKD), comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, a method is provided for treating a patient suffering from IPF, ILD, pulmonary fibrosis associated with autoimmune diseases such as rheumatoid arthritis, scleroderma or sjogren's syndrome, asthma-associated pulmonary fibrosis, COPD, asbestos-or silica-induced pulmonary fibrosis, silicosis, respiratory bronchiolitis, Idiopathic Interstitial Pneumonia (IIP), idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, desquamating interstitial pneumonia, acute interstitial pneumonia, rare IIP: a method of treating a subject for idiopathic lymphoid interstitial pneumonia, idiopathic pleural parenchymal fibroelastosis, unclassified idiopathic interstitial pneumonia, hypersensitivity pneumonitis, radiation-induced lung injury, progressive massive fibrosis-pneumoconiosis, bronchiectasis, pneumoconiosis, chronic respiratory disease, Chronic Obstructive Pulmonary Disease (COPD), emphysema, Pulmonary Arterial Hypertension (PAH), or cystic fibrosis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having a structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating a subject having scleroderma/systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, tardive skin porphyria, restrictive skin disease, Dupuytren's contracture, skin fibrosis, nephrogenic systemic fibrosis/nephrogenic fibrotic skin disease, mixed connective tissue disease, sclerosing mucoedema, eosinophilic fasciitis, fibrosis caused by exposure to chemical or physical substances, GvHD induced fibrosis, adult scleroderma, liposcleroderma, or a premature aging disorder (premature aging, premature limb aging, Werner syndrome), comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating a subject having atrial fibrosis, endocardial myocardial fibrosis, atherosclerosis, restenosis, or joint fibrosis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating a subject having mediastinal fibrosis, myelofibrosis, post-polycythemia vera myelofibrosis (post-polycythemia vera myelofibrosis) or post-essential thrombocythemia (post-essential thrombocythemia), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating a subject having crohn's disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, gastrointestinal fibrosis due to cystic fibrosis, or pancreatic fibrosis due to pancreatitis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating a subject having endometrial fibrosis, uterine fibroids or Peyronie's disease, comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating a subject having macular degeneration, diabetic retinopathy, retinal fibrovascular disease or vitreoretinopathy, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, there is provided a method of treating a subject having a scar associated with a wound (surgical complications, chemotherapy-induced fibrosis, radiation-induced fibrosis), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

As used herein, the term "administering" refers to providing a compound, a prodrug of a compound, or a pharmaceutical composition comprising the compound or prodrug as described herein. The compound or composition may be administered to the subject by another person, or may be self-administered by the subject. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

As used herein, the term "treatment" refers to an intervention that improves an indication or symptom of a disease or pathological condition. As used herein, the terms "treatment" and "treating" with respect to a disease, pathological condition, or symptom also refer to any observable beneficial effect of the treatment. For example, the beneficial effects can be demonstrated by: delayed onset of clinical symptoms of a disease in a susceptible subject, reduced severity of some or all of the clinical symptoms of a disease, slower progression of a disease, reduced number of relapses of a disease, improvement in the overall health or well-being of a subject, or other parameters known in the art to be specific to a particular disease. A prophylactic treatment is a treatment administered to a subject who does not show an indication of a disease or shows only an early indication, with the aim of reducing the risk of developing a pathology. A therapeutic treatment is a treatment administered to a subject after the signs and symptoms of a disease have developed.

As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). A subject treated according to the methods described herein may be a subject who has been diagnosed with a neurodegenerative disease involving demyelination, hypomyelination, or myelination insufficiency, e.g., a subject diagnosed with, or at risk of developing, multiple sclerosis or cerebral palsy. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will appreciate that a subject to be treated according to the present disclosure may have received standard testing, or may have been determined to be at risk without examination due to the presence of one or more risk factors associated with a disease or condition.

As used herein, the term "effective amount" refers to an amount of an agent sufficient to achieve a desired effect in a subject treated with the agent specified. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat a disease without causing substantial toxicity in the subject. The effective amount of the agent will depend upon the subject being treated, the severity of the disease, and the mode of administration of the pharmaceutical composition. In light of the present disclosure, one skilled in the art will appreciate methods of determining an effective amount of the disclosed compounds sufficient to achieve a desired effect in a subject.

As used herein, the term "chronic" refers to a medical disorder or condition that persists over time or recurs frequently.

Compounds having the structure of formula (I), (II), (III), (IV), (V) and (VI) can be synthesized using standard synthetic techniques known to those skilled in the art. For example, the compounds of the invention may be synthesized using appropriately modified synthetic procedures set forth in WO 2014/178892, WO 2014/178931, WO 2016/134292, WO 2017/201320, WO 2018/032012 and schemes 1-7 below.

For this reason, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the experimental section below, but are intended as guidance to the appropriate skilled artisan. For example, the reaction may be carried out in any suitable solvent or other reagent to effect the necessary conversion. Generally, suitable solvents are protic or aprotic solvents that do not substantially react with the reactants, intermediates or products at the temperature at which the reaction is carried out (i.e., a temperature that can range from freezing to boiling). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up after the reaction may be used.

Scheme 1.

The compounds of the invention may be prepared according to scheme 1. Commercially available 4-iodophenol is protected by treatment with an alkylating agent such as methoxymethyl chloride or benzyl bromide or triisopropylsilyl chloride in a solvent such as THF or DMF using a base such as sodium hydride or triethylamine to give protected phenol a. The 3, 5-disubstituted phenol is similarly protected using orthogonal protecting groups to afford B. The compound B is in the 4-position by using n-butyl lithium or n-butyl magnesium bromideDeprotonation and condensation of the resulting anion with a formylating agent such as DMF and the like affords aldehyde C. In the protection base PG₂In the case of acid sensitivity, free phenol can be released during the acid treatment; alternatively, PG₂It can be cleaved in a separate step. Alkylation of the phenol moiety of C with a protected acetic acid equivalent such as methyl chloroacetate or t-butyl bromoacetate or the like in a solvent such as THF or DMF or acetone using a base such as potassium carbonate or sodium hydride affords ester D.

The iodide A is transmetalated with isopropyl magnesium bromide or sec-butyl lithium or the like in a solvent such as THF or DME, and the resulting anion is condensed with aldehyde D to give diarylcarbinol species E. Deoxygenation of E using a hydride source such as triethylsilane in an acidic solvent such as TFA or aqueous HCl produces diarylmethane species F. At PG ₁In the case of acid-labile protecting groups (e.g., MOM, etc.), the deoxygenated product is isolated directly as a phenol. Alternatively, PG may be removed in a separate step₁. Phenol F is then reacted with a substituted benzyl alcohol or benzyl halide G, for example p-fluorobenzyl chloride or 1- (1-chloroethyl) -4-fluoro-benzene or 2, 4-difluorobenzyl alcohol, etc., in the presence of a lewis acid such as zinc chloride or aluminum chloride or boron trifluoride etherate, etc., to give a 3' -benzylated product such as ester H.

Scheme 2.

Ortho-iodination of phenol F as depicted in scheme 2 provides key intermediate I, for example using N-iodosuccinimide or solid iodine, or the like. To prepare the compounds of the invention, I is reacted with a meta-substituted boronic acid (or boronic ester) J under various Suzuki conditions to provide the ester K of the invention.

Scheme 3

Referring to scheme 3, a disubstituted phenol (e.g., 3, 5-dichlorophenol or 3-methyl-5-chlorophenol or 3-methyl-5-bromo-phenol, etc.) is reacted with a formaldehyde equivalent (e.g., aqueous formaldehyde or paraformaldehyde or dimethoxymethane, etc.) to provide the hydroxymethyl derivative (L), which is then reacted with an activated acetate moiety (e.g., ethyl chloroacetate or methyl bromoacetate, etc.) optionally at the phenolic oxygen in the presence of a base to provide intermediate (M). The hydroxymethyl group is activated (e.g., by reaction with thionyl chloride or oxalyl chloride or P-toluenesulfonyl chloride or the like) to give chloromethyl derivative (N) (or the corresponding tosylate, or mesylate, or bromomethyl analog or the like), which is condensed with 2-substituted phenol (O) in the presence of a lewis acid (e.g., zinc chloride or aluminum chloride or the like) to give ester (P).

Scheme 4.

As shown in scheme 4, for example, an aqueous sodium hydroxide solution (if R is used)¹Methyl) or TFA (if R is¹Hydrolysis of the ester group which is t-butyl), (H), (K) or (P) provides the acid (Q) of the invention. If desired, the acid (Q) may be converted into the amide (R) by condensation with a corresponding amine (e.g., methylamine or propylamine or 2-sulfonylethylamine, etc.) in the presence of a coupling agent such as DDC or EDCI, etc., or by formation of an activated intermediate (e.g., a corresponding acid chloride) using thionyl chloride, etc. Alternatively, if desired, the ester (H), (K) or (P) or the acid (Q) may be reacted with the amine R^1aR^1bNH₂E.g., methylamine or propylamine or 2-sulfonylethylamine, etc., to give the amide (R) of the present invention.

Scheme 5.

The benzyl alcohol or halide (G) used in scheme 1 may be sourced from commercial suppliers or may be prepared as described in scheme 5. For example, benzyl alcohols such as 1- (4-fluorophenyl) ethanol and the like are combined with reagents such as thionyl chloride or phosphorus tribromide to afford the corresponding benzyl halide (G).

Scheme 6.

The arylboronic acids or esters (J) used in scheme 2 may be of commercial origin or may be prepared as described in scheme 6. The aryl halide (S) may be reacted with bis (pinacolato) diboron or similar reagents using palladium catalysts and the like to give (J). Alternatively, (S) may be metallized with isopropyl magnesium bromide, n-butyl lithium, or the like, and then reacted with a trialkoxyborate ester, or the like, to provide (J).

Scheme 7.

The substituted phenols (O) used in scheme 3 can be prepared as shown in scheme 7. 2-halophenols such as 2-bromophenol and the like may be condensed with a boronic acid or ester (J) under Suzuki conditions in the presence of a palladium catalyst and the like to give a 2-substituted phenol (O). Alternatively, 2-bromophenol may be metalated using isopropyl magnesium bromide, n-butyl lithium, or the like, and then condensed with aldehyde or ketone (T) to give an intermediate such as (U). Deoxygenation of (U) in the presence of an acid such as TFA under hydrogenolysis conditions using hydrogen in the presence of a palladium or platinum catalyst or the like or in the presence of a reducing agent triethylsilane or the like under reduction-deoxygenation conditions produces a substituted phenol (O).

Examples

The invention is further illustrated by the following examples. The following examples are non-limiting and merely represent various aspects of the present invention. Solid and dashed wedges within the structures disclosed herein illustrate relative stereochemistry, absolute stereochemistry being described only when specifically illustrated or depicted.

General procedure

All reagents whose synthesis is not described in the experimental part are either commercially available or known compounds or can be formed by known methods by the person skilled in the art.

The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to those skilled in the art, and several ways of purifying the same compound are possible. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, the impurities may be stirred out using a suitable solvent.

In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using a specially prepared or pre-packed silica gel column and an eluent, for example a gradient of solvents such as heptane, diethyl ether, ethyl acetate, acetonitrile, ethanol, and the like. In some cases, the compounds may be purified by preparative HPLC using the methods described.

The purification methods described herein can provide a compound of the invention having a sufficiently basic or acidic functionality in the form of a salt, for example, a trifluoroacetate or formate salt in the case of a sufficiently basic compound of the invention, or an ammonium salt in the case of a sufficiently acidic compound of the invention. Salts of this type can be converted into their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent biological tests. It will be understood that the particular form of the compounds of the invention isolated and as described herein is not necessarily the only form in which the compounds may be applied in biological assays to quantify a particular biological activity.

All starting materials and reagents were commercially available and used as received. Unless otherwise stated, the solvents were used at approximately room temperature using a Bruker instrument operating at 400MHz¹H Nuclear Magnetic Resonance (NMR) spectroscopy. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shift (δ) in parts per millionOne is in units, the main peak is represented using conventional abbreviations: for example, s, singlet; d, double peak; t, three peaks; q, four peaks; dd, doublet of doublets; dt, double triplet; m, multimodal; br, wide. Preparative HPLC purification is carried out by reverse phase HPLC using a gradient of acetonitrile in aqueous TFA, or an equivalent HPLC system, e.g. methanol in aqueous ammonium acetate.

Chemical names were generated using ChemDraw naming software (version 17.0.0.206) from PerkinElmer information, inc. In some cases, the commonly accepted name of the commercial reagents is used in place of the name generated by the naming software.

Intermediate A1

Synthesis of 1-iodo-4- (methoxymethyloxy) benzene (intermediate A1)

A solution of 4-iodophenol (50g, 227mmol) in THF (400mL) was cooled to 0 deg.C. Sodium hydride (60% in mineral oil) (10.9g, 273mmol) was added portionwise. The mixture was stirred at 0 ℃ for 20 min. Chloromethyl methyl ether (21.96g, 273mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was poured into ice water (600mL) and extracted with EtOAc (200mL x 3). The combined organic phases were washed with brine (200mL) and Na ₂SO₄Drying and concentration in vacuo afforded intermediate a1(60g, 227mmol, 99% yield) as a colorless liquid.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.95

¹H NMR:(400MHz,DMSO-d₆)δ7.63–7.59(m,2H),6.89–6.84(m,2H),5.17(s,2H),3.36(s,3H)。

Intermediate A2

Synthesis of (3, 5-dichlorophenoxy) -triisopropyl-silane (Compound A2)

A solution of 3, 5-dichlorophenol (35.0g, 215mmol) and imidazole (21.93g, 322mmol) in DCM (400mL) was cooled to 0 ℃. Chloro (triisopropyl) silane (45.5g, 236mmol) was added. The mixture was stirred at room temperature for 2 h. Water (200mL) was added and the resulting mixture was extracted with DCM (100mL x 3). The combined DCM phases were washed with brine (200mL) and Na₂SO₄Drying and concentration in vacuo gave intermediate a2(68g, 213mmol, 99.2% yield) as a pale yellow liquid.

TLC EtOAc/petroleum ether 1/20(v/v) and Rf 0.95

¹H NMR:(400MHz,DMSO-d₆)δ7.21(t,J＝1.8Hz,1H),6.89(d,J＝1.8Hz,2H),1.29–1.23(m,3H),1.06(d,J＝7.4Hz,18H)。

Intermediate A3

Synthesis of 2, 6-dichloro-4-hydroxy-benzaldehyde (intermediate A3)

A solution of intermediate A2(70g, 219mmol) in THF (600mL) was cooled to-70 ℃. N-butyllithium (96.5mL, 241mmol, 2.5M in THF) was added dropwise at-70 ℃. The solution was stirred at-70 ℃ for 45 min. DMF (20.83g, 285mmol) was added dropwise. The mixture was stirred at-70 ℃ for 3 h. The reaction mixture was warmed to-10 ℃, quenched with 1N HCl (440mL), stirred at room temperature for 15min, and then extracted with EtOAc (300mL × 2). The combined organic phases were washed with brine (500mL) and Na ₂SO₄Dried and concentrated in vacuo. The residue was washed with hexanes and dried to give intermediate a3 as a white solid (28.5g, 149mmol, 68.1% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.5

¹H NMR:(400MHz,DMSO-d₆)δ10.25(s,1H),6.94(s,2H)。

Intermediate A4

Synthesis of methyl 2- (3, 5-dichloro-4-formyl-phenoxy) acetate (intermediate A4)

To a solution of intermediate A3(18.2g, 95.3mmol) in acetone (180mL) was added methyl 2-chloroacetate (12.4g, 114mmol) and potassium carbonate (26.34g, 191 mmol). The reaction mixture was heated to 60 ℃ and stirred for 2 h. Water (100mL) was added and the resulting mixture was extracted with EtOAc (50mL x 3). The combined organic phases were washed with brine (100mL) and Na₂SO₄Drying and concentration in vacuo afforded intermediate a4(25.0g, 95.1mmol, 99.9% yield) as a yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.45

¹H NMR:(400MHz,DMSO-d₆)δ10.28(s,1H),7.28(s,2H),5.04(s,2H),3.72(s,3H)。

Intermediate A5

Methyl 2- (3, 5-dichloro-4- (hydroxy (4- (methoxymethoxy) phenyl) methyl) phenoxy) acetate (intermediate) A5) Synthesis of (2)

A solution of intermediate A1(50g, 189mmol) in THF (250mL) was cooled to-20 ℃. Isopropyl magnesium chloride (20.8g, 202mmol, 1.0M in THF) was added dropwise. The mixture was stirred at room temperature for 2h, then cooled to-67 ℃. A solution of intermediate A4(33.2g, 126mmol) in THF (250mL) was added dropwise at-67 deg.C. The mixture was stirred at-67 ℃ for 2 h. By addition of saturated NH ₄The reaction was quenched with aqueous Cl (100 mL). The mixture was extracted with EtOAc (100mL x 3). The combined organic phases were washed with brine (200mL) and Na₂SO₄Drying, concentration in vacuo and purification by silica gel column chromatography (EtOAc/petroleum ether-1/50 to 1/10) gave intermediate a5(12.0g, 29.9mmol, 23.7% yield) as a white solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.3

¹H NMR:(400MHz,DMSO-d₆)δ7.16(d,J＝8.3Hz,2H),7.07(s,2H),6.94(d,J＝8.7Hz,2H),6.36(d,J＝4.9Hz,1H),6.01(d,J＝4.9Hz,1H),5.14(s,2H),4.91(s,2H),3.71(s,3H),3.35(s,3H)。

Intermediate A6

2- [3, 5-dichloro-4- [ (4-hydroxyphenyl) methyl group]Phenoxy radical]Synthesis of methyl acetate (intermediate A6)

To a room temperature solution of intermediate A5(10.0g, 24.9mmol) in DCM (100mL) was added triethylsilane (11.6g, 100mmol, 15.9 mL). The solution was cooled to 0 ℃. TFA (85.3g, 748mmol, 57.6mL) was added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was washed with hexane (10mL) and dried to give intermediate a6(6.86g, 20.1mmol, 80.7% yield) as a white solid.

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.32

¹H NMR:(400MHz,DMSO-d₆)δ9.16(s,1H),7.14(s,2H),6.91(d,J＝8.3Hz,2H),6.65(d,J＝8.4Hz,2H),4.89(s,2H),4.05(s,2H),3.71(s,3H)。

Intermediate A7

Synthesis of methyl 2- (3, 5-dichloro-4- (4-hydroxy-3-iodobenzyl) phenoxy) acetate (intermediate A7)

A solution of intermediate A6(2.0g, 5.86mmol) and p-toluenesulfinic acid (183mg, 1.17mmol) in DCM (20mL) was cooled to 0 ℃. N-iodosuccinimide (1.32g, 5.86mmol) was added portionwise. The mixture was stirred at 0 ℃ for 4 h. Water (15mL) was added and the mixture was extracted with DCM (10mL × 2). The combined organic phases were washed with brine (15mL) and Na ₂SO₄Drying and vacuum concentrating to obtainTo intermediate a7(2.4g, 5.14mmol, 87.7% yield) as an orange solid.

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.32

¹H NMR:(400MHz,DMSO-d₆)δ10.15(s,1H),7.40(d,J＝2.1Hz,1H),7.17(s,2H),6.96–6.90(m,1H),6.78(d,J＝8.3Hz,1H),4.90(s,2H),4.05(s,2H),3.71(s,3H)。

Intermediate A8

Synthesis of 3, 5-dichloro-4- (hydroxymethyl) phenol (intermediate A8)

To a solution of NaOH (6.7g,169mmol) in water (20mL) was added 3, 5-dichlorophenol (25.0g, 153 mmol). The mixture was heated to 45 ℃ and 36% aqueous formaldehyde (12.4g, 153mmol) was slowly added dropwise. The mixture was stirred at 45 ℃ for 2h and then cooled to room temperature. The pH was adjusted to about 3-4 with 1N HCl and the mixture was stirred at room temperature for 20 min. The solid was filtered, washed with water (50mL) and dried to give intermediate A8(11.5g, 59.6mmol, 39% yield) as an off-white solid.

TLC EtOAc/petroleum ether 1/3, Rf 0.36

¹H NMR:(400MHz,DMSO-d₆)δ10.02(s,1H),6.82(s,2H),4.98(s,1H),4.57(d,J＝2.1Hz,2H)

Intermediate A9

2- [3, 5-dichloro-4- (hydroxymethyl) phenoxy]Synthesis of methyl acetate (intermediate A9)

To a solution of intermediate A8(3.0g, 15.5mmol) in acetone (40mL) was added potassium carbonate (3.22g, 23.3mmol) and methyl 2-chloroacetate (2.02g, 18.6 mmol). The mixture was refluxed for 2 h. The mixture was cooled to room temperature, diluted with water (120mL) and extracted with EtOAc (80mL × 3). Incorporated by referenceThe organic phase was washed with brine (200mL) and Na ₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc ═ 20/1 to 5/1) to give intermediate a9(2.0g, 7.54mmol, 48.5% yield) as a white solid.

TLC EtOAc/petroleum ether 1/5, Rf 0.28

¹H NMR:(400MHz,DMSO-d₆)δ7.10(s,2H),5.08(t,J＝5.3Hz,1H),4.91(s,2H),4.61(d,J＝5.3Hz,2H),3.70(s,3H)。

Intermediate A10

2- [3, 5-dichloro-4- (chloromethyl) phenoxy]Synthesis of methyl acetate (intermediate A10)

To a mixture of intermediate A9(1.0g, 3.77mmol) in DCM (10mL) was added thionyl chloride (0.67g,5.66 mmol). The mixture was stirred at room temperature for 1h, then concentrated in vacuo to afford crude intermediate a10(1.0g, 3.53mmol, 93.5% yield) as a pale yellow solid.

TLC EtOAc/petroleum ether 1/5, Rf 0.72

¹H NMR:(400MHz,DMSO-d₆)δ7.21(s,2H),4.94(s,2H),4.85(s,2H),3.71(s,3H)。

Intermediate A11

Synthesis of ethyl 2- (3, 5-dichloro-4- (hydroxymethyl) phenoxy) acetate (intermediate A11)

To a room temperature solution of intermediate A8(13.0g, 67.4mmol) in DMF (120mL) was added ethyl 2-bromoacetate (11.25g, 67.4mmol) and K₂CO₃(11.17g, 80.8 mmol). The mixture was stirred at room temperature for 2h, then diluted with water (200mL) and extracted with EtOAc (100mL × 3). The combined organic phases were washed with water (100mL x 3) and brine (200mL) and washed with Na₂SO₄The mixture is dried and then is dried,and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc ═ 5/1) to give intermediate a11(15g, 79% yield) as an off-white solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.42

¹H NMR:(400MHz,DMSO-d₆)δ7.09(s,2H),5.09(t,J＝5.2Hz,1H),4.88(s,2H),4.60(d,J＝5.2Hz,2H),4.17(q,J＝7.1Hz,2H),1.21(t,J＝7.1Hz,3H)。

Intermediate A12

Synthesis of ethyl 2- (3, 5-dichloro-4- (chloromethyl) phenoxy) acetate (intermediate A12)

To a reaction mixture of intermediate a11(15.0g, 3.77mmol) in DCM (150mL) at 0 ℃ was added thionyl chloride (9.59g, 80.6mmol) dropwise. The mixture was stirred at room temperature for 1h, diluted with DCM (100mL) and concentrated in vacuo to give intermediate a12(15.0g, 93.5% yield) as a pale yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.72

¹H NMR:(400MHz,DMSO-d₆)δ7.20(s,2H),4.92(s,2H),4.86(s,2H),4.17(q,J＝7.2Hz,2H),1.21(t,J＝7.1Hz,3H)。

Intermediate A13

Synthesis of 3-chloro-4- (hydroxymethyl) -5-methyl-phenol (intermediate A13)

To a room temperature mixture of 3-chloro-5-methyl-phenol (3.55g, 24.9mmol) in water (10mL) was added NaOH (1.10g, 27.4 mmol). The mixture was heated to 45 ℃ and then aqueous formaldehyde (0.75g, 24.9mmol, 37%) was added dropwise. The resulting mixture was stirred at 45 ℃ for 2 h. The mixture was cooled to room temperature, then acidified to pH-3 with HCl (3N) and EtOAc (10)mL × 3) extraction. The combined organic phases were washed with brine (15mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc. 50/1 to 5/1) to give intermediate a13(0.76g, 4.40mmol, 17.7% yield) as an off-white solid.

TLC EtOAc/petroleum ether 1/1(v/v) and Rf 0.8

¹H NMR:(400MHz,DMSO-d₆)δ9.68(s,1H),6.62(d,J＝2.4Hz,1H),6.56(d,J＝2.4Hz,1H),4.73(t,J＝5.2Hz,1H),4.49(d,J＝5.2Hz,2H),2.31(s,3H)。

Intermediate A14

2- [ 3-chloro-4- (hydroxymethyl) -5-methyl-phenoxy]Synthesis of acetate (intermediate A14)

To a room temperature solution of intermediate A13(0.66g, 3.82mmol) in acetone (10mL) was added cesium carbonate (1.87g, 5.74mmol), sodium iodide (57mg, 380umol), and methyl 2-chloroacetate (540mg, 4.97 mmol). The mixture was stirred at room temperature for 4 h. Water (30mL) was added and the mixture was extracted with EtOAc (10mL x 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc. 100/1 to 5/1) to give intermediate a14(280mg, 1.14mmol, 29.9% yield) as a white solid.

TLC EtOAc/petroleum ether 1/2(v/v) and Rf 0.67

¹H NMR:(400MHz,DMSO-d₆)δ6.84(d,J＝2.6Hz,1H),6.78(d,J＝2.6Hz,1H),4.85-4.81(m,3H),4.53(d,J＝4.9Hz,2H),3.69(s,2H),2.37(s,3H)。

Intermediate A15

2- [ 3-chloro-4- (chloromethyl) -5-methyl-phenoxy]Synthesis of acetate (intermediate A15)

To a room temperature solution of intermediate a14(360mg, 1.47mmol) in DCM (6mL) was added thionyl chloride (263mg, 2.21 mmol). The mixture was stirred at room temperature for 1h, then concentrated in vacuo to afford intermediate a15(300mg, 1.14mmol, 77.5% yield) as a yellow solid.

TLC EtOAc/petroleum ether 1/2(v/v) and Rf 0.8

¹H NMR:(400MHz,DMSO-d₆)δ6.96(d,J＝2.4Hz,1H),6.87(d,J＝2.4Hz,1H),4.86(s,2H),4.82(s,2H),3.71(s,3H),2.41(s,3H)。

Intermediate A16

Synthesis of 3-bromo-4- (hydroxymethyl) -5-methylphenol (intermediate A16)

To a solution of 3-bromo-5-methyl-phenol (15g, 80.2mmol) and NaOH (3.5g, 88.2mmol) in water (100mL) at 45 ℃ was added dropwise an aqueous formaldehyde solution (6.5g, 80.2 mmol). The reaction was heated to 45 ℃ overnight. The reaction mixture was acidified to pH 6-7 with 1N HCl and extracted with EtOAc (50mL × 3); the combined organic phases were washed with brine (50mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1/20 to 1/5) to give intermediate a16(3.0g, 14% yield) as an off-white solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.41

¹H NMR:(400MHz,DMSO-d₆)δ9.67(s,1H),6.80(d,J＝2.5Hz,1H),6.60(d,J＝2.4Hz,1H),4.73(t,J＝5.1Hz,1H),4.51(d,J＝5.1Hz,2H),2.30(s,3H)。

Intermediate A17

Synthesis of ethyl 2- (3-bromo-4- (hydroxymethyl) -5-methylphenoxy) acetate (intermediate A17)

To a room temperature solution of intermediate A16(3.0g, 13.8mmol) in DMF (20mL) was added K₂CO₃(2.3g, 16.56mmol) and ethyl 2-bromoacetate (2.5g, 15.2 mmol); the mixture was stirred at room temperature for 2 h. Water (100mL) was added and the resulting mixture was extracted with EtOAc (40mL x 3). The combined organic phases were washed with brine (100mL) and Na₂SO₄Drying and vacuum concentrating; the residue was purified by reverse phase column chromatography to give intermediate a17(2.7g, 64% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.44

¹H NMR:(400MHz,DMSO-d₆)δ6.99(d,J＝2.7Hz,1H),6.82(dd,J＝2.7,0.7Hz,1H),4.84(t,J＝5.1Hz,1H),4.81(s,2H),4.79(s,2H),4.55(d,J＝5.2Hz,2H),4.17(q,J＝7.1Hz,2H),2.39(s,3H),1.21(t,J＝7.1Hz,3H)。

Intermediate A18

Synthesis of ethyl 2- (3-bromo-4- (chloromethyl) -5-methylphenoxy) acetate (intermediate A18)

To a room temperature solution of intermediate a17(2.8g, 9.24mmol) in DCM (10mL) was added thionyl chloride (2.19g, 18.48 mmol); the resulting mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to afford intermediate a18(2.9g, 97% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.6

¹H NMR:(400MHz,DMSO-d₆)δ7.10(d,J＝2.7Hz,1H),6.90(d,J＝2.7Hz,1H),4.83(d,J＝1.3Hz,4H),4.17(q,J＝7.1Hz,2H),2.42(s,3H),1.21(t,J＝7.1Hz,3H)。

Intermediate A19

Synthesis of tert-butyl 2- (4-formyl-3, 5-dimethylphenoxy) acetate (intermediate A19)

To a room temperature solution of 2, 6-dimethyl-4-hydroxybenzaldehyde (30g, 0.20mol) and tert-butyl bromoacetate (35mL, 0.25mol) in DMF (600mL) was added cesium carbonate (130g, 0.40 mol). The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (1000mL) and filtered. The filtrate was washed with water (1000mL x 3) and brine (500mL x 2) and then over Na₂SO₄Drying and concentration in vacuo afforded intermediate a19(47g, 89% yield) as a white solid.

TLC EtOAc/petroleum ether 1/20

¹H NMR:(400MHz,CDCl₃)δ10.48(s,1H),6.58(s,2H),4.55(s,2H),2.60(s,6H),1.49(s,9H)。

Intermediate A20

To a solution of intermediate A19(1.00g, 3.78mmol) in methanol (30mL) at 0 deg.C was added NaBH in portions₄(0.14g, 3.8 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with water (50mL), extracted with EtOAc (50mL x 3), and filtered over Na ₂SO₄Drying and concentration in vacuo afforded intermediate a20(0.9g, 89% yield) as a colorless oil.

TLC EtOAc/Petroleum Ether ═ 1/10(v/v)

¹H NMR:(400MHz,DMSO)δ6.53(d,J＝7.6Hz,2H),4.57(d,J＝7.6Hz,2H),4.40(s,2H),4.32(s,1H),2.30(d,J＝7.6Hz,6H),1.43(d,J＝7.8Hz,9H)。

Intermediate A21

To a room temperature solution of intermediate a20(0.9g, 3.38mmol) in DCM (20mL) was added thionyl chloride (0.44g, 3.72 mmol); the resulting solution was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo to afford intermediate a21(0.9g, 93% yield) as a white solid.

TLC EtOAc/Petroleum Ether ═ 1/10(v/v)

¹H NMR:(400MHz,DMSO)δ6.61(s,2H),4.75(s,2H),4.61(s,2H),2.31(d,J＝13.6Hz,6H),1.42(s,9H)。

Intermediate B1

(3-bromophenyl) -difluoromethyl ether (3.0g, 13.4mmol), bis (pinacol) diboron (6.8g, 26.9mmol), Pd (dppf) Cl₂A mixture of (984mg, 1.35mmol) and KOAc (4.0g, 40.4mmol) in dry 1, 4-dioxane (30mL) was stirred at 85 deg.C overnight. The resulting solution of intermediate B1 was used without further purification.

TLC EtOAc/petroleum ether 1/2(v/v) and Rf 0.2

Intermediate B2

3' -bromo-1-methylstyrene (500mg, 2.54mmol), Pd (dppf) Cl₂A mixture of (186mg, 0.25mmol), bis (pinacol) diboron (1.29g, 5.07mmol) and KOAc (748mg, 7.62mmol) in 1, 4-dioxane (10mL) was stirred at 80 ℃ for 4 h. The mixture was filtered through a pad of silica gel, concentrated to dryness, and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 20/1) to give intermediate B2(400mg, 65%) as a yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.87

¹H NMR:(400MHz,DMSO-d₆)δ7.76–7.72(m,1H),7.65–7.62(m,1H),7.63–7.58(m,1H),7.41–7.34(m,1H),5.39(dd,J＝1.7,0.8Hz,1H),5.11(t,J＝1.5Hz,1H),2.11(s,3H),1.30(s,12H)。

Intermediate B3

3- (2,2, 2-trifluoroethyl) -1-bromobenzene (500mg, 2.09mmol), Pd (dppf) Cl₂A mixture of (153mg, 0.21mmol), bis (pinacol) diboron (1.06g, 4.18mmol) and KOAc (616mg, 6.28mmol) in 1, 4-dioxane (10mL) was stirred at 80 ℃ for 4 h. The mixture was filtered through a pad of silica gel, concentrated to dryness, and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 20/1) to give intermediate B3(400mg, 84%) as a colorless oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.88

Intermediate B4

To 3-pentafluoroethyl-bromobenzene (400mg, 1.45mmol), bis (pinacol) diboron (406mg, 1.60mmol) and Pd (dppf) Cl₂(53mg, 0.07mmol) to a mixture in 1, 4-dioxane (10mL) was added potassium acetate (430mg, 4.36 mmol). The mixture was heated to 100 ℃ for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude intermediate B4(468mg, 99% yield), which was used without further purification.

TLC petroleum ether/EtOAc (v/v) 10/1, Rf 0.9

Intermediate B5

To a solution of 3-chlorothiophene (237mg, 2.0mmol) in hexane (3mL) were added 4,4 '-di-tert-butyl-2, 2' -bipyridine (16mg, 60umol), 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (128mg, 1.0mmol), and (1, 5-cyclooctadiene) (methoxy) iridium (I) dimer (40mg, 60 umol). The reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and intermediate B5 was used without further purification.

Intermediate B6

To a solution of 3-methylfuran (400mg, 4.87mmol) in THF (10mL) was added bis (pinacol) diboron (1.23g, 4.87mmol), (1, 5-cyclooctadiene) (methoxy) iridium (I) dimer (65mg, 97.4umol), and 4,4 '-di-tert-butyl-2, 2' -bipyridine (33mg, 122 umol). The mixture was heated to reflux for 2h, then cooled to room temperature and concentrated in vacuo to afford intermediate B6 as a mixture with the 2, 4-substituted isomer. The mixture was used without further purification.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.30

Intermediate B7

Sodium chlorodifluoroacetate (1.0g, 5.2mmol), 3-bromo-4-fluorophenol (1.60g, 10.5mmol) and K₂CO₃A mixture of (868mg, 6.3mmol) in DMF (10mL) was stirred at 100 ℃ for 2 h. The mixture was cooled to room temperature. Concentrated HCl (1.5mL) and water (3mL) were added and the mixture was stirred at room temperature for 1 h. The mixture was cooled to 0 ℃. NaOH (4M, 5mL) and water (25mL) were added and the mixture was treated with Et₂O (5mL × 3) extraction. The organic layer was washed with brine (15mL) and Na₂SO₄Dried and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 200/1 to 100/1) to give intermediate B7(150mg, 11% yield) as a colourless oil.

TLC petroleum ether/EtOAc (v/v) 100/1, Rf 0.55

¹H NMR:(400MHz,DMSO-d₆)δ7.62(dd,J＝6.0,3.2Hz,1H),7.46(t,J＝8.8Hz,1H),7.28(dt,J＝9.2,3.6Hz,1H),7.24(t,J＝73.6Hz,1H)。

¹⁹F NMR:(376MHz,DMSO-d₆)δ-82.81,-112.84。

Intermediate B8

To intermediate B7(150mg, 622umol), bis (pinacol) diboron (175mg, 684umol) and Pd (dppf) Cl₂·CH₂Cl₂(25mg, 31umol) to a room temperature mixture in 1, 4-dioxane (5.0mL) was added potassium acetate (183mg, 1.8 mmol). The mixture was heated to 110 ℃ for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude intermediate B8(175mg, 97% yield), which was used without further purification.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.65

Intermediate B9

(3-bromo-5-fluorophenyl) -difluoromethyl ether (120mg, 0.50mmol), KOAc (146mg, 1.50mmol), bis (pinacol) diboron (189mg, 0.75mmol) and Pd (dppf) Cl₂(18mg, 0.03mmol) of a mixture in 1, 4-dioxane (3mL) in N₂Stirred at 85 ℃ for 2h under an atmosphere. The crude solution of intermediate B9 was used without further purification.

TLC petroleum ether/EtOAc (v/v) 20/1, Rf 0.65

Intermediate B10

(3-bromo-6-fluorophenyl) -difluoromethyl ether (300mg, 1.2mmol), bis (pinacol) diboron (348mg, 1.4mmol), Pd (dppf) Cl₂A mixture of (91mg, 0.1mmol) and KOAc (365mg, 3.6mmol) in 1, 4-dioxane (3mL) was stirred at 80 deg.C overnight. The mixture was filtered and concentrated in vacuo to give intermediate B10(330mg, 95% yield) as a black oil, which was used without further purification.

TLC petroleum ether/EtOAc (v/v) 10/1, Rf 0.8

LCMS:RT＝4.324min；[M+1]＝289.1

Intermediate B11

Synthesis of 1-bromo-3- (difluoromethoxy) -2-fluorobenzene (intermediate B11)

Sodium chlorodifluoroacetate (1.0g, 5.2mmol), 3-bromo-2-fluorophenol (1.60g, 10.47mmol) and K₂CO₃A mixture of (868mg, 6.3mmol) in DMF (10mL) was stirred at 100 ℃ for 2 h. The mixture was cooled to room temperature. Concentrated HCl (1.5mL) and water (3mL) were added and the mixture was stirred at room temperature for 1 h. The mixture was cooled to 0 ℃ and NaOH (4M, 5ml) and H were added₂O (25 mL). The mixture was washed with Et₂O (5mL × 3) extraction. The combined organic phases were washed with brine (15mL) and Na₂SO₄Dried and purified by silica gel column chromatography (petroleum ether/EtOAc. 200/1 to 100/1) to give intermediate B11 as a colourless oil (800mg, 47% yield).

TLC petroleum ether/EtOAc (v/v) 100/1, Rf 0.55

¹H NMR:(400MHz,DMSO-d₆)δ7.66–7.60(m,1H),7.42(t,J＝8.0Hz,1H),7.303(t,J＝15.6Hz,1H),7.24(td,J＝8.4,1.6Hz,1H)。

¹⁹F NMR:(376MHz,DMSO-d₆)δ-82.56(d,J＝3.6Hz),-124.68。

Intermediate B12

2- (3- (difluoromethoxy) -2-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (middle) Synthesis of intermediate B12)

To intermediate B11(400mg, 1.7mmol), bis (pinacol) diboron (1.25g, 4.93mmol) and Pd (dppf) Cl₂·CH₂Cl₂(457mg, 1.8mmol) to a room temperature solution in 1, 4-dioxane (5.0mL) was added potassium acetate (500mg, 5.1 mmol). The mixture was heated to 110 ℃ for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude intermediate B12(470mg, 95% yield), which was used without further purification.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.65

Intermediate C1

3'- (Difluoromethoxy) - [1,1' -Biphenyl)]Synthesis of-2 alcohols (intermediate C1)

Intermediate B1(3.5g, 13mmol), 2-bromophenol (1.5g, 8.67mmol), Pd (dppf) Cl₂(634mg, 0.87mmol) and K₂CO₃A mixture of (3.6g, 26mmol) in 1, 4-dioxane (30mL) and water (3mL) was stirred at 90 deg.C overnight. Water (50mL) was added and the mixture was extracted with EtOAc (30mL × 2). The combined organic phases were washed with brine (50mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc ═ 20/1 to 5/1, v/v) to give intermediate C1 as a yellow oil (700mg, 34% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.54

LCMS:RT＝2.551min；[M-1]＝235.0

Intermediate C2

3 '-Ethyl- [1,1' -biphenyl]Synthesis of-2 alcohols (intermediate C2)

2-bromophenol (660mg, 3.81mmol), (3-ethylphenyl) boronic acid (630mg, 4.20mmol), and Na₂CO₃(809mg, 7.63mmol) and Pd (dppf) Cl₂(278mg, 381umol) in 1, 4-dioxane (10 mL)/water (2mL)In the mixture of (1) in N₂Stirred at 85 ℃ for 2h under an atmosphere. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether/EtOAc. 100/1, v/v) to give intermediate C2 as a yellow oil (600mg, 79% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.35

¹H NMR:(400MHz,DMSO)δ9.43(s,1H),7.41–7.07(m,6H),6.92(d,J＝7.7Hz,1H),6.86(t,J＝7.4Hz,1H),2.64(q,J＝7.6Hz,2H),1.21(t,J＝6.8Hz,3H)。

Intermediate C3

3'- (trifluoromethyl) - [1,1' -biphenyl]Synthesis of-2 alcohols (intermediate C3)

2-bromophenol (500mg, 2.89mmol), 3-trifluoromethyl-phenylboronic acid (659mg, 3.47mmol), Pd (dppf) Cl₂(211mg, 289umol) and K₂CO₃A mixture of (1.20g, 8.67mmol) in water (1mL) and 1, 4-dioxane (5mL) was stirred at 90 deg.C overnight. Water (30mL) was added and the mixture was extracted with EtOAc (20mL × 2). The combined organic layers were washed with brine (30mL) and Na₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/EtOAc ═ 20/1) gave intermediate C3(600mg, 87% yield) as a yellow oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.37

¹H NMR:(400MHz,DMSO-d₆)δ9.75(s,1H),7.93–7.82(m,2H),7.72–7.62(m,2H),7.32(dd,J＝7.6,1.8Hz,1H),7.24–7.20(m,1H),6.98(dd,J＝8.2,1.2Hz,1H),6.91(td,J＝7.4,1.2Hz,1H)。

Intermediate C4

Synthesis of 4- (hydroxy (2-hydroxyphenyl) methyl) benzonitrile (intermediate C4)

A solution of 2-bromophenol (2.0g, 11.6mmol) in diethyl ether (20mL) was cooled to-78 ℃. n-BuLi (2.5M) (25.5mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was cooled to-78 ℃. A solution of 4-cyanobenzaldehyde (1.7g, 12.7mmol) in THF (6mL) was added dropwise. The mixture was stirred at-78 ℃ for 1h and warmed to room temperature. With saturated NH₄The reaction was quenched with aqueous Cl (20mL) and extracted with EtOAc (10mL × 3). The combined organic phases were washed with brine (15mL) and Na ₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (EtOAc/petroleum ether-1/50 to 1/5) gave intermediate C4 as a white solid (1.7g, 65% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.20

¹H NMR:(400MHz,DMSO-d₆)δ9.56(s,1H),7.76–7.69(m,2H),7.59–7.53(m,2H),7.35(dd,J＝8.0,1.6Hz,1H),7.05(td,J＝7.6,1.6Hz,1H),6.81-6.77(m,2H),6.04(d,J＝4.4Hz,1H),5.93(d,J＝4.0Hz,1H)。

Intermediate C5

Synthesis of 4- (2-hydroxybenzyl) benzonitrile (intermediate C5)

To a solution of intermediate C4(1.7g, 7.5mmol) in DCM (20mL) was added Et₃SiH (3.5g, 30.7 mmol). The mixture was cooled to 0 ℃ and TFA (26.3g, 231mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (20mL) was added and the resulting mixture was extracted with DCM (10mL x 3). The combined organic phases were washed with brine (15mL) and Na₂SO₄Drying and vacuum concentrating; the residue was washed with hexane (10mL) to give intermediate C5(1.2g, 76% yield) as a white solid.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.45

¹H NMR:(400MHz,DMSO-d₆)δ9.47(s,1H),7.72(d,J＝8.2Hz,2H),7.40(d,J＝8.4Hz,2H),7.12–7.02(m,2H),6.81(d,J＝7.6Hz,1H),6.74(t,J＝7.4Hz,1H),3.95(s,2H)。

Intermediate C6

Synthesis of 2- (hydroxy (pyridin-4-yl) methyl) phenol (intermediate C6)

A solution of 2-bromophenol (2.0g, 11.6mmol) in ether (20mL) was cooled to-70 ℃; n-BuLi (25.5mmol, 10mL of 2.5M) was added dropwise. The mixture was stirred at-70 ℃ for 2 h. 4-pyridinecarboxaldehyde (1.4g, 12.7mmol) in THF (5mL) was added dropwise. The mixture was stirred at-70 ℃ for 1 h. With saturated NH ₄Aqueous Cl (15mL) quench the reaction; the pH was adjusted to pH 7 with HCl (1N). The resulting mixture was extracted with EtOAc (30mL x 2); the combined organic phases were washed with brine (50mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH ═ 100:1 to 20:1) to give intermediate C6(1.2g, 51% yield) as a white solid.

TLC:DCM/MeOH＝15/1(v/v),Rf＝0.3

¹H NMR:(400MHz,DMSO-d₆)δ9.56(s,1H),8.46–8.43(m,2H),7.34(d,J＝6.2Hz,3H),7.07–7.02(m,1H),6.81–6.75(m,2H),5.97(s,1H),5.89(d,J＝4.4Hz,1H)。

Intermediate C7

Synthesis of 2- (pyridin-4-ylmethyl) phenol (intermediate C7)

To a solution of intermediate C6(1.2g, 5.96mmol) in DCM (15mL) at 0 deg.C was added Et₃SiH (2.8g, 23.8mmol) and TFA (2.7g, 23.8 mmol). The mixture was stirred at room temperature for 1h, then concentrated in vacuo. Water (15mL) was added and NaHCO was used₃(2N) the mixture was adjusted to pH 7 and extracted with EtOAc (50 mL. times.2). The combined organic phases were washed with brine (100mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH ═ 100:1 to 30:1) to give intermediate C7(530mg, 48% yield) as a yellow oil.

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.7

¹H NMR:(400MHz,DMSO-d₆)δ9.45(s,1H),8.43–8.38(m,2H),7.21–7.17(m,2H),7.11–7.02(m,2H),6.81(dd,J＝8.2,1.2Hz,1H),6.75(dd,J＝7.4,1.2Hz,1H),3.87(s,2H)。

Intermediate C8

Synthesis of pyrimidine-5-carbaldehyde (intermediate C8)

To a room temperature solution of pyrimidine-5-methanol (2.0g, 18.1mmol) in chloroform (30mL) was added MnO₂(15.6g, 181 mmol). The mixture was stirred at 50 ℃ overnight. The reaction mixture was cooled to room temperature, then filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc: 2/1, v/v) to give intermediate C8 as a white solid (800mg, 40% yield).

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.44

¹H NMR:(400MHz,DMSO)δ10.15(s,1H),9.45(s,1H),9.26(s,2H)。

Intermediate C9

Synthesis of 2- (hydroxy (pyrimidin-5-yl) methyl) phenol (intermediate C9)

To a-70 ℃ solution of 2-bromophenol (1.28g, 7.40mmol) in THF (30mL) was added n-BuLi (16mmol, 6.51mL, 2.5M). The mixture was stirred at room temperature for 30min and then cooled to-70 ℃. Addition of intermediate C at-70 deg.C8(800mg, 7.40 mmol); the mixture was allowed to warm slowly to room temperature and stirred for 16 h. Quench the reaction with water (50 mL); the pH was adjusted to pH 6-7 with 2N HCl and the resulting mixture was extracted with EtOAc (50mL x 3). The combined organic phases were washed with brine (50mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc ═ 1/2, v/v) to give intermediate C9(800mg, 53% yield) as a white solid.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.4

¹H NMR:(400MHz,DMSO)δ9.60(s,1H),9.02(s,1H),8.70(s,2H),7.48(m,1H),7.09(m,1H),6.84(t,J＝7.4Hz,1H),6.77(d,J＝8.0Hz,1H),6.04(d,J＝4.4Hz,1H),5.98(d,J＝4.4Hz,1H)。

Intermediate C10

Synthesis of 2- (pyrimidin-5-ylmethyl) phenol (intermediate C10)

To a solution of intermediate C9(800mg, 3.95mmol) in DCM (10mL) at 0 deg.C was added Et₃SiH (1.84g, 15.8mmol) and TFA (118mmol, 9.0 mL). The mixture was stirred at room temperature for 0.5 h. The reaction was concentrated in vacuo and extracted with chloroform/isopropanol (30mL/10mL x 3). The combined organic phases are passed over Na ₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (DCM/MeOH ═ 20/1, v/v) gave intermediate C10(1.0g, 100% yield) as a white solid.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.5

¹H NMR:(400MHz,DMSO)δ9.57(s,1H),9.00(s,1H),8.66(s,2H),7.16(m,1H),7.06(d,J＝1.7Hz,1H),6.81(d,J＝8.0Hz,1H),6.76(d,J＝7.4Hz,1H),3.88(s,2H)。

Intermediate C11

Synthesis of methyl 4- (2,2, 2-trifluoroethyl) benzoate (intermediate C11)

Mixing (4-carbo-methoxyphenyl) borano acid ester (1.0g, 3.82mmol), 1,1, 1-trifluoro-2-iodo-ethane (1.6g, 7.6mmol), Pd₂(dba)₃A mixture of (175mg, 191umol), xanthphos (221mg, 382umol), CuCl (38mg, 382umol) and CsF (1.74g, 11.5mmol) in 1, 4-dioxane (10mL) and water (1mL) in N₂Stirred under atmosphere at 65 ℃ overnight. The mixture was cooled to room temperature and filtered; the filtrate was concentrated in vacuo. The residue was dissolved in DCM (100mL) and washed with H₂O (50mL) and brine (50mL) and then Na₂SO₄And (5) drying. The solution was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 10/1) to give intermediate C11(330mg, 40% yield) as a pale yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.82

¹H NMR:(400MHz,DMSO-d₆)δ7.97(d,J＝8.1Hz,2H),7.52(d,J＝7.9Hz,2H),3.86(s,3H),3.78(q,J＝11.6Hz,2H)。

Intermediate C12

Synthesis of (4- (2,2, 2-trifluoroethyl) phenyl) methanol (intermediate C12)

To a solution of intermediate C11(330mg, 1.51mmol) in anhydrous THF (6mL) at 0 deg.C was added LiAlH ₄(69mg, 1.82 mmol); the mixture was stirred at 0 ℃ for 1 h. Addition of saturated NH₄Cl (water) solution (5mL) and the resulting mixture was extracted with DCM (5mL × 2). The organic layer was washed with Na₂SO₄Drying and concentration in vacuo afforded intermediate C12(250mg, 87% yield) as a pale yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.49

¹H NMR:(400MHz,DMSO-d₆)δ7.33–7.29(m,4H),5.18(t,J＝5.7Hz,1H),4.49(d,J＝5.7Hz,2H),3.61(q,J＝11.7Hz,2H)。

Intermediate C13

Synthesis of 1- (chloromethyl) -4- (2,2, 2-trifluoroethyl) benzene (intermediate C13)

To a solution of intermediate C12(250mg, 1.31mmol) in DCM (4mL) was added thionyl chloride (235mg, 1.97 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give intermediate C13(250mg, 92% yield) as a pale yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.78

¹H NMR:(400MHz,DMSO-d₆)δ7.45(d,J＝7.9Hz,2H),7.37(d,J＝7.9Hz,2H),4.76(s,2H),3.66(q,J＝11.6Hz,2H)。

Intermediate C14

Synthesis of 2- (1- (4-fluorophenyl) -1-hydroxypropyl) phenol (intermediate C14)

A-30 ℃ solution of 2-bromophenol (3.41g, 19.7mmol) in THF (40mL) was added dropwise to n-BuLi (2.5M, 17.35 mL). After 2h, the mixture was cooled to-50 ℃ and (4-fluorophenyl) -ethyl ketone (3.0g, 19.7mmol) was added dropwise. The mixture was stirred at room temperature overnight and then with NH₄Aqueous Cl (30mL) was diluted, acidified to pH 6-7 with HCl (1N), and extracted with EtOAc (30mL × 3). The combined organic phases were washed with brine (30mL) and Na ₂SO₄Dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc. 20/1 to 5/1) to give intermediate C14 as a yellow oil (2.1g, 43% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.36

¹H NMR:(400MHz,DMSO-d₆)δ9.58(s,1H),7.41–7.30(m,3H),7.11–7.02(m,3H),6.80(td,J＝7.6,1.3Hz,1H),6.67(dd,J＝8.0,1.3Hz,1H),6.19(s,1H),2.42(dq,J＝14.4,7.3Hz,1H),2.14(dq,J＝14.3,7.2Hz,1H),0.77(t,J＝7.2Hz,3H)。

Intermediate C15

Synthesis of 2- (1- (4-fluorophenyl) propyl) phenol (intermediate C15)

To a room temperature solution of intermediate C14(2.10g, 8.53mmol) in DCM (20mL) was added Et₃SiH (3.97g, 34 mmol). The mixture was cooled to 0 ℃ and TFA (29.17g, 256mmol) was added dropwise. The mixture was stirred at room temperature for 3h, diluted with DCM (20mL) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc. 50/1 to 10/1) to give intermediate C15 as a yellow oil (1.7g, 86% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.60

¹H NMR:(400MHz,DMSO-d₆)δ9.31(s,1H),7.31–7.22(m,2H),7.17(dd,J＝8.0,1.6Hz,1H),7.10–7.01(m,2H),6.97(td,J＝7.5,1.7Hz,1H),6.75(dd,J＝7.8,6.6Hz,2H),4.16(t,J＝7.9Hz,1H),2.01–1.89(m,2H),0.80(t,J＝7.3Hz,3H)。

Intermediate C16

Synthesis of 2- (1- (4-fluorophenyl) -1-hydroxybutyl) phenol (intermediate C16)

A solution of 2-bromophenol (2.0g, 11.6mmol) in THF (20mL) was cooled to-78 deg.C. n-BuLi (10.2mL 2.5M; (25.5mmol) was added dropwise, the mixture was stirred at room temperature for 2h, then cooled to-78 deg.C, a solution of (4-fluorophenyl) -n-propyl ketone (1.7g, 12.7mmol) in THF (6mL) was added dropwise, the mixture was stirred at-78 deg.C for 1h, then warmed to 70 deg.C and stirred overnight . With saturated NH₄The reaction was quenched with aqueous Cl (20mL) and extracted with EtOAc (10mL × 3). The combined organic phases were washed with brine (15mL) and Na₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (EtOAc/petroleum ether-1/50 to 1/10) gave intermediate C16 as a white solid (750mg, 25% yield).

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.20

LCMS:RT＝4.018min；[M-1]＝259.0

Intermediate C17

Synthesis of 2- (1- (4-fluorophenyl) butyl) phenol (intermediate C17)

To a solution of intermediate C16(750mg, 2.9mmol) in DCM (10mL) was added Et₃SiH (1.3g, 11.4 mmol). The mixture was cooled to 0 ℃ and TFA (9.8g, 85.5mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (20mL) was added and the resulting mixture was extracted with DCM (10mL x 3). The combined organic phases were washed with brine (15mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was washed with hexane (10mL) to give intermediate C17(1.2g, 76% yield) as a white solid.

TLC EtOAc/Petroleum Ether 1/10(v/v), R_f＝0.6

¹H NMR:(400MHz,DMSO)δ9.35(s,1H),7.28(dd,J＝8.4,6.0Hz,2H),7.17(t,J＝9.2Hz,1H),7.05(t,J＝8.8Hz,2H),6.97(m,1H),6.80–6.71(m,2H),4.30(t,J＝8.0Hz,1H),1.99–1.84(m,2H),1.20(td,J＝14.0,7.2Hz,2H),0.88(t,J＝7.2Hz,2H)。

Intermediate C18

Synthesis of 2- (1- (4-fluorophenyl) -1-hydroxy-2-methylpropyl) phenol (intermediate C18)

To a-50 ℃ solution of 2-bromophenol (691mg, 4.00mmol) in anhydrous THF (5mL) was added n-BuLi (8.79mmol, 3.52mL 2.5M) dropwise. The mixture was allowed to warm to room temperature and stirred for 1h to give solution a. In parallel, (4-fluorophenyl) -isopropyl ketone (332mg, 2.00mmol) and ZnCl ₂(1mL, 1.00mmol) of the mixture was stirred at room temperature for 1h and then added dropwise to solution A. The resulting mixture was stirred at room temperature for 2h, then saturated NH was added₄The reaction was quenched with aqueous Cl (15 mL). The mixture was acidified to pH-4-5 with 1N HCl and then extracted with DCM (15mL × 2). The combined organic layers were washed with Na₂SO₄Drying, concentration in vacuo, and purification by reverse phase column chromatography gave intermediate C18(350mg, 67% yield) as a colorless oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.48

¹H NMR (400MHz, chloroform-d) δ 8.78(s,1H), 7.40-7.33 (m,2H), 7.15-7.11 (m,2H), 7.02-6.93 (m,2H), 6.86-6.77 (m,2H), 2.81-2.72 (m,1H),1.10(d, J ═ 6.8Hz,3H),0.82(d, J ═ 6.7Hz, 3H).

Intermediate C19

Synthesis of 2- (1- (4-fluorophenyl) -2-methylpropyl) phenol (intermediate C19)

A mixture of intermediate C18(250mg, 960umol) and 5% Pd/C (250mg) in THF (10mL) was stirred at 60 ℃ overnight. The mixture was cooled to room temperature and filtered, then concentrated to dryness to give intermediate C19(200mg, 85% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.66

¹H NMR:(400MHz,DMSO-d₆)δ9.39(s,1H),7.36–7.30(m,3H),7.06–7.01(m,2H),6.95–6.91(m,1H),6.75–6.71(m,2H),3.88(d,J＝11.3Hz,1H),2.58–2.51(m,1H),0.79(dd,J＝14.9,6.4Hz,6H)。

Intermediate C20

2- (cyclopropyl group)Synthesis of (4-fluorophenyl) (hydroxy) methyl) phenol (intermediate C20)

A solution of 2-bromophenol (1.58g, 9.13mmol) in THF (30mL) was cooled to-70 deg.C and n-BuLi (20mmol, 8.0mL 2.5M) was added dropwise. The mixture was stirred at room temperature for 30min, then cooled to-70 ℃; 4-fluorophenyl cyclopropyl ketone (1.50g, 9.13mmol) in THF (3mL) was added dropwise. The mixture was stirred at room temperature for 16 h. Quench the reaction with water (50 mL); the mixture was adjusted to pH 6-7 with 2N HCl and extracted with EtOAc (50mL x 3). The combined organic phases were washed with brine (50mL) and Na ₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc ═ 20/1, v/v) to give intermediate C20(2.0g, 87% yield) as a white solid.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.4

LCMS:(RT＝3.74min；[M-1]＝257.0)

Intermediate C21

Synthesis of 2- (cyclopropyl (4-fluorophenyl) methyl) phenol (intermediate C21)

To a solution of intermediate C20(1.0g, 3.87mmol) in DCM (10mL) at 0 deg.C was added Et₃SiH (1.8g, 15.5mmol) and TFA (116mmol, 8.6 mL). The mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo; water (10mL) was added and the mixture was extracted with DCM (30mL x 3). The combined organic phases are passed over Na₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/EtOAc. 20/1, v/v) gave intermediate C21(400mg, 25% yield, 60% purity) as a white solid.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.5

¹H NMR:(400MHz,DMSO)δ9.24(s,1H),7.36–7.23(m,3H),7.10–6.95(m,3H),6.76(m,2H),3.48(d,J＝10.0Hz,1H),0.53(m,2H),0.25(m,1H),0.12(m,1H)。

Intermediate C22

Synthesis of cyclobutyl (4-fluorophenyl) methanol (intermediate C22)

To a room temperature mixture of 4-fluorobenzaldehyde (2g, 16.1mmol), 1-bromocyclobutane (2.4g, 17.7mmol) and Mg (1.0g, 40.3mmol) in THF (20mL) was added I₂(1.61 mmol). The mixture was refluxed for 4 h. Water (40mL) was added and the mixture was extracted with EtOAc (20mL x 3). The combined organic phases were washed with brine (5mL) and Na ₂SO₄Drying, concentration in vacuo and purification by silica gel column chromatography (petroleum ether/EtOAc: 50/1 to 5/1) gave intermediate C22 as a pale yellow liquid (2.0g, 69% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.25

¹H NMR (400MHz, chloroform-d) δ 7.25-7.19 (m,2H), 6.99-6.90 (m,2H),4.49(d, J ═ 8.0Hz,1H),2.52(H, J ═ 8.0Hz,1H), 2.04-1.70 (m, 6H).

Intermediate C23

Synthesis of cyclobutyl (4-fluorophenyl) methanone (intermediate C23)

To a solution of intermediate C22(1.5g, 8.32mmol) in DCM (20mL) was added Dess-Martin oxidant (4.2g, 10.0 mmol). The mixture was stirred at room temperature for 2 h. Water (30mL) was added and the resulting mixture was extracted with DCM (15mL x 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Drying and concentration in vacuo afforded intermediate C23(1.4g, 94% yield) as a colorless liquid.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.7

¹H NMR (400MHz, chloroform-d) δ 7.87-7.79 (m,2H),7.03(t, J ═ 8.6Hz,2H),3.88(p, J ═ 8.0Hz,1H), 2.40-2.26 (m,2H), 2.26-2.15 (m,2H), 2.07-1.93 (m,1H),1.83(m, 1H).

Intermediate C24

Synthesis of 2- (cyclobutyl (4-fluorophenyl) (hydroxy) methyl) phenol (intermediate C24)

To a room temperature solution of intermediate C23(1g, 5.61mmol) in THF (10mL) was added ZnCl ₂(2.8mL, 1.3 mmol); the mixture was stirred at room temperature for 30min (solution A). Separately, a solution of 2-bromophenol (1.2g, 6.73mmol) in THF (2.5mL) was cooled to-78 deg.C, n-BuLi (2.5M in THF) (7.4mL, 18.5mmol) was added, and the solution was stirred at room temperature for 1h (solution B). Solution B was cooled to-78 deg.C and solution A was added. The resulting mixture was stirred at-78 ℃ for 2 h. Water (20mL) was added and the mixture was extracted with EtOAc (10mL x 3). The combined organic phases were washed with brine (5mL) and Na₂SO₄Dried, concentrated in vacuo and purified by reverse phase column chromatography (MeCN/H)₂O) to yield intermediate C24(800mg, 52% yield) as a light yellow oil.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.50

LCMS:RT＝4.030min；[M-1]＝271.1

Intermediate C25

Synthesis of 2- (cyclobutyl (4-fluorophenyl) methyl) phenol (intermediate C25)

Intermediate C24(800mg, 3.0mmol) and Et₃A solution of SiH (1.37g, 11.75mmol, 1.88mL) in DCM (8mL) was cooled to 0 ℃.TFA (10.1g, 88.5mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (20mL) was added and the mixture was extracted with DCM (10mL x 3). The combined organic phases were washed with brine (15mL) and Na₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/EtOAc: 50/1 to 10/1) gave intermediate C25 as a pale yellow oil (650mg, 86% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.45

¹H NMR:(400MHz,DMSO-d₆)δ9.28(s,1H),7.23(dd,J＝8.4,5.8Hz,2H),7.17(d,J＝7.0Hz,1H),7.02(t,J＝8.9Hz,2H),6.97(t,J＝7.6Hz,1H),6.74(t,J＝7.0Hz,2H),4.25(d,J＝11.4Hz,1H),3.15–3.04(m,1H),1.97–1.85(m,2H),1.83–1.72(m,2H),1.72–1.63(m,1H),1.56(q,J＝8.0,16.0Hz,1H)。

Intermediate C26

Synthesis of 6-fluoro-1- (2-hydroxyphenyl) -1,2,3, 4-tetrahydronaphthalen-1-ol (intermediate C26)

To a-78 deg.C solution A of 2-bromophenol (1.4g, 8.3mmol) in THF (15mL) was added n-BuLi (2.5M, 7.3mL) dropwise. The mixture was stirred at room temperature for 1 h. To a solution B of 6-fluoro-1-tetralone (1.5g, 9.14mmol) in THF (3mL) was added ZnCl₂(1M, 3.3 mL). The mixture was stirred at room temperature for 30 min. Solution A was cooled to-78 deg.C and solution B was added dropwise. The mixture was stirred at-78 ℃ for 2 h. Water (30mL) was added and the resulting mixture was extracted with EtOAc (15mL x 3). The combined organic phases were washed with brine (30mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by reverse phase column chromatography (MeCN/H)₂O) to yield intermediate C26 as a brown oil (220mg, 10% yield).

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.20

LCMS:RT＝3.835min；[M-1]＝257.0

Intermediate C27

Synthesis of 2- (6-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenol (intermediate C27)

Intermediate C26(220mg, 852umol) and Et₃A solution of SiH (396mg, 3.41mmol) in DCM (4mL) was cooled to 0 ℃. TFA (2.91g, 25.6mmol) was added dropwise. The solution was stirred at room temperature for 2 h. The reaction was quenched with water (20mL) and extracted with DCM (10mL × 3). The combined organic phases were washed with brine (10mL) and Na ₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/EtOAc: 50/1 to 10/1) gave intermediate C27 as a pale yellow oil (110mg, 53% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.6

Intermediate C28

Synthesis of 6-fluoro-1- (2-hydroxyphenyl) -2, 3-dihydro-1H-inden-1-ol (intermediate C28)

To a-78 deg.C solution A of 2-bromophenol (1.0g, 5.8mmol) in THF (15mL) was added n-BuLi (12.8mmol, 5.1mL 2.5M). The mixture was stirred at room temperature for 1 h. To a room temperature solution B of 6-fluoro-1-indanone (1.0g, 6.4mmol) in THF (3mL) was added ZnCl₂(1M, 2.3 mL). The mixture was stirred at room temperature for 30 min. Solution A was cooled to-78 deg.C and solution B was added. The reaction mixture was stirred at-78 ℃ for 2 h. Water (20mL) was added and the pH adjusted to pH 6-7 with 1N HCl. The mixture was extracted with EtOAc (10mL x 3). The combined organic phases were washed with brine (30mL) and Na₂SO₄Dried, concentrated in vacuo and purified by reverse phase column chromatography (MeCN/H)₂O) to yield intermediate C28(180mg, 11% yield) as a yellow oil.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.20

LCMS:RT＝3.661min；[M-1]＝243.0

Intermediate C29

Synthesis of 2- (6-fluoro-2, 3-dihydro-1H-inden-1-yl) phenol (intermediate C29)

Intermediate C28(220mg, 852umol) and Et ₃A solution of SiH (396mg, 3.41mmol) in DCM (4mL) was cooled to 0 ℃. TFA (2.91g, 25.6mmol) was added dropwise. The solution was stirred at room temperature for 2 h. The reaction was quenched with water (10mL) and extracted with DCM (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/EtOAc. 50/1 to 10/1) gave intermediate C29 as a pale yellow oil (130mg, 63% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.6

LCMS:RT＝3.997min；[M-1]＝227.0

Intermediate C30

Synthesis of 2- ((4-fluorophenyl) (hydroxy) methyl) phenol (intermediate C30)

To a-30 ℃ solution of 2-bromophenol (4.18g, 24.2mmol) in THF (40mL) was added n-BuLi (2.5M in hexane) (29.0mmol, 11.6mL) dropwise. After 0.5h, 4-fluorobenzaldehyde (3.0g, 24.2mmol) in THF (10mL) was added dropwise. The mixture was stirred for 1h and then saturated NH₄Aqueous Cl (50mL) was quenched, acidified to pH 6-7 with 1N HCl, and extracted with EtOAc (10mL × 3). The combined organic phases were washed with brine (15mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc. 20/1 to 5/1) to give intermediate C30 as a yellow oil (2.47g, 46% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.36

¹H NMR:(400MHz,DMSO-d₆)δ9.43(s,1H),7.36(td,J＝5.6,2.4Hz,3H),7.14–6.97(m,3H),6.82–6.70(m,2H),5.96(d,J＝4.2Hz,1H),5.72(d,J＝4.3Hz,1H)。

Intermediate C31

Synthesis of 2- (4-fluorobenzyl) phenol (intermediate C31)

To a room temperature solution of intermediate C30(2.47g, 11.3mmol) in DCM (25mL) was added Et₃SiH (5.26g, 45.3 mmol). The mixture was stirred at 0 ℃ for 10min, then TFA (38.7g, 340mmol) was added dropwise. The mixture was stirred at room temperature for 3h, diluted with DCM (20mL) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc. 50/1 to 10/1) to give intermediate C31 as a yellow oil (1.86g, 81% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.64

¹H NMR:(400MHz,DMSO-d₆)δ9.39(s,1H),7.25–7.20(m,2H),7.10–6.98(m,4H),6.81–6.78(m,1H),6.71(td,J＝7.4,1.3Hz,1H),3.84(s,2H)。

Intermediate C32

Synthesis of 2- (hydroxy (thien-3-yl) methyl) phenol (intermediate C32)

To a-78 deg.C solution of 2-bromophenol (1.0g, 5.78mmol) in THF (10mL) was added n-BuLi (14.5mmol, 5.8mL 2.5M); the mixture was stirred at-78 ℃ for 1 h. Thiophene-3-carbaldehyde (1.3g, 11.6mmol) in THF (5mL) at-78 deg.C was added to the resulting solution. The mixture was stirred at-78 ℃ for 2 h. The reaction mixture was quenched with water (20mL) and the solution was quenched with 1N HClThe pH is adjusted to 6-7. The resulting mixture was extracted with EtOAc (20mL x 2). The combined organic phases were washed with brine (20mL) and Na ₂SO₄Drying, concentration in vacuo, and purification by reverse phase column chromatography gave intermediate C32(850mg, 71% yield) as a yellow solid.

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.4

LCMS:RT＝2.809min,[M-1]＝205.1

¹H NMR:(400MHz,DMSO-d₆)δ9.41(s,1H),7.37(dd,J＝4.8,2.8Hz,1H),7.34(dd,J＝8.0,1.6Hz,1H),7.18(dt,J＝3.2,1.2Hz,1H),7.06–6.98(m,2H),6.79-6.75(m,2H),6.01(d,J＝4.4Hz,1H),5.68(d,J＝4.8Hz,1H)。

Intermediate C33

Synthesis of 2- (thien-3-ylmethyl) phenol (intermediate C33)

To a solution of intermediate C32(550mg, 2.67mmol) in DCM (15mL) at 0 deg.C was added Et₃SiH (930mg, 8.0mmol) and TFA (3.0g, 26.7 mmol); the mixture was stirred at room temperature for 2 h. The reaction was concentrated and purified by reverse phase column chromatography to give intermediate C33(230mg, 45% yield).

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.59

¹H NMR:(400MHz,DMSO-d₆)δ9.38(s,1H),7.40(dd,J＝4.8,3.2Hz,1H),7.10–7.08(m,1H),7.02–6.98(m,2H),6.96(dd,J＝4.8,1.6Hz,1H),6.83–6.77(m,1H),6.70(td,J＝7.2,1.2Hz,1H),3.84(s,2H)。

Intermediate C34

Synthesis of 2- (hydroxy (thien-2-yl) methyl) phenol (intermediate C34)

To 2-bromophenol (2.0g, 1)1.6mmol) in THF (20mL) at-78 deg.C was added n-BuLi (28.9mmol, 12mL of 2.5M); the mixture was stirred at-78 ℃ for 1 h. Thiophene-2-carbaldehyde (2.6g, 23.1mmol) was added and the mixture was stirred at-78 ℃ for 2 h. The reaction mixture was quenched with water (20mL), the pH was adjusted to pH 6-7 with 1N HCl, and the mixture was extracted with EtOAc (20mL × 2). The combined organic phases were washed with brine (30mL) and Na₂SO₄Drying and vacuum concentrating; the residue was purified by reverse phase column chromatography to give intermediate C34(2.0g, 83% yield) as a yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.4

¹H NMR:(400MHz,DMSO-d₆)δ9.47(s,1H),7.39(dd,J＝7.6,1.6Hz,1H),7.32(dd,J＝4.8,1.2Hz,1H),7.05(dd,J＝7.6,1.6Hz,1H),6.88(dd,J＝4.8,3.6Hz,1H),6.83–6.75(m,3H),6.17(d,J＝4.8Hz,1H),5.98(d,J＝4.8Hz,1H)。

Intermediate C35

Synthesis of 2- (thien-2-ylmethyl) phenol (intermediate C35)

To a solution of intermediate C34(2.0g, 9.70mmol) in DCM (20mL) at 0 deg.C was added Et₃SiH (3.4g, 29.1mmol) and TFA (11.1g, 97.0 mmol); the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified by reverse phase column chromatography to give intermediate C35(700mg, 37% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.7

¹H NMR:(400MHz,DMSO-d₆)δ9.47(s,1H),7.26(dd,J＝5.2,1.2Hz,1H),7.11–6.98(m,2H),6.90(dd,J＝5.2,3.2Hz,1H),6.86–6.77(m,2H),6.72(td,J＝7.2,1.2Hz,1H),4.03(s,2H)。

Intermediate C36

Synthesis of 2- (2,2, 2-trifluoro-1- (4-fluorophenyl) -1-hydroxyethyl) phenol (intermediate C36)

To N₂To a-70 ℃ mixture of 2-bromophenol (2.2g, 12.5mmol) in THF (30mL) under an atmosphere was added n-butyllithium (26.0mmol, 10.4mL 2.5M) dropwise. The mixture was stirred at room temperature for 1 h. (4-fluorophenyl) -trifluoromethyl ketone (2.0g, 10.4mmol) was added at 0 ℃. The mixture was stirred at room temperature for 3 h. With saturated NH₄The mixture was quenched with aqueous Cl (30 mL). The mixture was acidified to pH-5-6 with 2M HCl and then extracted with EtOAc (15mL × 2). The organic phase was washed with water (30mL x 2) then brine (30mL), concentrated in vacuo and purified by reverse phase column chromatography to afford intermediate C36 as a white solid (1.0g, 34% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.48

¹H NMR:(400MHz,DMSO-d₆)δ9.62(s,1H),7.42–7.34(m,3H),7.24–7.14(m,3H),6.87(td,J＝7.6,1.3Hz,1H),6.79(dd,J＝8.1,1.2Hz,1H)。

Intermediate C37

Synthesis of 2- (2,2, 2-trifluoro-1- (4-fluorophenyl) ethyl) phenol (intermediate C37)

A mixture of intermediate C36(1.0g, 3.49mmol), NaI (4.2g, 28.0mmol), TMSCl (2.3g, 21.0mmol) in acetonitrile (10mL) was microwaved at 120 ℃ for 2 h. The mixture was cooled to room temperature and concentrated to dryness; the residue was purified by Prep-TLC to give intermediate C37 as a colorless oil (300mg, 32% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.66

¹H NMR:(400MHz,DMSO-d₆)δ9.89(s,1H),7.45–7.40(m,3H),7.23–7.13(m,3H),6.91–6.82(m,2H),5.33(q,J＝10.8Hz,1H)。

Intermediate C38

Synthesis of 2- (3,3, 3-trifluoro-1- (4-fluorophenyl) propyl) phenol (intermediate C38)

To a mixture of 4-fluorostyrene (200mg, 1.6mmol), Tognis reagent (792mg, 2.4mmol) and 2-hydroxyphenylboronic acid (452mg, 3.3mmol) in DMA (10.0mL) was added Cu (CH)₃CN)₄PF₆(61mg, 164 umol). The mixture was stirred at 40 ℃ for 1 h. Water (10mL) was added and the resulting mixture was extracted with EtOAc (5mL x 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/EtOAc: 50/1 to 10/1) gave intermediate C38 as a yellow oil (360mg, 77% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.3

LCMS:RT＝1.569min,[M-1]:283.1

Intermediate C39

Synthesis of 1- (4-fluorophenyl) -2-methoxyethan-1-one (intermediate C39)

To a room temperature solution of 4-fluoroacetophenone (2.0g, 14.5mmol) in MeOH (60mL) was added TsNHNH₂(2.7g, 14.5mmol), TBHP (7.8g, 86.9mmol) and TBAI (1.1g, 2.89 mmol). The mixture was stirred at room temperature overnight. Water (100mL) was added and the resulting mixture was extracted with EtOAc (50mL × 2). The organic phase was washed with brine (20 mL. times.2) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether-1/100-1/10) to give intermediate C39(1.7g, 70% yield) as a yellow liquid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.49.

¹H NMR:(400MHz,DMSO-d₆)δ8.04–7.96(m,2H),7.40–7.32(m,2H),4.77(s,2H),3.35(s,3H)。

Intermediate C40

Synthesis of 2- (1- (4-fluorophenyl) -1-hydroxy-2-methoxyethyl) phenol (intermediate C40)

To a-78 deg.C solution of 2-bromophenol (3.0g, 17.3mmol) in THF (30mL) was added n-BuLi (38.2mmol, 15mL of 2.5M); the mixture was stirred at room temperature for 1 h. A-78 deg.C solution of intermediate C39(1.9g, 11.6mmol) in THF (5mL) was added to the reaction. The mixture was stirred at-5 ℃ overnight. Water (100mL) was added dropwise to the reaction mixture, which was then acidified to pH-6-7 with 2N HCl and extracted with EtOAc (30mL × 2). The organic phase was concentrated and purified by reverse phase column chromatography to give intermediate C40(800mg, 28% yield) as a yellow liquid.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.39

¹H NMR:(400MHz,DMSO-d₆)δ9.45(s,1H),7.39–7.32(m,2H),7.29(dd,J＝8.0,2.0Hz,1H),7.12–7.05(m,3H),6.79(td,J＝7.6,1.2Hz,1H),6.70(dd,J＝8.0,1.2Hz,1H),6.40(s,1H),3.98–3.88(m,2H),3.29(s,3H)。

Intermediate C41

Synthesis of 2- (1- (4-fluorophenyl) -2-methoxyethyl) phenol (intermediate C41)

To a room temperature solution of intermediate C40(400mg, 1.53mmol) in MeOH (8mL) was added Pd/C (400mg, 5% w/w); the mixture was stirred at 50 ℃ for 3 d. The reaction was filtered, concentrated in vacuo, and purified by Prep-TLC to give intermediate C41(90mg, 24% yield) as a white solid.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.50

¹H NMR:(400MHz,DMSO-d₆)δ9.40(s,1H),7.31–7.23(m,2H),7.11–7.04(m,3H),7.00(td,J＝7.6,1.6Hz,1H),6.80–6.69(m,2H),4.56(t,J＝7.6Hz,1H),3.86–3.75(m,2H),3.23(s,3H)。

Intermediate C42

Synthesis of 2- (1- (4-fluorophenyl) -1-hydroxyethyl) phenol (intermediate C42)

2-bromophenol (20.0g, 116mmol) in THF (100mL) was cooled to-78 deg.C. n-BuLi (232mmol, 92.5mL 2.5M) was added. The mixture was stirred at room temperature for 1h and then cooled to-78 ℃. 4-Fluoroacetophenone (16.0g, 116mmol) in THF (10mL) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was acidified to pH 6-7 with 2N HCl and then extracted with EtOAc (50mL x 3). The combined organic phases were washed with brine (100mL) and Na₂SO₄Drying, concentration in vacuo, and purification by reverse phase column chromatography gave intermediate C42(2.0g, 7.3% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.3

LCMS:RT＝3.46min；[M-1]＝231.1

Intermediate C43

Synthesis of 2- (1- (4-fluorophenyl) ethyl) phenol (intermediate C43)

To a solution of intermediate C42(5.7g, 24.5mmol) in DCM (50mL) at 0 deg.C was added Et₃SiH (11.4g, 98.0mmol) and TFA (84.0g, 735 mmol). The mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 10/1) to give intermediate C43(5.0g, 94.3% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.25

¹H NMR:(400MHz,DMSO)δ9.33(s,1H),7.28–7.19(m,2H),7.12–7.02(m,3H),6.99(m,1H),6.79–6.71(m,2H),4.44(d,J＝7.3Hz,1H),1.49(d,J＝7.3Hz,3H)。

Intermediate C44

Synthesis of 2- (2- (4-fluorophenyl) -1-hydroxyethyl) phenol (intermediate C44)

A solution of 2-bromophenol (571mg, 3.3mmol) in THF (5mL) was cooled to-78 deg.C. n-BuLi (2.5M in THF) (7.3mmol, 3.2mL) was added dropwise. The mixture was stirred at room temperature for 30min and then cooled to-78 ℃. A solution of 4-fluorophenylacetaldehyde (500mg, 3.6mmol) in THF (5mL) was added dropwise. The mixture was stirred at-78 ℃ for 1 h. With saturated NH₄The reaction was quenched with aqueous Cl (10mL) and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (15mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/petroleum ether 1/50 to 1/20) to give intermediate C44 as a colorless oil (200mg, 24% yield).

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.20

Intermediate C45

Synthesis of 2- (4-fluorophenethyl) phenol (intermediate C45)

To a solution of intermediate C44(200mg, 0.9mmol) in DCM (4mL) was added Et₃SiH (418mg, 3.6 mmol). The mixture was cooled to 0 ℃ and TFA (3.1g, 27mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (10mL) was added and the resulting mixture was extracted with DCM (5mL x 3). The combined organic phases were washed with brine (15mL) and Na₂SO₄Dried, concentrated in vacuo, and passed through Prep-TLCPurification (EtOAc/petroleum ether ═ 1/10) afforded intermediate C45(120mg, 65% yield) as a white solid.

TLC EtOAc/Petroleum Ether 1/10(v/v), R_f＝0.6

¹H NMR:(400MHz,DMSO)δ9.29(s,1H),7.26–7.19(m,1H),7.11–7.05(m,1H),7.03–6.97(m,1H),6.78(d,J＝8.0Hz,1H),6.68(dt,J＝7.6,1.2Hz,1H),2.84–2.74(m,1H)。

Intermediate D1

Synthesis of 1- (1-chloroethyl) -4-fluorobenzene (intermediate D1)

To a room temperature solution of 1- (4-fluorophenyl) -1-ethanol (1.00g, 7.13mmol) in DCM (10mL) was added thionyl chloride (1.27g, 10.7 mmol). The mixture was stirred for 1h and concentrated in vacuo to afford intermediate D1(1.13g, 7.12mmol, 99% yield).

TLC EtOAc/petroleum ether 3/1(v/v) and Rf 0.54

¹H NMR:(400MHz,DMSO-d₆)δ7.56–7.50(m,2H),7.20-7.16(m,2H),5.36(q,J＝6.8Hz,1H),1.78(d,J＝6.8Hz,3H)。

Intermediate D2

Synthesis of 1- (2-chloropropan-2-yl) -4-fluorobenzene (intermediate D2)

2- (4-F-phenyl) -2-propanol (500mg, 3.24mmol) and SOCl₂A solution of (579mg, 4.86mmol) in DCM (5mL) was stirred at room temperature overnight. The mixture was concentrated to dryness to give crude intermediate D2(500mg, 89% yield) as a colorless oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.57

¹H NMR:(400MHz,DMSO-d₆)δ7.68–7.62(m,2H),7.22-7.17(m,2H),1.96(s,6H)。

Intermediate D3

Synthesis of furan-3-ylcarbinol (intermediate D3)

To a solution of furan-3-carbaldehyde (200mg, 2.08mmol) in THF (2mL) at 0 deg.C was added NaBH₄(95mg, 2.50 mmol). The mixture was stirred at 0 ℃ for 2h, then quenched with water (10mL) and extracted with EtOAc (10 mL). The organic layer was washed with water (10mL), then brine (10mL), over Na₂SO₄Dried and concentrated to dryness to give intermediate D3(150mg, 73% yield) as a colourless oil.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.49

¹H NMR:(400MHz,DMSO-d₆)δ7.58(t,J＝1.7Hz,1H),7.53–7.50(m,1H),6.45–6.41(m,1H),4.93(t,J＝5.6Hz,1H),4.33(dd,J＝5.6,1.0Hz,2H)。

Intermediate D4

Synthesis of 3- (chloromethyl) furan (intermediate D4)

To a solution of intermediate D3(200mg, 2.04mmol) in DCM (2mL) was added thionyl chloride (364mg, 3.06 mmol). The mixture was stirred at 0 ℃ for 2 h. The mixture was concentrated to dryness to give intermediate D4(150mg, 63% yield) as a colourless solid.

TLC EtOAc/petroleum ether 1/10(v/v) and Rf 0.78

Example 1

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) methyl) phenoxy) Synthesis of acetic acid (Compound 1)

To intermediate A7(300mg, 642umol), 3-trifluoromethylphenylboronic acid (183mg, 963umol) and Pd (dppf) Cl₂(47.0mg, 64.2. mu. mol) to a room temperature solution in dioxane (5mL) was added sodium bicarbonate (1mL, 2M aqueous solution). The mixture was heated to 70 ℃ and stirred for 3 h. The mixture was cooled to room temperature. NaOH (1.9mL, 1.0M aqueous solution) was added and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5mL), acidified to pH-4-5 with aqueous HCl (1M), and extracted with EtOAc (3mL × 3). The combined organic phases were washed with brine (5mL) and Na ₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (DCM/MeOH ═ 10/1) to give compound 1(20mg, 42.4umol, 6.6% yield) as a white solid.

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.15

¹H NMR:(400MHz,DMSO-d₆)δ9.65(s,1H),7.84(s,1H),7.76(d,J＝5.5Hz,1H),7.64(d,J＝5.5Hz,2H),7.15(s,1H),7.11(s,2H),6.98–6.84(m,2H),4.74(s,2H),4.13(s,2H)。

Example 2

2- (3, 5-dichloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid methyl ester Synthesis of ester (Compound 2)

3-Ethylphenylboronic acid (101mg, 0.64mmol), intermediate A7(300mg, 0.57mmol), 2N NaHCO₃(1mL, 1.92mmol) and Pd (dppf) Cl₂(47mg, 0.06mmol) of a mixture in 1, 4-dioxane (5mL) in N₂Stirred at 70 ℃ for 8h under an atmosphere. The mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography to give compound 2(57mg, 19% yield) as a yellow oil.

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.45

¹H NMR:(400MHz,DMSO)δ9.33(s,1H),7.27(m,3H),7.15(s,2H),7.12(d,J＝7.0Hz,1H),7.02(s,1H),6.89(d,J＝8.3Hz,1H),6.82(d,J＝8.3Hz,1H),4.89(s,2H),4.11(s,2H),3.71(s,3H),2.63(q,J＝7.5Hz,2H),1.22–1.14(m,3H)。

Example 3

2- (3, 5-dichloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid (chemization) Synthesis of Compound 3)

To intermediate A7(200mg, 428umol), 3-ethylphenylboronic acid (96mg, 642umol) and Pd (dppf) Cl₂(31mg, 43umol) to a room temperature solution in dioxane (5mL) was added sodium bicarbonate (642uL, 2M aqueous solution). The mixture was heated to 70 ℃ and stirred overnight. The mixture was cooled to room temperature. NaOH (1.3mL, 1M aqueous solution) was added and the resulting mixture was stirred for 30 min. The reaction was quenched with water (10mL), acidified to pH-4-5 with aqueous HCl (1M), and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na ₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 3(30mg, 67umol, 15.7% yield) as a white solid.

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.26

¹H NMR:(400MHz,DMSO-d₆)δ9.34(s,1H),7.35–7.22(m,3H),7.13(d,J＝2.2Hz,1H),7.10(s,2H),7.03(d,J＝2.2Hz,1H),6.88(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.3Hz,1H),4.75(s,2H),4.11(s,2H),2.62(q,J＝7.6Hz,2H),1.19(t,J＝7.6Hz,3H)。

Example 4

2- (3, 5-dichloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) -N-methyl Synthesis of acetamide (Compound 4)

To a room temperature solution of Compound 2(57mg, 0.13mmol) in THF (2mL) was added 1N MeNH₂Aqueous solution (1.3mL, 1.30 mmol); the resulting mixture was stirred at 75 ℃ overnight. The reaction was concentrated in vacuo and purified by Prep-TLC (DCM/MeOH ═ 20/1, v/v) to give compound 4(37mg, 65% yield) as a light yellow oil.

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.4

¹H NMR:(400MHz,DMSO)δ9.34(s,1H),8.05(d,J＝4.7Hz,1H),7.31–7.22(m,3H),7.14(s,2H),7.13–7.10(m,1H),7.02(d,J＝2.3Hz,1H),6.89(m,1H),6.82(d,J＝8.3Hz,1H),4.53(s,2H),4.11(s,2H),2.64(d,J＝4.6Hz,3H),2.63–2.58(m,2H),1.19(t,J＝7.6Hz,3H)。

LCMS:RT＝4.10min；[M+1]＝443。

Example 5

2- (3, 5-dichloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy Synthesis of Yl) acetic acid (Compound 5)

To intermediate B1(173mg, 642umol), intermediate A7(300mg, 642umol) and Pd (dppf) Cl₂(23mg, 32umol) to a room temperature solution in 1, 4-dioxane (10mL) was added NaHCO₃(0.96mL, 2M aqueous solution). The mixture was heated to 70 ℃ and stirred overnight. The reaction was cooled to room temperature. NaOH (1.25mL, 1N aqueous solution) was added, and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (10mL), acidified to pH-4-5 with aqueous HCl (1M), and extracted with EtOAc (10mL × 2). The combined organic phases were washed with brine (10mL) and Na ₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 5(40mg, 85.2umol, 20% yield) as a white solid.

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.2

¹H NMR:(400MHz,DMSO-d₆)δ13.10(s,1H),9.55(s,1H),7.45–7.42(t,J＝8.0Hz,1H),7.24(t,J＝74.0Hz,1H),7.37–7.28(m,2H),7.12(s,1H),7.12–7.05(m,3H),6.92(dd,J＝8.4,2.3Hz,1H),6.86(d,J＝8.3Hz,1H),4.77(s,2H),4.12(s,2H)。

Example 6

2- (3, 5-dichloro-4- ((3'- (ethoxycarbonyl) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) Synthesis of acetic acid (Compound 6)

To intermediate A7(200mg, 428umol), 3-ethoxycarbonylphenylboronic acid (125mg, 644umol) and Pd (dppf) Cl₂·CH₂Cl₂(35mg, 43umol) to a room temperature mixture in 1, 4-dioxane (3.0mL) was added NaHCO₃Aqueous solution (2M, 0.5 mL). The mixture was heated to 70 ℃ overnight. The reaction mixture was cooled to room temperature. NaOH (1M, 0.4mL) was added and the resulting mixture was stirred for 30 min. The reaction was quenched with water (10mL), acidified to pH-4-5 with aqueous HCl (1M), and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 6(30mg, 14% yield) as a white solid.

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.20

LCMS:RT＝3.997min；[M-1]＝472.8

¹H NMR:(400MHz,DMSO)δ9.58(s,1H),8.10(s,1H),7.88(d,J＝7.6Hz,1H),7.74(d,J＝7.4Hz,1H),7.54(t,J＝7.6Hz,1H),7.12(s,1H),7.09(d,J＝1.8Hz,1H),6.94(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),4.77(s,1H),4.33(dd,J＝14.2,7.0Hz,1H),4.13(s,1H),1.33(t,J＝7.0Hz,1H)。

Example 7

2- (3, 5-dichloro-4- ((6-hydroxy-3 '-methoxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid Synthesis of (Compound 7)

To intermediate A7(250mg, 540umol), 3-methoxyphenylboronic acid (122mg, 800umol) and Pd (dppf) Cl ₂·CH₂Cl₂(39mg, 54umol) to a room temperature mixture in 1, 4-dioxane (5.0mL) was added NaHCO₃Aqueous solution (2M, 0.5 mL). The mixture was heated to 70 ℃ and stirred overnight. Cooling the reaction mixture to room temperature; addition of LiOH. H₂O (67mg, 1.6mmol), and the mixture was stirred for 30 min. The reaction was quenched with water (10mL), acidified to pH-4-5 with aqueous HCl (1M), and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 7 as a white solid (30mg, 29% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.20

LCMS:RT＝3.887min；[M-1]＝430.8

¹H NMR:(400MHz,DMSO)δ13.11(s,1H),9.40(s,1H),7.29(dd,J＝10.2,6.0Hz,1H),7.12(s,1H),7.05–7.00(m,1H),6.93–6.89(m,1H),6.85(dd,J＝14.0,5.0Hz,1H),4.77(s,1H),4.11(s,1H),3.76(s,1H)。

Example 8

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (hydroxymethyl) - [1,1' -biphenyl)]-3-yl) methyl) phenoxy) Synthesis of acetic acid (Compound 8)

Intermediate A7(200mg, 428umol), 3-hydroxymethyl-phenylboronic acid (78mg, 514umol), Pd (dppf) Cl₂(31mg, 43umol) and NaHCO₃A mixture of (aqueous) (1M, 1mL) in 1, 4-dioxane (3mL) was stirred at 75 ℃ overnight. The mixture was cooled to room temperature and lioh was added₂O (54mg, 1.3mmol), and the mixture was stirred at room temperature for 30 min. Water (10mL) was added, pH was adjusted to pH 4-5 with 1N HCl, and the mixture was extracted with EtOAc (10mL × 2). The combined organic phases were washed with brine (30mL) and Na ₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 8(50mg, 27% yield) as a pale yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝3.298min；[M-1]＝430.8/432.8

¹H NMR:(400MHz,DMSO-d₆)δ13.13(s,1H),9.35(s,1H),7.42(s,1H),7.34–7.29(m,2H),7.24–7.19(m,1H),7.11(s,2H),7.03(d,J＝2.0Hz,1H),6.89(dd,J＝8.4,2.2Hz,1H),6.83(d,J＝8.4Hz,1H),5.17(s,1H),4.75(s,2H),4.51(s,2H),4.11(s,2H)。

Example 9

2- (4- ((3 '-acetamido-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -3, 5-dichlorophenoxy) ethyl Synthesis of acid (Compound 9)

To intermediate A7(200mg, 428umol), 3-acetamido-phenylboronic acid (115mg, 642umol) and Pd (dppf) Cl₂·CH₂Cl₂(39mg, 54umol) to a room temperature mixture in 1, 4-dioxane (5.0mL) was added NaHCO₃Aqueous solution (2M, 0.5 mL). The mixture was heated to 70 ℃ and stirred overnight. The reaction was cooled to room temperature; addition of LiOH. H₂O (55mg, 1.3mmol), and the resulting mixture was stirred for 30 min. Quench the reaction by adding water (10 mL); the mixture was acidified to pH 4-5 with aqueous HCl (1M) and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 9(10mg, 5% yield) as a white solid.

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.15

LCMS:RT＝3.276min；[M-1]＝457.9

¹H NMR:(400MHz,DMSO-d₆)δ9.94(s,1H),8.86(s,1H),7.19(dd,J＝4.4,2.0Hz,4H),6.65(d,J＝8.4Hz,1H),6.48(d,J＝8.4Hz,1H),6.19(d,J＝8.4Hz,1H),6.07(d,J＝8.4Hz,1H),5.24–5.21(m,1H),4.93(d,J＝3.6Hz,4H),4.69(dd,J＝2.4,1.1Hz,1H),4.05(s,2H),3.97(s,2H),3.72(d,J＝0.8Hz,4H),2.45(s,2H),2.23(s,3H),1.93(s,3H)。

Example 10

2- (4- ((3 '-acetyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -3, 5-dichlorophenoxy) acetic acid Synthesis of methyl ester (Compound 10)

To a room temperature solution of intermediate A7(200mg, 0.43mmol) in 1, 4-dioxane (3mL) was added 3-acetylphenylboronic acid (106mg, 0.65mmol), Pd (dppf) Cl ₂(29mg, 0.04mmol) and NaHCO₃(2N) (1.29mmol, 0.6 mL). The mixture was stirred at 85 ℃ overnight, then diluted with EtOAc (20mL) and filtered. The filtrate was washed with brine (30mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 10 as a white solid (17mg, 9% yield).

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.6

Example 11

2- (4- ((3 '-acetyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -3, 5-dichlorophenoxy) acetic acid Synthesis of (Compound 11)

To a solution of compound 10(17mg, 0.04mmol) in THF (3mL) and water (2mL) was added LiOH₂O (5mg, 0.12 mmol). The mixture was stirred at room temperature for 2 h. With 1N HClThe pH was adjusted to about 4 and the resulting mixture was extracted with EtOAc (20mL × 2). The organic layer was washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 11 as a white solid (8mg, 44% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.1

LCMS:RT＝3.744min；[M-1]＝442.8

¹H NMR:(400MHz,DMSO-d₆)δ9.76(s,1H),8.05(s,1H),7.88(d,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.54(t,J＝7.6Hz,1H),7.11(s,1H),6.94(d,J＝16.0Hz,4H),4.28(s,2H),4.11(s,2H),2.60(s,3H)。

Example 12

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (trifluoromethoxy) - [1,1' -biphenyl) s]-3-yl) methyl) phenoxy Synthesis of Yl) acetic acid (Compound 12)

Intermediate A7(200mg, 0.43mmol), Pd (dppf) Cl₂(35mg，0.64mmol)、NaHCO₃(108mg, 1.28mmol) and 3-trifluoromethoxyphenylboronic acid (132mg, 0.64mmol) in H ₂A solution in O (0.5mL) and 1, 4-dioxane (5mL) was refluxed overnight. Cooling the mixture to room temperature; addition of LiOH₂O (54mg, 1.28mmol), and the resulting mixture was stirred at room temperature for 30 min. Water (10mL) was added and the mixture was extracted with ether (10mL x 2); the aqueous phase was adjusted to pH-3 with HCl (1N) and then re-extracted with EtOAc (10mL × 2). The combined EtOAc phases were washed with brine (5mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-HPLC (MeCN/H)₂O) to give compound 12 as a white solid (5mg, 2% yield).

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.1

LCMS:RT＝4.21min；[M-1]＝485

¹H NMR:(400MHz,DMSO-d₆)δ13.13(s,1H),9.66(s,1H),7.53–7.47(m,4H),7.28(d,J＝7.8Hz,1H),7.11(d,J＝3.8Hz,3H),6.95–6.91(m,1H),6.87(d,J＝8.4Hz,1H),4.73(s,2H),4.12(s,2H)。

Example 13

2- (3, 5-dichloro-4- ((6-hydroxy-3 '-isopropyl- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid Synthesis of (Compound 13)

To intermediate A7(200mg, 428umol), 3-isopropylphenylboronic acid (105mg, 642umol) and Pd (dppf) Cl₂·CH₂Cl₂(39mg, 54umol) to a room temperature mixture in 1, 4-dioxane (5.0mL) was added NaHCO₃Aqueous solution (2M, 0.5 mL). The mixture was heated to 70 ℃ and stirred overnight. Cooling the reaction system to room temperature; addition of LiOH. H₂O (55mg, 1.3mmol), and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with water (10mL), acidified to pH-4-5 with aqueous HCl (1M), and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na ₂SO₄Dried, concentrated in vacuo, and purified by Prep-HPLC (MeCN/H)₂O) to give compound 13 as a white solid (25mg, 13% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.3

LCMS:RT＝4.358min；[M-1]＝442.9

¹H NMR:(400MHz,DMSO-d₆)δ13.11(s,1H),9.36(s,1H),7.34–7.25(m,3H),7.15(d,J＝6.8Hz,1H),7.12(s,2H),7.03(d,J＝2.2Hz,1H),6.89(dd,J＝8.4,2.4Hz,1H),6.82(d,J＝8.4Hz,1H),4.76(s,2H),4.11(s,2H),2.90(p,J＝6.8Hz,1H),1.22(d,J＝6.8Hz,6H)。

Example 14

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (methylsulfonyl) - [1,1' -biphenylyl)]-3-yl) methyl) phenoxy Synthesis of Yl) acetic acid (Compound 14)

To intermediate A7(200mg, 0.40mmol), 3-methylsulfonyl-phenylboronic acid (128mg, 0.60mmol) and NaHCO under a nitrogen atmosphere₃(2M, 0.5mL) to a room temperature solution in 1, 4-dioxane (3mL) was added Pd (dppf) Cl₂(31mg, 0.04 mmol); the resulting mixture was heated at 70 ℃ overnight. The reaction mixture was cooled to room temperature and lioh was added₂O (84mg, 2.0mmol), and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with water (10mL), the pH was adjusted to pH-4-5 with 1N HCl, and the mixture was extracted with EtOAc (10mL × 2). The combined organic phases were washed with brine (10mL x 2) and over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (methanol/DCM ═ 1/10) to give 87mg of crude product. Further purification by Prep-HPLC (ACN/water range 20/80 to 90/10, 25min) gave compound 14 as an off-white solid (21mg, 10% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.21

LCMS:RT＝3.39min；[M-1]＝478.8

¹H NMR:(400MHz,DMSO)δ13.11(s,1H),9.69(s,1H),8.06(t,J＝2.0Hz,1H),7.85-7.80(m,2H),7.67(t,J＝7.6Hz,1H),7.17(d,J＝2.0Hz,1H),7.12(s,2H),6.93(dd,J＝8.4,2.4Hz,1H),6.88(d,J＝8.4Hz,1H),4.78(s,2H),4.14(s,2H),3.23(s,3H)。

Example 15

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (methoxymethyl) - [1,1' -biphenylyl) ]-3-yl) methyl) phenoxy Synthesis of Yl) acetic acid (Compound 15)

Intermediate A7(200mg, 0.43mmol), NaHCO₃(1.29mmol，0.6mL)、Pd(dppf)Cl₂(30mg, 0.04mmol) and 3-methoxymethyl-phenylboronic acid (106mg, 0.64mmol) in 1, 4-dioxaneAlkane (10mL) and H₂The solution in O (2mL) was refluxed overnight. Cooling the mixture to room temperature; addition of LiOH₂O (54mg, 1.29mmol), and the resulting mixture was stirred at room temperature for 30 min. Water (10mL) was added and the mixture was extracted with ether (10mL x 2). The aqueous phase was adjusted to pH-3 with HCl (1N) and then re-extracted with EtOAc (10mL × 2). The combined EtOAc phases were washed with brine (5mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-TLC (DCM/MeOH ═ 10/1) and Prep-HPLC (MeCN/H)₂O) purification to afford compound 15 as a white solid (10mg, 5% yield).

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.1

LCMS:RT＝3.77min；[M-1]＝444.8

¹H NMR:(400MHz,DMSO-d₆)δ13.11(s,1H),9.40(s,1H),7.42(s,1H),7.36(dd,J＝4.8,2.1Hz,2H),7.24–7.20(m,1H),7.12(s,2H),7.04(d,J＝2.2Hz,1H),6.89(dd,J＝8.4,2.2Hz,1H),6.83(d,J＝8.4Hz,1H),4.77(s,2H),4.43(s,2H),4.11(s,2H),3.30(s,3H)。

Example 16

2- (3, 5-dichloro-4- ((6-hydroxy-3 '-propyl- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid (chemization) Synthesis of Compound 16)

To intermediate A7(200mg, 428umol), 3-n-propylphenylboronic acid (105mg, 642umol) and Pd (dppf) Cl₂·CH₂Cl₂(39mg, 54umol) to a room temperature mixture in 1, 4-dioxane (5.0mL) was added NaHCO₃Aqueous solution (2M, 0.5 mL). The mixture was heated to 70 ℃ and stirred overnight. The reaction was cooled to room temperature; addition of LiOH. H ₂O (55mg, 1.3mmol), and the resulting mixture was stirred for 30 min. The reaction was quenched with water (10mL), acidified to pH-4-5 with aqueous HCl (1M), and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-HPLC(MeCN/H₂O) to give compound 16(35mg, 18% yield) as a white solid.

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.25

LCMS:RT＝4.361min；[M-1]＝442.9

¹H NMR:(400MHz,DMSO-d₆)δ13.11(s,1H),9.34(s,1H),7.29–7.22(m,3H),7.10(s,2H),7.08(dd,J＝4.0,1.2Hz,1H),7.02(d,J＝2.0Hz,1H),6.87(dd,J＝8.4,2.4Hz,1H),6.81(d,J＝8.0Hz,1H),4.75(s,2H),4.09(s,2H),2.55(d,J＝7.6Hz,2H),1.63–1.54(m,2H),0.90(t,J＝7.2Hz,3H)。

Example 17

2- (3, 5-dichloro-4- ((6-hydroxy-3 '-methyl- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid (chemization) Synthesis of Compound 17)

To a room temperature solution of intermediate A7(200mg, 428umol) in 1, 4-dioxane (4mL) was added Pd (dppf) Cl₂(34.97mg，42.82umol)、NaHCO₃(2N, 1mL) and toluene-3-boronic acid (87.3mg, 642 umol). The mixture was heated to 70 ℃ overnight and then cooled to room temperature. Addition of LiOH₂O (135mg, 7.5 mmol); the mixture was stirred at room temperature for 30min, diluted with water (5mL), acidified to pH-4-5 with 1N HCl and extracted with DCM (5mL × 3). The combined organic phases were washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC (ACN/water range 30/70 to 85/15) to give compound 17 as an off-white solid (30mg, 16% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.33

LCMS:RT＝2.441min；[M-1]＝414.8。

¹H NMR:(400MHz,DMSO-d₆)δ13.11(s,1H),9.35(s,1H),7.29–7.20(m,3H),7.11(s,2H),7.09(d,J＝7.0Hz,1H),7.02(d,J＝2.2Hz,1H),6.88(dd,J＝8.3,2.3Hz,1H),6.82(d,J＝8.3Hz,1H),4.77(s,2H),4.10(s,2H),2.32(s,3H)。

Example 18

2- (3, 5-dichloro-4- ((3 '-cyano-6-hydroxy- [1,1' -biphenyl) ]-3-yl) methyl) phenoxy) acetic acid methyl ester Synthesis of ester (Compound 18)

3-cyanophenylboronic acid (77mg, 0.48mmol), intermediate A7(150mg, 0.32mmol), 2N NaHCO₃(0.48mL, 0.96mmol) and Pd (dppf) Cl₂(11mg, 0.02mmol) of a mixture in 1, 4-dioxane (2mL) in N₂Stirred at 85 ℃ for 16h under an atmosphere. The resulting solution of compound 18 was used in the next step without further purification.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.44

LCMS:RT＝2.48min；[M-1]＝440.0

Example 19

2- (3, 5-dichloro-4- ((3 '-cyano-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid (chemization) Synthesis of Compound 19)

To a room temperature solution of compound 18(141mg, 0.32mmol) dissolved in THF (1 mL)/water (5mL) was added LiOH (39mg, 0.96 mmol); the resulting mixture was stirred at room temperature for 1 h. The reaction was acidified to pH-6-7 with 2N HCl, concentrated in vacuo, and purified by Prep-HPLC to give compound 19 as a pale yellow solid (10mg, 10% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

¹H NMR:(400MHz,DMSO)δ13.07(s,1H),9.68(s,1H),7.92(s,1H),7.80(m,1H),7.75(m,1H),7.60(t,J＝7.8Hz,1H),7.17–7.07(m,3H),6.91(m,2H),4.75(s,2H),4.12(s,2H)。

LCMS:RT＝3.64Min；[M-1]＝427。

Example 20

2- (3, 5-dichloro-4- ((6-hydroxy-3 '-vinyl- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid Synthesis of methyl ester (Compound 20)

To a room temperature solution of intermediate A7(100mg, 0.21mmol) and styrene-2-boronic acid (48mg, 0.32mmol) in 1, 4-dioxane (3mL) was added Pd (PPh) under a nitrogen atmosphere ₃)₂Cl₂(15mg, 0.21mmol) and K₃PO₄(91mg, 0.43 mmol). The mixture was heated to 70 ℃ overnight. The reaction mixture was diluted with EtOAc (10mL), washed with brine (10mL), and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (EtOAc/petroleum ether ═ 1/10) to give compound 20(20mg, 21% yield) as a light yellow solid.

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.41

LCMS:RT＝2.97min；[M-1]＝441.0

Example 21

2- (3, 5-dichloro-4- ((6-hydroxy-3 '-vinyl- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid Synthesis of (Compound 21)

To a room temperature solution of compound 20(20mg, 0.04mmol) in water (0.5mL)/THF (2mL) was added LiOH. H₂O (4mg, 0.08 mmol); the resulting mixture was stirred overnight. The reaction was diluted with water (10mL), acidified to pH-5 with HCl (2N), and extracted with EtOAc (5mL × 2). The combined extracts are purified over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (methanol/DCM ═ 1/10) to give compound 21 as a white solid (12mg, 61% yield).

TLC methanol/DCM equals 1/10(v/v) and Rf equals 0.23

LCMS:RT＝3.99min；[M-1]＝427.0

¹H NMR:(400MHz,DMSO)δ9.53(s,1H),7.53(s,1H),7.45–7.31(m,3H),7.06(s,1H),6.95(s,2H),6.88(s,2H),6.76(dd,J＝17.6,10.8Hz,1H),5.82(d,J＝17.6Hz,1H),5.26(d,J＝10.8Hz,1H),4.24(s,2H),4.09(s,2H)。

Example 22

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (prop-1-en-2-yl) - [1,1' -biphenyl)]-3-yl) methyl) phenoxy Synthesis of Yl) acetic acid (Compound 22)

Intermediate B2(118mg, 482umol), intermediate A7(150mg, 321umol), NaHCO ₃(2M, 0.48mL) and Pd (dppf) Cl₂A mixture of (24mg, 32.1umol) in 1, 4-dioxane (2mL) was stirred at 100 ℃ overnight. Cooling the mixture to room temperature; addition of LiOH₂O (40mg, 963umol), and the mixture was stirred for 1 h. Acidifying the mixture with 1N HCl to pH 5-6; water (30mL) was added and the mixture was extracted with EtOAc (25mL × 2). The combined organic layers were washed with water (25mL), then brine (50mL), and Na₂SO₄Drying and purification by Prep-HPLC gave compound 22 as a white solid (20mg, 14% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝4.151min；[M-1]＝441.0/443.0

¹H NMR:(400MHz,DMSO-d₆)δ13.08(s,1H),9.39(s,1H),7.57(d,J＝2.1Hz,1H),7.44–7.31(m,3H),7.11(s,2H),7.06(d,J＝2.2Hz,1H),6.91(dd,J＝8.3,2.3Hz,1H),6.84(d,J＝8.3Hz,1H),5.41(s,1H),5.11(t,J＝1.6Hz,1H),4.77(s,2H),4.12(s,2H),2.12(s,3H)。

Example 23

2- (3, 5-dichloro-4- ((3 '-formyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methylYl) phenoxy) acetic acid Synthesis of methyl ester (Compound 23)

To intermediate A7(500mg, 1.0mmol), 2-formylphenylboronic acid (225mg, 1.5mmol) and Pd (dppf) Cl₂·CH₂Cl₂(82mg, 100. mu. mol) to a room temperature mixture of 1, 4-dioxane (5.0mL) was added NaHCO₃Aqueous solution (2M, 1.5 mL). The mixture was heated to 70 ℃ overnight. The reaction mixture was cooled to room temperature, quenched with water (10mL), acidified to pH-4-5 with aqueous HCl (1M), and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na ₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 23 as a white solid (130mg, 27% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.3

LCMS:RT＝2.018min；[M-1]＝457.1

¹H NMR:(400MHz,DMSO-d₆)δ10.05(s,1H),9.60(s,1H),8.03(s,1H),7.86–7.75(m,2H),7.63(t,J＝7.6Hz,1H),7.15(s,2H),7.13(s,1H),6.92(s,1H),6.89(s,1H),4.88(s,2H),4.21–4.15(m,2H),4.14(s,2H),1.19(t,J＝7.2Hz,3H)。

Example 24

2- (3, 5-dichloro-4- ((3 '-ethynyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid Synthesis of methyl ester (Compound 24)

To compounds 23(120mg, 261umol) and K₂CO₃(72mg, 523umol) to a mixture of MeOH (1mL) and THF (1mL) was added 1-dimethylphosphonyl-1-diazo-acetone (60mg, 314 umol). The mixture was stirred at room temperature overnight. Water (10mL) was added to the reaction mixture,and the resulting mixture was extracted with EtOAc (5mL x 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (EtOAc/petroleum ether ═ 1/3) to give compound 24(50mg, 42% yield) as a light yellow oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.35

Example 25

2- (3, 5-dichloro-4- ((3 '-ethynyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid (Compound 25) Synthesis

To compound 24(50mg, 110umol) in THF/H₂LiOH. H was added to a room temperature solution of O (1mL/0.5mL)₂O (14mg, 330 umol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (5mL), acidified to pH-4-5 with 1N HCl, and extracted with EtOAc (3mL × 3). The combined organic phases were washed with brine (5mL) and Na ₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC (MeCN/H)₂O) to give compound 25 as a white solid (10mg, 21% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.30

LCMS:RT＝1.691min；[M-1]＝425.0

¹H NMR:(400MHz,DMSO-d₆)δ9.52(s,1H),7.58(d,J＝1.6Hz,1H),7.49(dt,J＝6.4,2.4Hz,1H),7.43–7.38(m,2H),7.12(s,2H),7.07(d,J＝2.4Hz,1H),6.91(dd,J＝8.4,2.4Hz,1H),6.85(d,J＝8.4Hz,1H),4.77(s,2H),4.17(s,1H),4.12(s,2H)。

Example 26

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (2,2, 2-trifluoroethyl) - [1,1' -biphenyl)]-3-yl) methyl) benzene Synthesis of oxy) acetic acid (Compound 26)

Intermediate B3(138mg, 482umol), intermediate A7(150mg, 321umol), NaHCO₃(2M, 0.48mL) and Pd (dppf) Cl₂A mixture of (24mg, 32.1umol) in 1, 4-dioxane (2mL) was stirred at 100 ℃ overnight. Cooling the mixture to room temperature; addition of LiOH₂O (40mg, 963umol), and the resulting mixture was stirred for 1 h. Acidifying the mixture with 1N HCl to pH 5-6; water (30mL) was added and the mixture was extracted with EtOAc (25mL × 2). The combined organic layers were washed with water (25mL), then brine (50mL), and Na₂SO₄Drying and purification by Prep-HPLC gave compound 26 as a white solid (20mg, 13% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝3.884min；[M-1]＝483.0/484.9

¹H NMR:(400MHz,DMSO-d₆)δ13.04(s,1H),9.45(s,1H),7.45(d,J＝10.6Hz,2H),7.38(t,J＝7.6Hz,1H),7.27(d,J＝7.5Hz,1H),7.11(s,2H),7.05(d,J＝2.1Hz,1H),6.90(dd,J＝8.2,2.2Hz,1H),6.84(d,J＝8.3Hz,1H),4.77(s,2H),4.11(s,2H),3.67(q,J＝11.6Hz,2H)。

Example 27

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (perfluoroethyl) - [1,1' -biphenyl)]-3-yl) methyl) phenoxy) Synthesis of methyl acetate (Compound 27)

To intermediate A7(300mg, 0.64mmol), intermediate B4(310mg, 0.96mmol) and NaHCO ₃(2M, 1mL) to a room temperature solution in 1, 4-dioxane (10mL) was added Pd (dppf) Cl₂(66mg, 0.09 mmol). The mixture was refluxed overnight. The mixture was cooled to room temperature, poured into water (10mL) and extracted with EtOAc (10mL × 2). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying and vacuum concentratingAnd purified by Prep-HPLC (MeCN/H)₂O) to give compound 27 as a white solid (30mg, 16% yield).

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.4

¹H NMR:(400MHz,DMSO-d₆)δ9.68(s,1H),7.80(d,J＝7.2Hz,2H),7.67(t,J＝7.8Hz,1H),7.61(d,J＝7.8Hz,1H),7.16(s,2H),7.12(d,J＝2.2Hz,1H),6.95(dd,J＝8.4,2.4Hz,1H),6.87(d,J＝8.4Hz,1H),4.89(s,2H),4.13(s,2H),3.70(s,3H)。

Example 28

2- (3, 5-dichloro-4- ((6-hydroxy-3 '- (perfluoroethyl) - [1,1' -biphenyl)]-3-yl) methyl) phenoxy) Synthesis of acetic acid (Compound 28)

To a solution of compound 27(30mg, 0.05mmol) in THF (5mL) was added LiOH₂O (13mg, 0.30mmol) in water (0.2 mL); the mixture was stirred at room temperature for 2 h. Water (5mL) was added and the reaction was acidified to pH 6-7 with 2N HCl and extracted with EtOAc (10mL × 2). The combined organic phases were washed with brine (20mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-HPLC (MeCN/H)₂O) to give compound 28 as a white solid (25mg, 85% yield).

TLC petroleum ether/EtOAc (v/v) 1/1, Rf 0.1

LCMS:RT＝4.253min；[M-1]＝519

¹H NMR:(400MHz,DMSO-d₆)δ13.08(s,1H),9.66(s,1H),7.82–7.76(m,2H),7.69–7.59(m,2H),7.13(d,J＝2.4Hz,1H),7.12(s,2H),6.95(dd,J＝8.4,2.3Hz,1H),6.88(d,J＝8.4Hz,1H),4.77(s,2H),4.13(s,2H)。

Example 29

2- (3, 5-dichloro-4- ((3 '-chloro-6-hydroxy- [1,1' -biphenyl) ]-3-yl) methyl) phenoxy) acetic acid (compound Synthesis of substance 29)

To a room temperature solution of intermediate A7(150mg, 321umol) in 1, 4-dioxane (3mL) was added Pd (dppf) Cl₂(27mg，32umol)、NaHCO₃(2N, 1mL) and 3-chlorophenylboronic acid (76mg, 482 umol). The mixture was heated to 70 ℃ overnight. The mixture was cooled to room temperature and lioh was added₂O (67mg, 1.6mmol), and the resulting mixture was stirred at room temperature for 1 h. The reaction was diluted with water (5mL), acidified to pH-3 with 1N HCl, and extracted with DCM (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC to give compound 29 as an off-white solid (40mg, 28% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.33

LCMS:RT＝2.319min；[M-1]＝435。

¹H NMR:(400MHz,DMSO-d₆)δ9.61(s,1H),7.53(q,J＝1.3Hz,1H),7.44–7.39(m,2H),7.35(dt,J＝6.5,2.4Hz,1H),7.12(s,2H),7.09(d,J＝2.2Hz,1H),6.92(dd,J＝8.3,2.2Hz,1H),6.86(d,J＝8.3Hz,1H),4.78(s,2H),4.11(s,2H)。

Example 30

2- (3, 5-dichloro-4- ((3 '-chloro-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid methyl ester Synthesis of (Compound 30)

To a room temperature solution of intermediate A7(500mg, 1.07mmol) in 1, 4-dioxane (5mL) was added Pd (dppf) Cl₂(88mg，107umol)、NaHCO₃(2N, 1mL) and 3-chlorophenylboronic acid (251mg, 1.61 mmol). The mixture was heated to 70 ℃ overnight. The mixture was diluted with water (5mL) and acidified to pH with 1N HCl<7, and extracted with DCM (5mL × 3). The combined organic phases were washed with brine (10mL) Over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC to give compound 30 as an off-white solid (200mg, 41% yield).

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.44

¹H NMR:(400MHz,DMSO-d₆)δ9.58(s,1H),7.54–7.52(m,1H),7.41(dd,J＝5.0,1.9Hz,2H),7.37–7.32(m,1H),7.16(s,2H),7.08(d,J＝2.0Hz,1H),6.92(dd,J＝8.3,2.2Hz,1H),6.86(d,J＝8.3Hz,1H),4.89(s,2H),4.12(s,2H),3.70(s,3H)。

Example 31

2- (3, 5-dichloro-4- ((3 '-chloro-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) -N-methylethyl Synthesis of amide (Compound 31)

To a room temperature solution of compound 30(100mg, 221umol) in THF (0.5mL) was added aqueous methylamine (40% wt/wt, 1.5 mL). The mixture was heated to 70 ℃ overnight in a sealed tube, then cooled to room temperature, diluted with water (10mL), and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (MeOH/DCM ═ 1/30) to give compound 31(20mg, 20% yield) as a brown solid.

TLC:DCM/MeOH＝5/1(v/v),Rf＝0.44

LCMS:RT＝4.059；[M-1]＝448。

¹H NMR:(400MHz,DMSO-d₆)δ9.57(s,1H),8.05(s,1H),7.55–7.51(m,1H),7.44–7.39(m,2H),7.35(dt,J＝6.4,2.4Hz,1H),7.15(s,2H),7.08(d,J＝2.2Hz,1H),6.96–6.89(m,1H),6.86(d,J＝8.3Hz,1H),4.54(s,2H),4.12(s,2H),2.65(d,J＝4.6Hz,3H)。

Example 32

2- (3, 5-dichloro-4- ((3 '-chloro-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) -N, N-dimethyl Synthesis of a phenylacetamide (Compound 32)

To an ice-bath cooled solution of compound 29(80mg, 183umol) in DCM (2mL) was added DMF (one drop) and oxalyl chloride (46mg, 366 umol). The mixture was stirred at room temperature for 2h and concentrated in vacuo. The crude product (80mg, 175umol) in DCM (1mL) was added to a stirred solution of methylamine (2mL, 34mmol) in DCM (3mL) in an ice bath. The mixture was allowed to warm to room temperature and stirred for 2h, then concentrated in vacuo. The crude product was purified by Prep-TLC (MeOH/DCM ═ 1/30) to give compound 32 as an off-white solid (50mg, 61% yield).

TLC:DCM/MeOH＝30/1(v/v),Rf＝0.34

LCMS:RT＝4.109；[M-1]＝462。

¹H NMR:(400MHz,DMSO-d₆)δ9.57(s,1H),7.56–7.50(m,1H),7.39-7.45(m,2H),7.32-7.36(m,1H),7.10(s,2H),7.09(d,J＝2.2Hz,1H),6.92(dd,J＝8.4,2.3Hz,1H),6.86(d,J＝8.3Hz,1H),4.90(s,2H),4.11(s,2H),2.96(s,3H),2.84(s,3H)。

Example 33

Synthesis of methyl 2- (3, 5-dichloro-4- (4-hydroxy-3- (thien-2-yl) benzyl) phenoxy) acetate (Compound 33) Become into

To a room temperature solution of intermediate A7(200mg, 0.43mmol) in 1, 4-dioxane (3mL) was added thiophene-2-boronic acid (82mg, 0.64mmol), Pd (dppf) Cl₂(32mg, 0.04mmol) and NaHCO₃(2N) (1.29mmol, 0.6 mL). The mixture was stirred at 85 ℃ overnight. The mixture was diluted with EtOAc (20mL) and filtered. The filtrate was washed with brine (30mL) and Na₂SO₄Drying and concentration in vacuo afforded compound 33(100mg, 55% yield) which was purified without further purificationIt is used after being dissolved.

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.4

LCMS:RT＝4.333min；[M-1]＝421.0

Example 34

Synthesis of 2- (3, 5-dichloro-4- (4-hydroxy-3- (thien-2-yl) benzyl) phenoxy) acetic acid (Compound 34)

To compound 33(100mg, 0.35mmol) in THF (3mL) and H₂To the solution in O (2mL) was added LiOH₂O (44mg, 1.05 mmol). The mixture was stirred at room temperature for 2 h; the pH was adjusted to about 4 with 1N HCl. The aqueous layer was extracted with EtOAc (20mL x 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 34 as a white solid (40mg, 28% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.2

LCMS:RT＝3.857min；[M-1]＝407.0

¹H NMR:(400MHz,DMSO-d₆)δ12.99(s,1H),10.01(s,1H),7.47(d,J＝3.6Hz,1H),7.45(s,1H),7.40(s,1H),7.13(s,2H),7.07(t,J＝4.8Hz,1H),6.85(s,2H),4.78(s,2H),4.11(s,2H)。

Example 35

Methyl 2- (3, 5-dichloro-4- (3- (4-chlorothien-2-yl) -4-hydroxybenzyl) phenoxy) acetate (Compound 35) Synthesis of (2)

To a room temperature solution of intermediate A7(150mg, 0.31mmol) and intermediate B5(152mg, 0.62mmol) in water (1mL) and 1, 4-dioxane (6mL) was added NaHCO₃(52mg, 0.62mmol) and Pd (dppf) Cl₂(11mg, 15.6 umol). The reaction was carried out at 75 deg.CStirring was continued overnight. The mixture was concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 35(30mg, 20% yield) as a pale yellow solid.

TLC EtOAc/petroleum ether 1/5, Rf 0.52

Example 36

Synthesis of 2- (3, 5-dichloro-4- (3- (4-chlorothien-2-yl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 36) Become into

To a room temperature solution of compound 35(100mg, 0.21mmol) in water (2mL)/THF (4mL) was added NaOH (34mg, 0.84 mmol); the resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified to pH-3 with HCl (1N) and extracted with EtOAc (10mL x 3); the combined organic phases are passed over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (methanol/DCM ═ 1/10) to give compound 36(25mg, 26% yield) as a white solid.

TLC EtOAc/petroleum ether 1/5, Rf 0.21

LCMS:RT＝3.92min；[M-1]:＝440.9

¹H NMR:(400MHz,DMSO-d₆)δ10.66(brs,1H),7.51–7.43(m,3H),6.95(s,2H),6.91(d,J＝8.4Hz,1H),6.83(dd,J＝8.4,2.4Hz,1H),4.22(s,2H),4.08(s,2H)。

Example 37

2- (3, 5-dichloro-4- (4-hydroxy-3- (5- (trifluoromethyl) thiophen-2-yl) benzyl) phenoxy) acetic acid (Compound No.) Synthesis of substance 37)

Reacting [5- (trifluoromethyl) thienyl]Borapidate (58mg, 0.21mmol), intermediate A7(100mg, 0.21mmol), Cs₂CO₃(135mg, 0.42mmol) and Pd (dppf) Cl₂(16mg, 0.02mmol) of a mixture in 1, 4-dioxane (3 mL)/water (1mL) in N₂Stirred at 85 ℃ for 16h under an atmosphere. The reaction was acidified to pH-6-7 with 2N HCl, concentrated in vacuo, and purified by Prep-HPLC to give compound 37 as a pale yellow solid (7mg, 5% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

¹H NMR:(400MHz,DMSO)δ10.62(s,1H),7.65(d,J＝4.0Hz,1H),7.60(s,1H),7.56(d,J＝4.1Hz,1H),7.14(s,2H),6.91(d,J＝2.0Hz,2H),4.79(s,2H),4.14(s,2H)。

LCMS:RT＝4.07min；[M-1]＝477。

Example 38

Synthesis of 2- (3, 5-dichloro-4- (3- (furan-2-yl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 38)

To a room temperature solution of intermediate A7(150mg, 321umol) in 1, 4-dioxane (4mL) was added Pd (dppf) Cl₂(27mg，32umol)、NaHCO₃(2M, 0.5mL) and furan-2-boronic acid (54mg, 482 umol). The mixture was heated to 70 ℃ overnight. The mixture was cooled to room temperature and lioh was added₂O (67mg, 1.6mmol), and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5mL), acidified to pH-4-5 with 1N HCl, and extracted with DCM (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC (ACN/water range 30/70 to 85/15) to give compound 38 as an off-white solid (40mg, 31% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.33

LCMS:RT＝3.494min；[M-1]＝391

¹H NMR:(400MHz,DMSO-d₆)δ9.97(s,1H),7.67(dd,J＝1.8,0.8Hz,1H),7.43(d,J＝2.1Hz,1H),7.13(s,2H),6.91(dd,J＝3.3,0.8Hz,1H),6.87(d,J＝2.2Hz,1H),6.84(d,J＝8.3Hz,1H),6.54(dd,J＝3.3,1.8Hz,1H),4.78(s,2H),4.11(s,2H)。

Example 39

Synthesis of methyl 2- (3, 5-dichloro-4- (3- (furan-3-yl) -4-hydroxybenzyl) phenoxy) acetate (Compound 39) Become into

To intermediate A7(200mg, 0.43mmol), furan-3-boronic acid (72mg, 0.64mmol) and NaHCO₃(2M, 0.6mL) to a room temperature solution in 1, 4-dioxane (10mL) was added Pd (dppf) Cl₂(31mg, 0.04 mmol). The mixture was refluxed overnight. The mixture was cooled to room temperature, water (10mL) was added, and the mixture was extracted with EtOAc (10mL × 2). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-HPLC (MeCN/H)₂O) to give compound 39(100mg, 57% yield) as a yellow liquid.

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.4

Example 40

Synthesis of 2- (3, 5-dichloro-4- (3- (furan-3-yl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 40)

To a room temperature solution of compound 39(100mg, 0.24mmol) in THF (5 mL)/water (0.2mL) was added LiOH₂O (30mg, 0.72 mmol); the resulting mixture was stirred at room temperature for 1 h. The reaction was acidified to pH 6-7 with 2N HCl and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC to give compound 40 as a white solid (50mg, 52% yield).

TLC petroleum ether/EtOAc (v/v) 1/1, Rf 0.1

LCMS:RT＝3.579min；[M-1]＝391

¹H NMR:(400MHz,DMSO-d₆)δ13.10(s,1H),9.80(s,1H),8.08(d,J＝1.8Hz,1H),7.68(t,J＝1.7Hz,1H),7.35(d,J＝2.2Hz,1H),7.12(s,2H),6.85–6.78(m,2H),6.74(dd,J＝8.4,2.2Hz,1H),4.78(s,2H),4.11(s,2H)。

EXAMPLE 41

Synthesis of methyl 2- (3, 5-dichloro-4- (4-hydroxy-3- (thien-3-yl) benzyl) phenoxy) acetate (Compound 41) Become into

Thiophene-3-boronic acid (82mg, 642umol), intermediate A7(150mg, 321umol), Pd (dppf) Cl₂(24mg, 32.1umol) and NaHCO₃A solution of (2M, 0.48mL) in 1, 4-dioxane (5mL) was stirred at 85 ℃ overnight. The mixture was concentrated to dryness. Water (30mL) was added and the mixture was extracted with EtOAc (25mL × 2). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried and purified by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 41(80mg, 29% yield, 50% purity) as a yellow solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.42

Example 42

Synthesis of 2- (3, 5-dichloro-4- (4-hydroxy-3- (thien-3-yl) benzyl) phenoxy) acetic acid (Compound 42)

To a solution of compound 41(80mg, 50% purity, 94.4umol) in water (1mL) and MeOH (2mL) was added LiOH₂O (12mg, 283 umol). The mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 5-6 with 1N HCl and extracted with DCM (5 mL). The organic layer was concentrated to dryness and purified by Prep-HPLC to give compound 42 as a white solid (15mg, 38% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝1.728min；[M-1]＝407.0/409.0

¹H NMR:(400MHz,DMSO-d₆)δ13.10(s,1H),9.62(s,1H),7.73(dd,J＝3.0,1.3Hz,1H),7.53(dd,J＝5.0,3.0Hz,1H),7.42(dd,J＝5.0,1.3Hz,1H),7.30(s,1H),7.12(s,2H),6.83(d,J＝1.3Hz,2H),4.77(s,2H),4.11(s,2H)。

Example 43

Synthesis of 2- (3, 5-dichloro-4- (3- (5-chlorothien-3-yl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 43) Become into

Mixing 2-chlorothiophene-4-boronic pinacol ester (50mg, 240umol), intermediate A7(98mg, 240umol), NaHCO₃(2M, 0.36mL) and Pd (dppf) Cl₂A mixture of (15mg, 24.5umol) in 1, 4-dioxane (2mL) was stirred at 100 ℃ overnight. The mixture was cooled to room temperature and lioh was added₂O (25mg, 613umol), and the resulting mixture was stirred for 1 h. The mixture was acidified to pH-5-6 with 1N HCl, water (30mL) was added, and the resulting mixture was extracted with EtOAc (25mL × 2). The combined organic layers were washed with water (25mL x 2), then brine (50mL), over Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 43 as a white solid (35mg, 39% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝2.419min；[M-1]＝440.9/442.9

¹H NMR:(400MHz,DMSO-d₆)δ13.11(s,1H),9.77(s,1H),7.62(d,J＝1.8Hz,1H),7.43(d,J＝1.8Hz,1H),7.30(d,J＝1.7Hz,1H),7.12(s,2H),6.85–6.80(m,2H),4.78(s,2H),4.10(s,2H)。

Example 44

2- (3, 5-dichloro-4- (4-hydroxy-3- (3-methylfuran-2-yl) benzyl) phenoxy) acetic acid(Compound 44) preparation of Synthesis of

To intermediate A7(200mg, 0.43mmol) and intermediate B6(179mg, 0.86mmol) in 1, 4-dioxane/H₂To a solution in O (5/2mL) was added Pd (dppf) Cl₂(16mg, 0.022mmol) and NaHCO ₃(109mg, 1.29 mmol). The reaction was heated to 80 ℃ overnight. Cooling the reaction mixture to room temperature; addition of LiOH₂O (90mg, 2.15mmol), and the resulting mixture was stirred at room temperature for 30 min. Water (10mL) was added, pH was adjusted to pH-3-4 with 1N HCl, and the mixture was extracted with EtOAc (10mL x 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Drying and vacuum concentrating; the residue was purified by Prep-HPLC to give compound 44(10mg) as a pale yellow solid, a minor product of two similar products.

LCMS:RT＝3.795min；[M-1]＝405.1/406.9

¹H NMR:(400MHz,DMSO-d₆)δ12.96(s,1H),9.51(s,1H),7.56(d,J＝1.7Hz,1H),7.11(s,2H),7.03–6.91(m,2H),6.84(d,J＝8.3Hz,1H),6.36(d,J＝1.4Hz,1H),4.77(s,2H),4.09(s,2H),1.94(s,3H)

Example 45

2- (3, 5-dichloro-4- ((2' -fluoro-6-hydroxy-5 ' - (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) methyl) benzene Synthesis of oxy) acetic acid (Compound 45)

To a room temperature solution of intermediate A7(150mg, 321umol) in 1, 4-dioxane (3mL) was added Pd (dppf) Cl₂(27mg，32umol)、NaHCO₃(2M, 0.5mL) and 2-fluoro-5-trifluoromethyl-phenylboronic acid (100mg, 482 umol). The mixture was heated to 70 ℃ overnight. Cooling the mixture to room temperature and addingAddition of LiOH₂O (67mg, 1.6mmol), and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5mL), acidified to pH-4-5 with 1N HCl, and extracted with DCM (5mL × 3). The combined organic phases were washed with brine (10mL) and Na ₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC (ACN/water range 30/70 to 85/15) to give compound 45 as an off-white solid (10mg, 6% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.33

LCMS:RT＝2.291min；[M-1]＝487。

¹H NMR:(400MHz,DMSO-d₆)δ13.09(s,1H),9.66(s,1H),7.77(dt,J＝7.8,3.1Hz,1H),7.72–7.66(m,1H),7.48(t,J＝9.1Hz,1H),7.12(s,2H),7.05(s,1H),6.98(dd,J＝8.4,2.1Hz,1H),6.87(d,J＝8.4Hz,1H),4.77(s,2H),4.11(s,2H)。

Example 46

2- (3, 5-dichloro-4- ((2' -fluoro-6-hydroxy-5 ' - (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) methyl) benzene Synthesis of oxy) -N-methylacetamide (Compound 46)

To compound 45(100mg, 0.2mmol) in DCM (2mL) was added a catalytic amount of DMF (1 drop). The mixture was cooled to 0 ℃ and oxalyl chloride (51mg, 0.4mmol) was added. The mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo to give 2- (3, 5-dichloro-4- ((2' -fluoro-6-hydroxy-5 ' - (trifluoromethyl) - [1,1' -biphenyl) as a pale yellow solid]-3-yl) methyl) phenoxy) acetyl chloride (100mg, 99% yield). TLC MeOH/DCM-1/10 (v/v), R_f＝0.90

To 2- (3, 5-dichloro-4- ((2' -fluoro-6-hydroxy-5 ' - (trifluoromethyl) - [1,1' -biphenyl) in DCM (2mL) at 0 deg.C]-3-yl) methyl) phenoxy) acetyl chloride (50mg, 0.1mmol) MeNH was added dropwise₂(in H)₂40% w/w in O, 2 mL). The reaction was stirred at room temperature for 30 min. Water (10mL) was added and the mixture was extracted with DCM (5mL x 3). MergingThe organic phase of (2) was washed with brine (15mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 46 as a white solid (12mg, 24% yield).

TLC:MeOH/DCM＝1/10(v/v),R_f＝0.60

LCMS:RT＝3.004min；[M-1]＝502.1

¹H NMR:(400MHz,DMSO)δ9.66(s,1H),8.05(s,1H),7.77(s,1H),7.70(d,J＝6.8Hz,1H),7.49(t,J＝9.2,19.2Hz,1H),7.15(s,1H),7.05(s,1H),6.99(d,J＝7.2Hz,1H),6.87(d,J＝8.0Hz,1H),4.54(s,1H),4.12(s,1H),2.65(d,J＝4.8Hz,1H)。

¹⁹F NMR:(376MHz,DMSO)δ-60.31(s),-108.13(s)。

Example 47

2- (3, 5-dichloro-4- ((2' -fluoro-6-hydroxy-5 ' - (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) methyl) benzene Synthesis of oxy) -N, N-dimethylacetamide (Compound 47)

To compound 45(100mg, 0.2mmol) in DCM (2mL) was added a catalytic amount of DMF (1 drop). The mixture was cooled to 0 ℃ and oxalyl chloride (51mg, 0.4mmol) was added. The mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo to give 2- (3, 5-dichloro-4- ((2' -fluoro-6-hydroxy-5 ' - (trifluoromethyl) - [1,1' -biphenyl) as a pale yellow solid]-3-yl) methyl) phenoxy) acetyl chloride (100mg, 99% yield). TLC MeOH/DCM-1/10 (v/v), R_f＝0.90

To 2- (3, 5-dichloro-4- ((2' -fluoro-6-hydroxy-5 ' - (trifluoromethyl) - [1,1' -biphenyl) in DCM (2mL) at 0 deg.C]-3-yl) methyl) phenoxy) acetyl chloride (50mg, 0.1mmol) dimethylamine (2M in THF, 0.15mL) was added dropwise. The mixture was stirred at room temperature for 30 min. Water (10mL) was added and the mixture was extracted with DCM (5mL x 3). The combined organic phases were washed with brine (15mL) and Na₂SO₄Drying, vacuum concentrating, and purifying by Prep-HPLC to obtainTo compound 47 as a white solid (20mg, 39% yield).

TLC:MeOH/DCM＝1/10(v/v),R_f＝0.60

LCMS:T＝3.004min；[M-1]＝502.1

¹H NMR:(400MHz,DMSO)δ9.64(s,1H),7.76(d,J＝3.0Hz,1H),7.70(dd,J＝6.4,2.0Hz,1H),7.49(t,J＝8.8Hz,1H),7.10(s,1H),7.05(s,1H),6.98(dd,J＝8.0,2.4Hz,1H),6.88(d,J＝8.4Hz,1H),4.90(s,1H),4.11(s,1H),2.96(s,1H),2.84(s,1H)。

¹⁹F NMR:(376MHz,DMSO)δ-60.31(s),-108.11(s)。

Example 48

2- (3, 5-dichloro-4- ((4' -fluoro-6-hydroxy-3 ' - (trifluoromethyl) - [1,1' -biphenyl) ]-3-yl) methyl) benzene Synthesis of oxy) acetic acid (Compound 48)

Reacting [3- (trifluoromethyl) -4-fluorophenyl]Boronol ester (140mg, 482umol), intermediate A7(150mg, 321umol), Pd (dppf) Cl₂(24mg, 32umol) and NaHCO₃A solution of (aqueous) (2M, 0.48mL) in 1, 4-dioxane (5mL) was stirred at 85 ℃ overnight. The mixture was cooled to room temperature and lioh was added₂O (23mg, 963umol), and the resulting mixture was stirred for 20 min. The mixture was acidified to pH 5-6 with 1M HCl. Water (30 mL); the mixture was extracted with EtOAc (25mL × 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (DCM/MeOH ═ 10/1) to give compound 48(10mg, 6% yield) as a brown solid.

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.32

LCMS:T＝2.427min；[M-1]:486.8/488.8

¹H NMR:(400MHz,DMSO-d₆)δ13.19(s,1H),9.72(s,1H),7.88-7.85(m,1H),7.84–7.77(m,1H),7.56-7.51(m,1H),7.15(d,J＝2.0Hz,1H),7.10(s,2H),6.95–6.85(m,2H),4.73(s,2H),4.12(s,2H)。

Example 49

2- (3, 5-dichloro-4- ((2' -fluoro-6-hydroxy-3 ' - (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) methyl) benzene Synthesis of oxy) acetic acid (Compound 49)

To intermediate A7(150mg, 321umol), [3- (trifluoromethyl) -2-fluorophenyl]Boric acid (100mg, 482umol) and Pd (dppf) Cl₂·CH₂Cl₂(26mg, 32umol) to a room temperature mixture in 1, 4-dioxane (5.0mL) was added NaHCO₃Aqueous solution (2M, 0.5 mL). The mixture was heated to 70 ℃ and stirred overnight. Cooling the reaction mixture to room temperature; addition of LiOH. H ₂O (55mg, 1.3mmol), and the resulting mixture was stirred for 30 min. The reaction was quenched with water (10mL), acidified to pH-4-5 with aqueous HCl (1N), and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-HPLC (MeCN/H)₂O) to give compound 49 as a white solid (10mg, 6% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.3

LCMS:RT＝4.534min；[M-1]＝487.8

¹H NMR:(400MHz,DMSO-d₆)δ9.66(s,1H),7.74(t,J＝6.8Hz,1H),7.65(t,J＝6.4Hz,1H),7.43(t,J＝8.0Hz,1H),7.10(s,2H),7.04–6.95(m,2H),6.87(d,J＝8.0Hz,1H),4.72(s,2H),4.11(s,2H)。

¹⁹F NMR:(376MHz,DMSO-d₆)δ-59.85,-59.89,-116.66,-116.70,-116.73,-116.76。

Example 50

2- (3, 5-dichloro-4- ((3' -fluoro-6-hydroxy-5 ' - (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) methyl) benzene Synthesis of oxy) acetic acid (Compound 50)

To 3-fluoro-5-trifluoromethylphenylboronic acid (100mg, 0.48mmol), intermediate A7(150mg, 0.32mmol) and NaHCO₃(0.7mL, 1.44mmol) to a room temperature solution in 1, 4-dioxane (5mL) was added Pd (dppf) Cl₂(16mg, 0.03 mmol); the mixture was refluxed overnight. The reaction was cooled to room temperature; addition of LiOH₂O (61mg, 1.44mmol), and the resulting mixture was stirred at room temperature for 30 min. Water (10mL) was added and the mixture was extracted with ether (10mL x 2). The aqueous phase was adjusted to pH-3 with HCl (2N) and then re-extracted with EtOAc (10mL × 2). The combined EtOAc extracts were washed with brine (10mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-HPLC (MeCN/H)₂O) purification to afford compound 50 as a white solid (4mg, 4% yield).

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.1

LCMS:RT＝4.156min；[M-1]＝487

¹H NMR:(400MHz,DMSO-d₆)δ13.10(s,1H),9.81(s,1H),7.70(s,1H),7.65(d,J＝9.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.24(d,J＝2.0Hz,1H),7.12(s,2H),6.94–6.87(m,2H),4.77(s,2H),4.13(s,2H)。

Example 51

2- (3, 5-dichloro-4- ((5' -ethyl-2 ' -fluoro-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) Synthesis of acetic acid (Compound 51)

To intermediate A7(100mg, 0.21mmol), 2-fluoro-5-ethylphenylboronic acid (80mg, 0.32mmol) and NaHCO₃(0.3mL, 0.63mmol) in 1, 4-dioxane (5mL) was added Pd (dppf) Cl₂(16mg, 0.02 mmol); the mixture was refluxed overnight. The reaction was cooled to room temperature; addition of LiOH₂O(27mg，0.63mmol), and the resulting mixture is stirred for 30 min. Water (10mL) was added and the mixture was extracted with ether (10mL x 2). The aqueous phase was adjusted to pH-3 with HCl (2N) and then re-extracted with EtOAc (10mL × 2). The combined EtOAc extracts were washed with brine (10mL) and Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-HPLC (MeCN/H)₂O) to give compound 51 as a white solid (4mg, 4% yield).

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.1

LCMS:RT＝4.011min；[M-1]＝417

¹H NMR:(400MHz,DMSO-d₆)δ13.11(s,1H),9.40(s,1H),7.17(dd,J＝8.4,4.8Hz,1H),7.11(s,3H),7.08(d,J＝8.6Hz,1H),6.93(d,J＝10.0Hz,2H),6.82(d,J＝8.2Hz,1H),4.77(s,2H),4.10(s,2H),2.60(q,J＝7.6Hz,2H),1.17(t,J＝7.6Hz,3H)。

Example 52

2- (3, 5-dichloro-4- ((5' - (difluoromethoxy) -2' -fluoro-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl group) Synthesis of phenoxy) acetic acid (Compound 52)

To intermediate B8(470mg, 1.6mmol), intermediate A7(150mg, 0.32mmol) and Pd (dppf) Cl₂·CH₂Cl₂(13mg, 0.016mmol) in 1, 4-dioxane (5mL) and H ₂NaHCO was added to the room temperature mixture in O (0.5mL)₃(0.96mmol, 0.48 mL). In N₂The reaction was heated to 80 ℃ overnight (under gas). The reaction mixture was cooled to room temperature. Addition of LiOH. H₂O (25mg, 0.6mmol), and the resulting mixture was stirred for 30 min. Water (20mL) was added and the mixture was extracted with EtOAc (10mL x 3), and the combined organic phases were washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC to give compound 52 as a white solid (20mg, 12% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.2

LCMS:RT＝3.779min；[M-1]＝485.0

¹H NMR:(400MHz,DMSO-d₆)δ13.09(s,1H),9.58(s,1H),7.29(t,J＝9.2Hz,1H),7.16(ddd,J＝11.6,6.0,3.6Hz,2H),6.98(dd,J＝12.0,3.6Hz,2H),6.86(d,J＝8.2Hz,1H),4.76(s,2H),4.11(s,2H)。

¹⁹F NMR:(376MHz,DMSO-d₆)δ-81.96,-118.49。

Example 53

2- (3, 5-dichloro-4- ((3' - (difluoromethoxy) -5' -fluoro-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl group) Synthesis of phenoxy) methyl acetate (Compound 53)

Intermediate B9(144mg, 0.50mmol), intermediate A7(155mg, 0.33mmol), 2N NaHCO₃(0.5mL, 1.0mmol) and Pd (dppf) Cl₂(17mg, 0.02mmol) of a mixture in 1, 4-dioxane (5mL) in N₂Stirred at 85 ℃ for 16h under an atmosphere. The reaction mixture was concentrated in vacuo and compound 53 was used in the next step without further purification.

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.4

LCMS:RT＝2.87min；[M-1]＝499.0。

Example 54

2- (3, 5-dichloro-4- ((3' - (difluoromethoxy) -5' -fluoro-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl group) Synthesis of phenoxy) acetic acid (Compound 54)

To a room temperature solution of compound 53(165mg, 0.33mmol) in THF (1 mL)/water (5mL) was added LiOH (155mg, 1.0 mmol); the resulting mixture was stirred at 50 ℃ for 1 h. The reaction was acidified to pH 6-7 with 2N HCl, concentrated in vacuo, and purified by Prep-HPLC to give compound 54(45mg, 57% yield).

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.4

LCMS:RT＝2.09min；[M-1]＝485。

¹H NMR:(400MHz,DMSO)δ13.10(s,1H),9.71(s,1H),7.50(s,0.24H),7.32(s,0.52H),7.22(M,1H),7.16(t,J＝2.2Hz,2H),7.14(s,0.33H),7.12(s,2H),7.06(m,1H),6.92(m,1H),6.86(d,J＝8.4Hz,1H),4.77(s,2H),4.12(s,2H)。

Example 55

2- (3, 5-dichloro-4- ((3' - (difluoromethoxy) -4' -fluoro-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl group) Synthesis of phenoxy) acetic acid (Compound 55)

Compound A7(138mg, 0.48mmol), intermediate B10(150mg, 0.32mmol), Pd (dppf) Cl₂(22mg, 0.03mmol) and NaHCO₃(2N) (0.96mmol, 0.48mL) mixture in 1, 4-dioxane (4mL) in N₂Stirring was continued overnight at 85 ℃. The mixture was cooled to room temperature and lioh was added₂O (67mg, 1.6mmol), and the resulting mixture was stirred at room temperature for 30 min. The mixture was adjusted to pH 4 with 1N HCl. The aqueous layer was extracted with EtOAc (20mL x 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 55 as a white solid (8mg, 5% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.2

LCMS:RT＝3.885min；[M-1]＝485.0

¹H NMR:(400MHz,DMSO-d₆)δ13.08(s,1H),9.62(s,1H),7.51-7.49(dd,J₁＝8.0Hz,J₂＝7.2Hz,1H),7.45-7.42(dd,J₁＝8.0Hz,J₂＝12Hz,1H),7.40-7.38(dd,J₁＝3.2Hz,J₂＝5.2Hz,1H),7.27(t,J＝73.6Hz,1H),7.27(s,1H),7.13(s,2H),7.10(d,J＝2.0Hz,1H),6.93-6.91(dd,J₁＝8.0Hz,J₂＝8.4Hz,1H),6.86(d,J＝8.4Hz,1H),4.78(s,2H),4.12(s,2H)。

Example 56

2- (3, 5-dichloro-4- ((3' - (difluoromethoxy) -2' -fluoro-6-hydroxy- [1,1' -biphenyl) ]-3-yl) methyl group) Synthesis of phenoxy) acetic acid (Compound 56)

To intermediate B12(470mg, 1.6mmol), intermediate A7 and Pd (dppf) Cl₂·CH₂Cl₂(150mg, 321.14umol) in 1, 4-dioxane (5mL) and H₂NaHCO was added to the room temperature mixture in O (0.5mL)₃Aqueous solution (2M, 0.48 mL). Will react in N₂Heat to 80 ℃ overnight (under gas). The reaction mixture was cooled to room temperature. Addition of LiOH. H₂O (55mg, 1.3mmol), and the resulting mixture was stirred for 30 min. The mixture was adjusted to pH-4 with 1N HCl and the resulting mixture was extracted with EtOAc (10mL x 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC to give compound 56 as a white solid (30mg, 19% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.2

LCMS:RT＝3.835min；[M-1]＝485.0

¹H NMR:(400MHz,DMSO-d₆)δ13.09(s,1H),9.55(s,1H),7.31(t,J＝8.0Hz,1H),7.25(t,J＝73.2Hz,1H),7.25–7.16(m,2H),7.11(s,2H),6.99(m,2H),6.86(d,J＝8.2Hz,1H),4.77(s,2H),4.11(s,2H)。

¹⁹F NMR:(376MHz,DMSO-d₆)δ-81.95,-132.15。

Example 57

2- (3, 5-dichloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy Yl) Synthesis of methyl acetate (Compound 57)

Intermediate C1(750mg, 3.17mmol), intermediate A10(300mg, 1.06mmol) and ZnCl₂A solution of (2.65mmol, 2.6mL) in DCE (10mL) was stirred at 85 deg.C overnight. The mixture was concentrated to dryness and purified by silica gel column chromatography (petroleum ether/EtOAc 20/1 to 5/1, v/v) to give compound 57 as a white solid (180mg, 35% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.45

Example 58

2- (3, 5-dichloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy Synthesis of yl) -N-methylacetamide (Compound 58)

A solution of compound 57(200mg, 414umol) and methylamine (321mg, 4.14mmol, 40% in water) in THF (2mL) was stirred in a tube at 70 ℃ overnight. The mixture was concentrated and purified by Prep-HPLC to give compound 58(50mg, 25% yield) as a white solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.35

LCMS:RT＝3.894min；[M-1]＝479.8/481.9

¹H NMR:(400MHz,DMSO-d₆)δ9.09(s,1H),7.28(d,J＝2.8Hz,1H),7.17(d,J＝2.4Hz,1H),6.96(s,1H),6.68–6.61(m,2H),4.88(s,2H),4.17(q,J＝7.2Hz,2H),4.08(s,2H),3.16-3.09(m,1H),1.20(t,J＝7.2Hz,3H),1.10(d,J＝6.8Hz,6H)。

Example 59

2- (3-chloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylphenoxy) acetic acid Synthesis of methyl ester (Compound 59)

To a room temperature solution of intermediate A15(135mg, 0.69mmol) in DCE (5mL) was added intermediate C2(60mg, 0.23mmol) and ZnCl₂THF (1M) (0.57mL, 0.58 mmol). The resulting mixture was stirred at 80 ℃ overnight. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 5/1, v/v) to give compound 59(80mg, 83% yield) as a yellow oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.4

¹H NMR:(400MHz,DMSO)δ9.29(s,1H),7.27(m,3H),7.11(d,J＝6.9Hz,1H),6.94(m,2H),6.81(m,3H),4.81(s,2H),4.00(s,2H),3.69(s,3H),2.61(m,2H),2.23(s,3H),1.16(m,3H)。

Example 60

2- (3-chloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylphenoxy) acetic acid

Synthesis of (Compound 60)

To a room temperature solution of compound 59(80mg, 0.19mmol) in water (5mL)/THF (1mL) was added LiOH (23mg, 0.57 mmol); the resulting mixture was stirred at room temperature for 1 h. The reaction was acidified to pH 6-7 with 2N HCl and then extracted with DCM (30mL × 3). The combined organic phases were washed with brine (50mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 60(20mg, 25% yield) as a pale yellow solid.

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.0

LCMS:RT＝4.09min；[M+1]＝410.13。

¹H NMR:(400MHz,DMSO)δ13.02(s,1H),9.29(s,1H),7.31–7.22(m,3H),7.11(m,1H),6.95(d,J＝2.1Hz,1H),6.89(m,1H),6.84–6.76(m,3H),4.67(s,2H),4.00(s,2H),2.62(m,2H),2.22(s,3H),1.19(t,J＝7.6Hz,3H)。

Example 61

2- (3-chloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylbenzene Synthesis of oxy) methyl acetate (Compound 61)

Intermediate C1(162mg, 0.68mmol), intermediate A15(60mg, 0.23mmol) and ZnCl₂A solution of (1M, 0.57mL) in DCE (2mL) was stirred at 85 ℃ overnight. The mixture was concentrated to dryness and purified by silica gel column chromatography (petroleum ether/EtOAc. 5/1, v/v) to give compound 61 as a white solid (50mg, 47% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.39

Example 62

2- (3-chloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylbenzene Synthesis of oxy) acetic acid (Compound 62)

To a solution of compound 61(40mg, 86.4umol) in water (1mL) and MeOH (2mL) was added LiOH₂O (6mg, 0.26 mmol). The mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 5-6 with 1N HCl (20mL) and extracted with DCM (20 mL). The organic phase was concentrated to dryness and purified by Prep-HPLC and Prep-TLC (DCM/MeOH ═ 5/1) to give compound 62 as a white solid (5mg, 12% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝3.829min；[M-1]＝446.9

¹H NMR:(400MHz,DMSO-d₆)δ13.19(s,1H),9.57(s,1H),7.43(t,J＝8.0Hz,1H),7.34–7.27(m,2H),7.24(t,J＝74.4Hz,1H),7.10–7.05(m,1H),7.01(d,J＝2.0Hz,1H),6.89–6.75(m,4H),4.60(s,2H),4.00(s,2H),2.22(s,3H)。

Example 63

2- (3-chloro-4- ((6-hydroxy-3 '- (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) methyl) -5-methylphenoxy Yl) Synthesis of methyl acetate (Compound 63)

Intermediate A15(70mg, 266umol), intermediate C3(190mg, 800umol) and ZnCl₂A solution of (1M, 0.65mL) in DCE (2mL) was stirred at 85 ℃ overnight. The mixture was concentrated to dryness and then purified by silica gel column chromatography (petroleum ether/EtOAc: 5/1, v/v) to give intermediate 63 as a white solid (50mg, 40% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.4

¹H NMR:(400MHz,DMSO-d₆)δ9.61(s,1H),7.82(s,1H),7.75(s,1H),7.64(d,J＝1.2Hz,2H),7.06(d,J＝2.0Hz,1H),6.94(d,J＝2.4Hz,1H),6.86–6.82(m,3H),4.81(s,2H),4.03(s,2H),3.70(s,3H),2.23(s,3H)。

Example 64

2- (3-chloro-4- ((6-hydroxy-3 '- (trifluoromethyl) - [1,1' -biphenyl)]-3-yl) methyl) -5-methylphenoxy Synthesis of Yl) acetic acid (Compound 64)

To compound 63(50mg, 107umol) in H₂To a solution of O (1mL) and MeOH (2mL) was added NaOH (13mg, 323 umol). The mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 5-6 with 1N HCl (20mL) and extracted with DCM (20 mL). The organic layer was concentrated to dryness and then purified by Prep-HPLC to give compound 64 as a white solid (15mg, 31% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝4.053min；[M-1]＝448.9

¹H NMR:(400MHz,DMSO-d₆)δ13.04(s,1H),9.60(s,1H),7.83(s,1H),7.78–7.71(m,1H),7.67–7.57(m,2H),7.07(d,J＝2.0Hz,1H),6.93–6.76(m,4H),4.68(s,2H),4.02(s,2H),2.23(s,3H)。

Example 65

2- (3-bromo-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylbenzene Synthesis of oxy) Ethyl acetate (Compound 65)

To a room temperature solution of intermediate C1(1.7g, 7.47mmol) in DCE (5mL) was added intermediate A18(800mg, 2.49mmol) and 1M ZnCl₂(6.22mL, 6.22 mmol). The resulting mixture was stirred at 85 ℃ overnight. The mixture was poured into water (20mL) and extracted with DCM (30mL × 3). The combined organic phases are passed over Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc-10/1, v/v) to give compound 65 as a yellow oil (1.1g, 84% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.4

¹H NMR:(400MHz,DMSO-d₆)δ9.51(s,1H),7.46–7.38(m,1.44H),7.36–7.27(m,2H),7.24(s,0.54H),7.12–7.04(m,3H),6.99(m,1H),6.88–6.80(m,4H),4.79(s,2H),4.16(m,2H),4.05(m,2H),2.23(s,3H),1.19–1.15(m,3H)。

Example 66

2- (3-bromo-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylbenzene Synthesis of oxy) acetic acid (Compound 66)

To a room temperature solution of compound 65(1.2g, 2.30mmol) in water (10mL)/THF (5mL) was added LiOH₂O (278mg, 6.90 mmol); the resulting mixture was stirred at room temperature for 1 h. The reaction was acidified to pH-3-4 with 2N HCl, concentrated in vacuo, and purified by reverse phase column chromatography to give compound 66(731mg, 67% yield).

TLC, petroleum ether/EtOAc (1/5 (v/v)), Rf (0)

LCMS:RT:3.91min；[M-1]＝491.0

¹H NMR:(400MHz,DMSO-d₆)δ9.51(s,1H),7.45–7.39(m,1.25H),7.36–7.28(m,2H),7.23(s,0.48H),7.10(m,1H),7.06–7.03(m,1H),7.01(m,1H),6.83(m,3H),4.68(s,2H),4.05(s,2H),2.23(s,3H)。

Example 67

2- (3-bromo-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylbenzene Synthesis of oxy) -N-methylacetamide (Compound 67)

To a solution of compound 66(80mg, 0.16mmol) in DCM (15mL) was added oxalyl chloride (62mg, 0.48mmol) and DMF (cat.). After stirring at room temperature for 1h, the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (5mL) and methylamine/THF (1M, 1.6mL) was added. After stirring at room temperature for 2h, the mixture was poured into water (20mL) and extracted with DCM (30mL × 3). The combined organic phases were washed with brine (30mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-TLC afforded compound 67 as a white solid (53mg, 64% yield).

TLC EtOAc/petroleum ether 1/1(v/v) and Rf 0.3

LCMS:RT＝3.86min；[M-1]＝504.0

¹H NMR:(400MHz,DMSO)δ9.51(s,1H),8.02(d,J＝5.1Hz,1H),7.43(m,1H),7.35–7.27(m,2H),7.24(s,0.54H),7.13–7.04(m,2.47H),7.02–6.98(m,1H),6.86(m,3H),4.46(s,2H),4.05(s,2H),2.65(d,J＝4.6Hz,3H),2.23(s,3H)。

Example 68

2- (3-bromo-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylbenzene Synthesis of oxy) -1- (pyrrolidin-1-yl) ethan-1-one (Compound 68)

To a solution of compound 66(80mg, 0.16mmol) in DCM (10mL) was added oxalyl chloride (62mg, 0.48mmol) and DMF (cat.). After stirring at room temperature for 1h, the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (5mL) and the solution was added dropwise to Na ₂CO₃(52mg, 0.48mmol) and pyrrolidine (11mg, 0.16mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1h, then poured into water (20mL) and extracted with DCM (10mL × 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (petroleum ether/EtOAc ═ 1:1) to give compound 68(60mg, 67% yield) as a white solid.

TLC EtOAc/petroleum ether 1/1(v/v) and Rf 0.2

LCMS:RT＝4.08min；[M-1]＝544.1

¹H NMR:(400MHz,DMSO)δ9.51(s,1H),7.42(m,1.34H),7.36–7.27(m,2.27H),7.24(s,0.24H),7.11–7.04(m,2H),7.00(s,1H),6.83(s,3H),4.72(s,2H),4.04(s,2H),3.48–3.40(m,2H),3.29(s,1H),2.22(s,3H),1.94–1.83(m,2H),1.81–1.72(m,2H)。

Example 69

Process for preparing methyl 2- (3, 5-dichloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) phenoxy) acetate (compound 69)Synthesis of

To a room temperature solution of intermediate A6(300mg, 0.88mmol) in 1, 2-dichloroethane (5mL) was added ZnCl₂(1N/hexane) (1.76mmol, 1.8mL) and 4-fluorobenzyl chloride (166mg, 0.88 mmol). The reaction was heated to 90 ℃ overnight. The reaction mixture was cooled to room temperature, quenched with water (20mL), and extracted with DCM (20mL × 2). The combined organic phases were washed with water (2 x 10mL) and brine (2 x 10mL) and washed with Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (petroleum ether/EtOAc ═ 3/1) to give compound 69(60mg, 0.15mmol, 43% yield) as a brown liquid.

TLC petroleum ether/EtOAc (v/v) 1/3, Rf 0.5

Example 70

Synthesis of 2- (3, 5-dichloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 70)

To a solution of compound 69(100mg, 0.22mmol) in THF (5mL) was added LiOH₂O (46mg, 1.1mmol) in water (1 mL). The reaction was stirred at room temperature for 1 h. Water (10mL) was added and the pH adjusted to pH 6 with HCl (1N). The mixture was extracted with EtOAc (10mL x 2); the combined organic phases were washed with brine (10mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by preparative-HPLC (ACN/water range 15/85 to 75/25) to give compound 70 as a grey solid (25mg, 0.057mmol, 26% yield).

TLC petroleum ether/EtOAc (v/v) 1/1, Rf 0.1

¹H NMR:(400MHz,DMSO-d₆)δ9.36(s,1H),7.18(dd,J＝8.5,5.6Hz,2H),7.05(t,J＝8.9Hz,2H),7.00(s,2H),6.85(s,1H),6.72(s,2H),4.51(s,2H),3.98(s,2H),3.78(s,2H)。

Example 71

2- (3, 5-dichloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) phenoxy) -N-methylacetamide (Compound 71) Synthesis of (2)

To a room temperature solution of compound 69(100mg, 223umol) in THF (5mL) was added methylamine (in H)₂40% in O) (8 mL). The mixture was stirred in a sealed tube at 65 ℃ overnight. The mixture was diluted with water (10mL) and extracted with EtOAc (5mL x 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (petroleum ether/EtOAc ═ 1/1) to give compound 71 as an off-white solid (80mg, 80% yield).

TLC EtOAc/Petroleum Ether 1/1(v/v), R_f＝0.39

LCMS:RT＝2.039min；[M-1]＝446。

¹H NMR:(400MHz,DMSO-d₆)δ9.27(s,1H),8.06(d,J＝5.3Hz,1H),7.21–7.15(m,2H),7.11(s,2H),7.05(m,2H),6.85(d,J＝2.1Hz,1H),6.73(dd,J＝8.3,2.2Hz,1H),6.68(d,J＝8.2Hz,1H),4.53(s,2H),4.00(s,2H),3.78(s,2H),2.65(d,J＝4.6Hz,3H)。

Example 72

Methyl 2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) acetate (compound 72) Synthesis of (2)

To a room temperature solution of intermediate D1(2.6g, 7.62mmol) in DCE (50mL) was added intermediate A6(806mg, 5.08mmol) and ZnCl₂(10mL, 10.2 mmol). The reaction was heated to 85 ℃ and stirred overnight. The reaction mixture was cooled to room temperature, diluted with DCM (20mL), washed with brine (2 x 10mL) and filtered over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1/10) to give compound 72(1.2g, 50% yield) as a colorless oil.

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.55

LCMS:RT＝4.47min；[M-1]＝462.1

¹H NMR:(400MHz,DMSO-d₆)δ9.24(s,1H),7.21-7.19(m,2H),7.12(s,2H),7.05(t,J＝8.8Hz,2H),6.96(d,J＝2.2Hz,1H),6.70(dd,J＝2.4,8.4Hz,1H),6.65(d,J＝8.2Hz,1H),4.89(s,2H),4.37-4.39(m,1H),4.02(d,J＝3.2Hz,2H),3.70(s,3H),1.44(d,J＝7.2Hz,3H)。

Example 73

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 73) Synthesis of (2)

To compound 72(100mg, 0.22mmol) in THF/H₂To a room temperature solution in O (4/1mL) was added NaOH (17.2mg, 432 umol). The mixture was stirred for 4h, then diluted with water (15 mL). 1N HCl was added to adjust to pH 3-4. The mixture was extracted with EtOAc (10mL x 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Drying and concentration in vacuo afforded compound 73(20mg, 45umol, 20.6% yield) as a white solid.

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.21

¹H NMR:(400MHz,DMSO-d₆)δ13.10(s,1H),9.21(s,1H),7.21-7.19(m,2H),7.08(s,2H),7.07–7.02(m,2H),6.96(d,J＝2.2Hz,1H),6.70(dd,J＝2.2,8.2Hz,1H),6.64(d,J＝8.2Hz,1H),4.76(s,2H),4.37-4.39(m,1H),4.01(d,J＝3.4Hz,2H),1.44(d,J＝7.2Hz,3H)。

Example 74

(S) -2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound) 74) Synthesis of (2)

To a room temperature solution of compound 72(1.2g, 2.58mmol) in THF (3 mL)/water (20mL) was added LiOH₂O (326mg, 7.74 mmol). The mixture was stirred at room temperature for 1 h. The reaction was acidified to pH-3-4 with 2N HCl and concentrated in vacuo to afford crude compound 73. Compound 73 was purified by chiral HPLC (chiral HPLC preparative conditions: column: SuperchiralS-AD (Chiralway Biotech)21X250 mm, 5 μm, temperature: 35 ℃, wavelength: 220nm, mobile phase: isocratic hexane/EtOH/formic acid 70:30:0.05, flow rate: 15 ml/min; chiral HPLC analytical conditions: SuperchiralS-AD (Chiralway Biotech)4.6X150 mm, 5 μm, temperature: 35 ℃, wavelength: 220nm, mobile phase: isocratic hexane/EtOH/formic acid 70:30:0.05, flow rate: 0.9ml/min) to give compound 73 as an early elution peak (analytical chiral peak 1 retention time: 3.4min,>98% ee) of compound 74(380mg, 32% yield).

Example 75

(R) -2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) acetic acid (compound) 75) Synthesis of (2)

Compound 75(380mg, 32% yield) was isolated from the above chiral HPLC purification of compound 73 as a late eluting peak (analytical chiral HPLC peak 2 retention time: 5.2min, > 98% ee).

Example 76

(R) -methyl 2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) acetate Synthesis of Compound 76)

To a room temperature solution of compound 75(100mg, 0.22mmol) in MeOH (5mL) was added thionyl chloride (52mg, 0.44 mmol); the mixture was stirred at 80 ℃ for 1 h. The reaction was concentrated in vacuo to afford compound 76(101mg, 100% yield).

TLC petroleum ether/EtOAc (v/v) 1/1, Rf 0.1

LCMS:RT＝3.01min；[M-1]＝461.0

Example 77

(R) -2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) -N-methylacetoacetyl Synthesis of amine (Compound 77)

To a room temperature solution of compound 76(103mg, 0.23mmol) in THF (1mL) was added aqueous methylamine (1M, 4.45 mL). The resulting mixture was stirred at 75 ℃ for 16 h. The reaction was concentrated and purified by silica gel column chromatography (petroleum ether/EtOAc ═ 2/1) to give compound 77(60mg, 57% yield).

TLC petroleum ether/EtOAc (v/v) 1/1, Rf 0.2

LCMS:(RT＝2.23min；[M-1]＝459.9)

¹H NMR:(400MHz,DMSO)δ9.22(s,1H),8.05(d,J＝5.1Hz,1H),7.22–7.16(m,2H),7.12(s,2H),7.09–7.02(m,2H),6.96(d,J＝2.2Hz,1H),6.71(m,1H),6.64(d,J＝8.2Hz,1H),4.53(s,2H),4.38(m,1H),4.07–3.96(m,2H),2.65(d,J＝4.7Hz,3H),1.45(d,J＝7.3Hz,3H)。

Example 78

(R) -2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) -N, N-dimethyl Synthesis of acetamide (Compound 78)

To a room temperature solution of compound 76(103mg, 0.23mmol) in THF (5mL) was added dimethylamine/THF (1M, 3.58 mL). The resulting mixture was stirred at 75 ℃ for 16 h. The reaction was concentrated and purified by Prep-TLC (petroleum ether/EtOAc ═ 1/1) to give compound 78(4mg, 4% yield).

TLC petroleum ether/EtOAc (v/v) 1/1, Rf 0.2

LCMS:RT＝2.45min；[M-1]＝474.0)

¹H NMR:(400MHz,DMSO)δ9.21(s,1H),7.23–7.15(m,2H),7.05(m,4H),6.97(d,J＝2.2Hz,1H),6.71(m,1H),6.64(d,J＝8.2Hz,1H),4.90(s,2H),4.38(d,J＝7.2Hz,1H),4.01(d,J＝3.8Hz,2H),2.97(s,3H),2.84(s,3H),1.45(d,J＝7.3Hz,3H)。

Example 79

Process for preparing methyl 2- (3, 5-dichloro-4- (3- (4-cyanobenzyl) -4-hydroxybenzyl) phenoxy) acetate (compound 79) Synthesis of

To a solution of intermediate C5(443mg, 2.2mmol) and intermediate A6(200mg, 0.71mmol) in DCE (6mL) was added ZnCl₂(1M in THF) (1.8 mmol). The mixture was stirred at 85 ℃ for 3 h. Water (5mL) was added and the resulting mixture was extracted with DCM (3mL x 3). The combined organic phases were washed with brine, over Na₂SO₄Dried, concentrated in vacuo, and purified by Prep-TLC (petroleum ether/EtOAc ═ 3/1). The product was washed with MeOH to give compound 79 as a white solid (70mg, 22% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.2

¹H NMR:(400MHz,DMSO-d₆)δ9.35(s,1H),7.71(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.13(s,2H),6.89(s,1H),6.76(dd,J＝8.4,2.0Hz,1H),6.70(d,J＝8.3Hz,1H),4.89(s,2H),4.01(s,2H),3.89(s,2H),3.70(s,3H)。

Example 80

Synthesis of 2- (3, 5-dichloro-4- (3- (4-cyanobenzyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 80)

To compound 79(70mg, 153umol) in THF/H₂LiOH (20mg, 461umol) was added to a room temperature solution in O (2mL/0.5 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (5mL), acidified to pH-5-6 with 1N HCl, and extracted with EtOAc (3mL × 3). The combined organic phases were washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (DCM/MeOH ═ 10/1) to give compound 80 as a white solid (60mg, 89% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.25

LCMS:RT＝3.86min；[M-1]＝439.8

¹H NMR:(400MHz,DMSO)δ9.36(s,1H),7.71(d,J＝8.2Hz,1H),7.35(d,J＝8.0Hz,1H),7.06(s,1H),6.90(s,1H),6.79–6.74(m,1H),6.70(d,J＝8.2Hz,1H),4.70(s,1H),4.01(s,1H),3.89(s,1H)。

Example 81

Methyl 2- (3, 5-dichloro-4- (4-hydroxy-3- (pyridin-4-ylmethyl) benzyl) phenoxy) acetate (Compound 81) Synthesis of (2)

To a room temperature solution of intermediate C7(200mg, 0.74mmol) and intermediate A10(411mg, 2.22mmol) in DCE (8mL) was added ZnCl₂(1.9mL, 1.85 mmol). The mixture was heated to 85 ℃ overnight. The reaction mixture was cooled to room temperature and DCM (10mL) was added. The mixture was washed with water (2 x 10mL) and brine (2 x 10mL), over Na₂SO₄Dried and concentrated in vacuo. The residue was washed with MeOH to give compound 81 as a white solid (40mg, 12% yield).

TLC:MeOH/DCM＝1/15(v/v),Rf＝0.6

¹H NMR:(400MHz,DMSO-d₆)δ9.34(s,1H),8.40(d,J＝5.4Hz,2H),7.15(d,J＝5.4Hz,2H),7.13(s,2H),6.90(d,J＝2.2Hz,1H),6.77(d,J＝8.4Hz,1H),6.71(d,J＝8.2Hz,1H),4.89(s,2H),4.02(s,2H),3.82(s,2H),3.70(s,3H)。

Example 82

Synthesis of 2- (3, 5-dichloro-4- (4-hydroxy-3- (pyridin-4-ylmethyl) benzyl) phenoxy) acetic acid (Compound 82) Become into

To compound 81(40mg, 0.09mmol) in THF (5mL) and H₂To a solution in O (0.5mL) was added LiOH₂O (12mg, 0.27 mmol). The mixture was stirred at room temperature for 1 h; water (5mL) was added, the mixture was adjusted to pH-5-6 with HCl (1N) and extracted with EtOAc (10mL × 2). The combined organic phases were washed with brine (20mL) and Na₂SO₄Drying and concentration in vacuo afforded compound 82(30mg, 77% yield) as a white solid.

TLC:MeOH/DCM＝1/15(v/v),Rf＝0.1

LCMS:RT＝2.518min；[M-1]＝416

¹H NMR:(400MHz,DMSO-d₆)δ9.40(s,1H),8.46(d,J＝5.0Hz,2H),7.24(s,2H),7.09(s,2H),6.92(s,1H),6.79–6.70(m,2H),4.77(s,2H),4.02(s,2H),3.86(s,2H)。

Example 83

Synthesis of methyl 2- (3, 5-dichloro-4- (3- (2-fluorobenzyl) -4-hydroxybenzyl) phenoxy) acetate (Compound 83) Become into

Intermediate A6(100mg, 0.3mmol), 2-fluorobenzyl chloride (52mg, 0.36mmol) and ZnCl₂(1M in THF, 0.6mL, 0.6mmol) in DCE (3mL) was stirred at 95 ℃ overnight. The mixture was diluted with DCM (10mL) and washed with water (10mL) and brine (10 mL). The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to giveIntermediate 83(30mg, 22% yield) was obtained as a white solid.

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.4

LCMS:RT＝2.998min；[M-1]＝447.7

Example 84

Synthesis of 2- (3, 5-dichloro-4- (3- (2-fluorobenzyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 84)

To a mixture of intermediate 83(30mg, 0.07mmol) in THF (2mL) and water (1mL) was added LiOH₂O (9mg, 0.21 mmol). The mixture was stirred at room temperature for 2 h. Adjusting the pH to 4 with 1N HCl; the aqueous layer was extracted with EtOAc (20mL x 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 84 as a white solid (14mg, 47% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.1

LCMS:RT＝3.974min；[M-1]＝432.8

¹H NMR:(400MHz,DMSO-d₆)δ9.37(s,1H),7.22(d,J＝10.2Hz,1H),7.13(d,J＝7.0Hz,2H),7.08(d,J＝7.8Hz,1H),6.99(s,2H),6.77(d,J＝16.8Hz,2H),6.70(d,J＝7.8Hz,1H),4.54(s,2H),3.97(s,2H),3.80(s,2H)。

Example 85

Synthesis of methyl 2- (3, 5-dichloro-4- (3- (3-fluorobenzyl) -4-hydroxybenzyl) phenoxy) acetate (Compound 85) Become into

To a room temperature solution of 3-fluorobenzyl chloride (42mg, 293umol) in DCE (6mL) was added ZnCl in THF ₂(1M, 6mL) and intermediate A6(200mg, 586 umol). The mixture was heated to reflux overnight. The mixture was diluted with DCM (5mL), washed with brine (5mL), and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 85(23mg, 17% yield) as a colorless oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.36

¹H NMR:(400MHz,DMSO-d₆)δ9.30(s,1H),7.28(q,J＝7.3Hz,1H),7.12(s,2H),7.01(d,J＝7.7Hz,1H),6.96(t,J＝8.9Hz,2H),6.89(d,J＝2.0Hz,1H),6.77–6.73(dd,J＝8.4Hz,1.6Hz,1H),6.70(d,J＝8.2Hz,1H),4.88(s,2H),4.01(s,2H),3.82(s,2H),3.70(s,3H)。

Example 86

Synthesis of 2- (3, 5-dichloro-4- (3- (3-fluorobenzyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 86)

To a room temperature solution of compound 85(23mg, 51.19umol) in THF (3mL) and water (1mL) was added LiOH (2mg, 76.79 umol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (3mL), acidified to pH-6-7 with 1N HCl, and extracted with EtOAc (3mL × 3). The combined organic phases were washed with brine (5mL) and Na₂SO₄Drying and concentration in vacuo afforded compound 86(15mg, 68% yield) as a grey solid.

TLC:MeOH/DCM＝1/10(v/v),R_f＝0.25

LCMS:RT＝2.067min；[M-1]＝433。

¹H NMR:(400MHz,DMSO-d₆)δ9.38(s,1H),7.28(q,J＝7.7Hz,1H),7.01(d,J＝7.6Hz,1H),6.99–6.92(m,2H),6.89(d,J＝5.5Hz,3H),6.72(q,J＝8.2Hz,2H),4.19(s,2H),3.98(s,2H),3.82(s,2H)。

Example 87

Methyl 2- (3, 5-dichloro-4- (3- (2, 4-difluorobenzyl) -4-hydroxybenzyl) phenoxy) acetate (Compound 87) Synthesis of (2)

2, 4-difluorobenzyl chloride (96mg, 0.6mmol), intermediate A6(200mg, 0.6mmol) and ZnCl₂A mixture of (1M in THF) in DCE (5mL) was stirred at 95 ℃ overnight. The mixture was cooled to room temperature, diluted with DCM (10mL) and washed with water (10 mL). The combined organic layers were washed with brine (20mL) and Na ₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 87 as a white solid (20mg, 7% yield).

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.4

LCMS:RT＝3.360min；[M-1]＝464.8

Example 88

Synthesis of 2- (3, 5-dichloro-4- (3- (2, 4-difluorobenzyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 88) Become into

To a solution of compound 87(20mg, 0.04mmol) in THF (2mL) and water (1mL) was added LiOH₂O (5mg, 0.12 mmol). The mixture was stirred at room temperature for 2h, then adjusted to pH-4 with 1N HCl and extracted with EtOAc (20mL × 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by Prep-HPLC to give compound 88 as a white solid (5mg, 28% yield).

TLC:DCM/MeOH＝10/1(v/v),Rf＝0.1

LCMS:RT＝3.992min；[M-1]＝450.8

¹H NMR:(400MHz,DMSO-d₆)δ9.35(s,1H),7.20–7.13(dd,J₁＝16.4Hz,J₂＝19.2Hz,2H),7.06(s,2H),6.97(t,J＝7.6Hz,1H),6.77(d,J＝8.0Hz,2H),6.70(d,J＝7.6Hz,1H),4.74(s,2H),3.98(s,2H),3.77(s,2H)。

Example 89

Synthesis of methyl 2- (3, 5-dichloro-4- (3- (4-chlorobenzyl) -4-hydroxybenzyl) phenoxy) acetate (Compound 89) Become into

To a room temperature solution of 4-chlorobenzyl chloride (95mg, 586umol) in DCE (5mL) was added ZnCl in THF₂(1M, 1.17mL) and intermediate A6(200mg, 586 umol). The mixture was heated to reflux overnight. The mixture was diluted with DCM (5 mL). The combined organic phases were washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 89(30mg, 11% yield) as a white solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.36

¹H NMR:(400MHz,DMSO-d₆)δ9.28(s,1H),7.29(d,J＝8.3Hz,2H),7.18(d,J＝8.4Hz,2H),7.12(s,2H),6.87–6.85(m,1H),6.74(dd,J＝8.3,1.9Hz,1H),6.69(d,J＝8.2Hz,1H),4.89(s,2H),4.01(s,2H),3.79(s,2H),3.70(s,3H)。

Example 90

Synthesis of 2- (3, 5-dichloro-4- (3- (4-chlorobenzyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 90)

To a room temperature solution of compound 89(30mg, 64umol) in THF (2mL) and water (1mL) was added LiOH (3mg, 97 umol). The mixture was stirred at room temperature for 2h, diluted with water (5mL), acidified to pH-6-7 with 1N HCl, and extracted with EtOAc (5mL × 2). The combined organic phases were washed with brine (5mL) and Na₂SO₄Drying and concentration in vacuo afforded compound 90(20mg, 69% yield) as a white solid.

TLC:MeOH/DCM＝1/10(v/v),R_f＝0.25

LCMS:RT＝2.515min；[M-1]＝449。

¹H NMR:(400MHz,DMSO-d₆)δ9.43(s,1H),7.32–7.25(m,2H),7.22–7.15(m,2H),6.88(m,3H),6.75–6.67(m,2H),4.20(s,2H),3.97(s,2H),3.78(s,2H)。

Example 91

Process for preparing methyl 2- (3, 5-dichloro-4- (4-hydroxy-3- (4-methylbenzyl) benzyl) phenoxy) acetate (Compound 91) Synthesis of

To a room temperature solution of 4-methylbenzyl chloride (83mg, 586umol) in DCE (5mL) was added ZnCl in THF₂(1M, 1.17mL) and intermediate A6(200mg, 586 umol). The mixture was heated to reflux overnight. The mixture was diluted with DCM (5 mL). The combined organic phases were washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 91(40mg, 16% yield) as a colourless oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.31

¹H NMR:(400MHz,DMSO-d₆)δ9.19(s,1H),7.12(s,2H),7.04(s,4H),6.84(s,1H),6.73–6.69(m,1H),6.67(d,J＝8.3Hz,1H),4.89(s,2H),3.99(s,2H),3.74(s,2H),3.70(s,3H),2.23(s,3H)。

Example 92

Synthesis of 2- (3, 5-dichloro-4- (4-hydroxy-3- (4-methylbenzyl) benzyl) phenoxy) acetic acid (Compound 92)

To a room temperature solution of compound 91(17mg, 38umol) in THF (3mL) and water (1mL) was added LiOH (1.4mg, 57 umol). The mixture was allowed to stand at room temperatureStirring for 2 h. The mixture was diluted with water (3mL), acidified to pH-6-7 with 1N HCl, and extracted with EtOAc (3mL × 3). The combined organic phases were washed with brine (5mL) and Na₂SO₄Drying and concentration in vacuo afforded compound 92(15mg, 91% yield) as a grey solid.

TLC:MeOH/DCM＝1/10(v/v),R_f＝0.25

LCMS:RT＝2.296min；[M-1]＝429。

¹H NMR:(400MHz,DMSO-d₆)δ9.33(s,1H),7.04(d,J＝1.4Hz,4H),6.89–6.83(m,3H),6.68(d,J＝1.7Hz,2H),4.16(s,2H),3.96(s,2H),3.74(s,2H),2.23(s,3H)。

Example 93

Methyl 2- (3, 5-dichloro-4- (4-hydroxy-3- (pyrimidin-5-ylmethyl) benzyl) phenoxy) acetate (compound 93) Synthesis of (2)

To a room temperature solution of intermediate C10(197mg, 1.05mmol) in DCE (10mL) was added intermediate A6(100mg, 0.35mmol) and ZnCl₂THF (1M, 0.87 mL). The reaction was heated to 100 ℃ for 2 days. The mixture was cooled to room temperature and diluted with DCM (20 mL); the resulting mixture was washed with brine (2 x 10 mL). The organic phase is passed through Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (EtOAc/petroleum ether ═ 1/3) to give compound 93(150mg, 20% purity) as a light yellow oil.

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.4

LCMS:RT＝3.53min；[M-1]＝432.0

Example 94

Synthesis of 2- (3, 5-dichloro-4- (4-hydroxy-3- (pyrimidin-5-ylmethyl) benzyl) phenoxy) acetic acid (compound 94) Become into

To a room temperature solution of compound 93(150mg, 0.35umol) in THF/water (2/1mL) was added LiOH₂O (30mg, 0.70 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was acidified to pH-3-4 with 2N HCl, concentrated in vacuo, and purified by Prep-HPLC to give compound 94(13mg, 2.9% yield over 2 steps).

TLC, petroleum ether/EtOAc (1/5 (v/v)), Rf (0)

LCMS:RT＝3.00min；[M-1]＝418.9

¹H NMR:(400MHz,DMSO)δ13.11(s,1H),9.45(s,1H),8.99(s,1H),8.61(s,2H),7.09(s,2H),6.98(d,J＝2.2Hz,1H),6.77(m,1H),6.70(d,J＝8.2Hz,1H),4.77(s,2H),4.03(s,2H),3.83(s,2H)。

Example 95

2- (3, 5-dichloro-4- (4-hydroxy-3- (4- (2,2, 2-trifluoroethyl) benzyl) phenoxy) acetic acid methyl ester Synthesis of (Compound 95)

To a solution of intermediate C13(100mg, 479umol) and intermediate A6(327mg, 958umol) in chlorobenzene (5mL) was added ZnCl₂(1.2mmol, 1.20 mL). The mixture was stirred at 120 ℃ overnight. The mixture was concentrated to dryness, water (20mL) was added, and the resulting mixture was extracted with DCM (20mL × 2). The organic layer was washed with Na₂SO₄Drying and concentration in vacuo afforded compound 95(200mg, 16% yield, 20% purity), which was used without further purification.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.38

Example 96

2- (3, 5-dichloro-4- (4-hydroxy-3- (4- (2,2, 2-trifluoroethyl) benzyl) phenoxy) acetic acid (Compound No.) Substance 96) Synthesis

To a solution of compound 95(200mg, 77.9umol, 20% purity) in MeOH (3mL) and water (1mL) was added lioh₂O (16mg, 389.6 umol). The mixture was stirred at room temperature for 2 h. Water (10mL) was added and the mixture was acidified to pH 4-5 with 1N HCl. The mixture was extracted with DCM (10mL × 2). The organic layer was concentrated to dryness and then purified by Prep-TLC (DCM/MeOH ═ 10/1) and Prep-HPLC to give compound 96 as a white solid (30mg, 77% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝3.994min；[M-1]＝496.8/498.8

¹H NMR:(400MHz,DMSO-d₆)δ13.12(s,1H),9.27(s,1H),7.22(d,J＝7.9Hz,2H),7.17(d,J＝8.0Hz,2H),7.08(s,2H),6.88(d,J＝2.1Hz,1H),6.74(dd,J＝8.3,2.2Hz,1H),6.69(d,J＝8.2Hz,1H),4.77(s,2H),4.00(s,2H),3.80(s,2H),3.56(q,J＝11.6Hz,2H)。

Example 97

Methyl 2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) propyl) -4-hydroxybenzyl) phenoxy) acetate (compound 97) Synthesis of (2)

To a room temperature solution of intermediate C15(244mg, 1.06mmol) in DCE (2mL) was added intermediate A10(100mg, 0.36mmol) and ZnCl₂(1.0M in THF) (1.0M, 0.9 mL). The mixture was heated to reflux overnight. The mixture was cooled to room temperature and diluted with DCM (5 mL); the organic phase was washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 97(52mg, 30% yield) as a colorless oil.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.36

¹H NMR:(400MHz,DMSO-d₆)δ9.19(s,1H),7.20(ddd,J＝8.2,5.2,2.3Hz,2H),7.14(s,2H),7.08–7.01(m,3H),6.71(dd,J＝8.3,2.2Hz,1H),6.63(d,J＝8.3Hz,1H),4.89(s,2H),4.10(t,J＝7.9Hz,1H),4.03(s,2H),3.70(s,3H),1.89(td,J＝7.5,3.3Hz,2H),0.78(t,J＝7.2Hz,3H)。

Example 98

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) propyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 98) Synthesis of (2)

To a room temperature solution of compound 97(43mg, 90umol) in THF (2mL) was added lioh.h in water (1mL)₂O (7.5mg, 180 umol). The mixture was stirred at room temperature for 2h, diluted with water (10mL), acidified to pH-3 with HCl (1N) and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC to give compound 98 as an off-white solid (10mg, 23% yield).

TLC:DCM/MeOH＝10/1(v/v),R_f＝0.39

LCMS:RT＝2.543min；[M-1]＝461。

¹H NMR:(400MHz,DMSO-d₆)δ13.15(s,1H),9.18(s,1H),7.21(t,J＝7.1Hz,2H),7.05(dd,J＝16.7,7.2Hz,5H),6.70(d,J＝8.1Hz,1H),6.63(d,J＝8.3Hz,1H),4.74(s,2H),4.09(d,J＝8.7Hz,1H),4.03(s,2H),1.89(s,2H),0.78(t,J＝7.2Hz,3H)。

Example 99

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) propyl) -4-hydroxybenzyl) phenoxy) -N-methylacetamide Synthesis of (Compound 99)

Compound 97(150mg, 305umol) and aqueous methylamine solution (1mL of 40%) in THF (5mL) was stirred in a sealed tube at 70 deg.C overnight. Water (30mL) was added and the mixture was extracted with EtOAc (25mL × 2). The combined organic layers were washed with water (20mL x 2) and brine (20mL) and washed with Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (DCM/MeOH ═ 20/1) to give compound 99(50mg, 34% yield) as a white solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.17

LCMS:RT＝4.134min；[M-1]＝476.1

¹H NMR:(400MHz,DMSO-d₆)δ9.17(s,1H),8.05(d,J＝6.4Hz,1H),7.24–7.18(m,2H),7.12(s,2H),7.08–7.00(m,3H),6.71(dd,J＝8.4,2.4Hz,1H),6.63(d,J＝8.4Hz,1H),4.53(s,2H),4.10(t,J＝7.9Hz,1H),4.04(s,2H),2.65(d,J＝4.8Hz,3H),1.92–1.87(m,2H),0.78(t,J＝7.2Hz,3H)。

Example 100

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) propyl) -4-hydroxybenzyl) phenoxy) -N, N-dimethylacetoacetate Synthesis of amine (Compound 100)

To a mixture of compound 98(130mg, 281umol) in DCM (5mL) was added oxalyl chloride (107mg, 842 umol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give the crude acid chloride (130mg, 96% yield), which was combined with 2mL dimethylamine solution (2M in THF) and stirred at room temperature for 5 min. The mixture was concentrated to dryness. Water (30mL) was added and the resulting mixture was extracted with EtOAc (15mL x 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-TLC (DCM/MeOH ═ 20/1) and Prep-HPLC gave compound 100(80mg, 60% yield) as a white solid.

TLC:DCM/MeOH＝20/1(v/v),Rf＝0.4

LCMS:RT＝4.261min；[M-1]＝488.1

¹H NMR:(400MHz,DMSO-d₆)δ9.16(s,1H),7.24–7.18(m,2H),7.10–7.01(m,5H),6.74–6.69(m,1H),6.64(d,J＝8.4Hz,1H),4.90(s,2H),4.11(t,J＝8.0Hz,1H),4.03(s,2H),2.96(s,3H),2.84(s,3H),1.92–1.87(m,2H),0.78(t,J＝7.2Hz,3H)。

Example 101

Methyl 2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) butyl) -4-hydroxybenzyl) phenoxy) acetate (compound 101) Synthesis of (2)

To a solution of intermediate C17(338mg, 1.6mmol) and intermediate A10(150mg, 0.5mmol) in DCE (5mL) was added ZnCl₂(1M in THF) (1.3mmol, 1.3 mL). The mixture was stirred at 85 ℃ overnight. Water (5mL) was added and the mixture was extracted with DCM (3mL x 3). The combined organic phases were washed with brine, over Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (EtOAc/petroleum ether ═ 1/10) to give compound 101(55mg, 22% yield) as a white solid.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.2

Example 102

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) butyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 102) Synthesis of (2)

To compound 101(55mg, 112umol) in THF/H₂LiOH (14mg, 336umol) was added to a room temperature solution in O (2mL/0.5 mL). The mixture was stirred at room temperature for 2 h; the mixture was quenched with water (5mL), acidified to pH-5-6 with 1N HCl and extracted with EtOAc (3mL × 3). The combined organic phases were washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC (MeCN/H)₂O/TFA) to give compound 102(45mg, 85% yield) as a white solid.

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.30

LCMS:RT＝4.338min；[M-1]＝474.9

¹H NMR:(400MHz,DMSO)δ9.24(s,1H),7.21(dd,J＝6.0,2.8Hz,2H),7.05(dd,J＝4.8,2.4Hz,2H),7.03(s,2H),7.02(s,1H),6.70(dd,J＝8.4,2.0Hz,1H),6.64(d,J＝8.0Hz,1H),4.60(s,2H),4.23(t,J＝8.0Hz,1H),4.02(s,2H),1.92–1.78(m,2H),1.15(m,2H),0.84(t,J＝7.2Hz,3H)。

Example 103

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) -2-methylpropyl) -4-hydroxybenzyl) phenoxy) acetic acid ethyl ester Synthesis of (Compound 103)

To a solution of intermediate C19(382mg, 1.56mmol) and intermediate A12(155mg, 521umol) in DCE (10mL) was added ZnCl₂(1.3mmol, 1.30mL, 1M in THF). The mixture was stirred at 90 ℃ overnight. The mixture was cooled to room temperature and concentrated to dryness, water (20mL) was added, and the resulting mixture was extracted with DCM (20mL × 2). The organic layer was washed with Na₂SO₄Drying, concentration in vacuo, and purification by Prep-TLC (petroleum ether/EtOAc ═ 5/1) gave compound 103(140mg, 32% yield, 60% purity) as a white solid.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.38

Example 104

(ization) of 2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) -2-methylpropyl) -4-hydroxybenzyl) phenoxy) acetic acid Synthesis of Compound 104)

To compound 103(140mg, 166 um)ol, 60% pure) in MeOH (3mL) and water (1mL) LiOH (21mg, 499umol) was added. The mixture was stirred at room temperature for 1 h. Water (10mL) was added, the mixture was acidified to pH 4-5 with 1N HCl and extracted with DCM (10 mL). The organic layer was washed with Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 104 as a white solid (40mg, 50% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝4.181min；[M-1]＝475.1/477.1

¹H NMR:(400MHz,DMSO-d₆)δ13.10(s,1H),9.14(s,1H),7.30–7.22(m,2H),7.18(d,J＝2.2Hz,1H),7.10(s,2H),7.07–6.98(m,2H),6.68(dd,J＝8.3,2.2Hz,1H),6.61(d,J＝8.3Hz,1H),4.77(s,2H),4.04(s,2H),3.82(d,J＝11.3Hz,1H),2.45–2.36(m,1H),0.77(dd,J＝14.4,6.4Hz,6H)。

Example 105

2- (3, 5-dichloro-4- (3- (2- (4-fluorophenyl) propan-2-yl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound No.) Object 105) Synthesis

To a solution of intermediate D2(200mg, 1.16mmol), intermediate A6(395mg, 1.16mmol) in DCE (5mL) was added ZnCl₂(1M, 2.32 mL). The mixture was stirred at 85 ℃ overnight. The mixture was cooled to room temperature and concentrated to dryness; addition of THF/H₂O (5/2mL) and LiOH.H₂O (146mg, 3.48mmol), and the resulting mixture was stirred at room temperature for 30 min. Water (10mL) was added, the mixture was acidified to pH-4-5 with 1N HCl and extracted with DCM (10mL × 2). The organic layer was concentrated in vacuo and then purified by Prep-TLC (DCM/MeOH ═ 5/1) and Prep-HPLC to give compound 105 as a white solid (10mg, 2% yield). TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

¹H NMR:(400MHz,DMSO-d₆)δ8.83(s,1H),7.21(d,J＝2.1Hz,1H),7.11–7.08(m,2H),7.04–6.91(m,4H),6.80–6.75(m,1H),6.55(d,J＝8.2Hz,1H),4.35(s,2H),4.07(s,2H),1.57(s,6H)。

Example 106

Methyl 2- (3, 5-dichloro-4- (3- (cyclopropyl (4-fluorophenyl) methyl) -4-hydroxybenzyl) phenoxy) acetate Synthesis of Compound 106)

To a room temperature solution of intermediate C21(100mg, 0.39mmol) in DCE (10mL) was added intermediate A10(40mg, 0.13mmol) and ZnCl₂THF (1M, 0.32 mL). The reaction was heated to 95 ℃ for 2 days. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL); the resulting mixture was washed with brine (2 x 10mL) and over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (EtOAc/petroleum ether ═ 1/5) to give compound 106 as a light yellow oil (20mg, 28% yield).

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.4

¹H NMR:(400MHz,DMSO)δ9.10(s,1H),7.21(m,3H),7.14(m,3H),7.08–7.01(m,2H),6.77–6.71(m,1H),6.61(m,1H),4.89(s,2H),4.08–4.04(m,2H),3.70(s,3H),3.50–3.41(m,3H),1.41–1.29(m,1H),1.09(m,2H),0.58(m,2H),0.23(m,1H),0.08(m,1H)。

Example 107

2- (3, 5-dichloro-4- (3- (cyclopropyl (4-fluorophenyl) methyl) -4-hydroxybenzyl) phenoxy) acetic acid (compound) 107) Synthesis of (2)

To a room temperature solution of compound 106(20mg, 0.04mmol) in THF/water (2/1mL) was added LiOH₂O (5mg, 0.12 mmol); the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was acidified to pH 3-4 with 2N HCl, concentrated in vacuo, and purified by Prep-HPLC,compound 107(4mg, 21% yield) was obtained.

TLC, petroleum ether/EtOAc (1/5 (v/v)), Rf (0)

LCMS:RT:2.41min；[M+1]＝472.9

¹H NMR(400MHz,DMSO)δ9.02(s,1H),7.12(s,3H),6.96(m,4H),6.64(d,J＝7.1Hz,1H),6.53(d,J＝8.0Hz,1H),4.65(s,2H),3.96(s,2H),3.40(s,1H),1.26(s,1H),0.41(d,J＝28.8Hz,2H),0.13(s,1H),0.00(s,1H)。

Example 108

Methyl 2- (3, 5-dichloro-4- (3- (cyclobutyl (4-fluorophenyl) methyl) -4-hydroxybenzyl) phenoxy) acetate (formula) Synthesis of Compound 108)

To a room temperature solution of intermediate C25(287.11mg, 1.1mmol) in DCE (4mL) was added intermediate A10(100mg, 0.4mmol) and ZnCl₂(1M in THF) (0.8 mL). The reaction was heated to 85 ℃ and stirred overnight. The reaction mixture was diluted with DCM (10mL), washed with brine (5mL × 3) and taken over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether-1/30 to 1/10) to give compound 108 as a colourless oil (90mg, 50% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.2

¹H NMR(400MHz,DMSO-d₆)δ9.13(s,1H),7.16(dd,J＝8.4,6.4Hz,2H),7.10(s,2H),7.05–6.98(m,3H),6.72(dd,J＝8.0,1.6Hz,1H),6.61(d,J＝8.2Hz,1H),4.76(s,2H),4.16(d,J＝11.2Hz,1H),4.04(s,2H),2.96(q,J＝9.4,8.6Hz,1H),1.92–1.61(m,6H)。

Example 109

2- (3, 5-dichloro-4- (3- (cyclobutyl (4-fluorophenyl) methyl) -4-hydroxybenzyl) phenoxy) acetic acid (compound) 109) Synthesis of (2)

To compound 108(90mg, 185umol) in THF/H₂LiOH. H was added to the mixture in O (2mL/0.5mL)₂O (13.3mg, 556 umol). The mixture was stirred at room temperature for 2 h. Water (2mL) was added and the pH adjusted to pH 3-4 with 1N HCl. The resulting mixture was extracted with EtOAc (5mL x 3); the combined organic phases were washed with brine (15mL) and Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (DCM/MeOH ═ 10/1) to give compound 109 as a white solid (30mg, 34% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.25

LCMS:RT＝4.394min；[M-1]＝487.0

¹H NMR(400MHz,DMSO-d₆)δ13.19(s,1H),9.13(s,1H),7.20–7.13(m,2H),7.10(s,2H),7.06–6.97(m,3H),6.72(d,J＝7.2Hz,1H),6.62(d,J＝8.2Hz,1H),4.77(s,2H),4.16(d,J＝11.2Hz,1H),4.04(s,2H),3.02–2.93(m,1H),1.90–1.65(m,5H),1.55–1.45(m,1H)。

Example 110

2- (3, 5-dichloro-4- (3- (6-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4-hydroxybenzyl) phenoxy) acetic acid methyl ester Synthesis of ester (Compound 110)

To a solution of intermediate C27(110mg, 454umol) and intermediate A10(65mg, 227umol) in DCE (5mL) was added ZnCl₂(1M/THF) (567. mu. mol, 0.6 mL). The mixture was stirred at 85 ℃ overnight. Water (10mL) was added and the mixture was extracted with DCM (5mL x 3). The combined organic phases were washed with brine, over Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (EtOAc/petroleum ether ═ 1/5) to give compound 110 as a colorless oil (35mg, 31% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.2

LCMS:RT＝3.298min；[M-1]＝486.9

Example 111

2- (3, 5-dichloro-4- (3- (6-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) -4-hydroxybenzyl) phenoxy) acetic acid (phosphonium chloride) Synthesis of Compound 111)

To compound 110(35mg, 74umol) in THF/H₂LiOH. H was added to a room temperature solution of O (2mL/0.5mL)₂O (5mg, 221 umol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (10mL), acidified to pH-3-4 with 1N HCl and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC to give compound 111 as a white solid (15mg, 44% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.30

LCMS:RT＝4.170min；[M-1]＝473.0

¹H NMR(400MHz,DMSO-d₆)δ13.12(s,1H),9.30(s,1H),7.03(s,2H),6.92(dd,J＝10.0,2.8Hz,1H),6.81(td,J＝8.4,2.8Hz,1H),6.77–6.69(m,3H),6.37(s,1H),4.75(s,2H),4.33(t,J＝5.6Hz,1H),3.89(s,2H),3.34(s,2H),2.77(m,2H),1.85(m,2H),1.63(m,2H)。

¹⁹F NMR(376MHz,DMSO)δ-117.90(s)。

Example 112

2- (3, 5-dichloro-4- (3- (5-fluoro-2, 3-dihydro-1H-inden-1-yl) -4-hydroxybenzyl) phenoxy) acetic acid methyl ester Synthesis of ester (Compound 112)

To a solution of intermediate C29(110mg, 454umol) and intermediate A10(65mg, 227umol) in DCE (5mL) was added ZnCl₂(1M/THF) (567. mu. mol, 0.6 mL). The mixture was stirred at 85 ℃ overnight. Water (10mL) was added and the resulting mixture was extracted with DCM (5mL x 3). The combined organic phases were washed with brine, over Na₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (EtOAc/petroleum ether 1/30 to 1/10) gave compound 112 as a colorless oil (30mg, 33% yield).

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.1

LCMS:RT＝4.534min；[M-1]＝472.9

Example 113

2- (3, 5-dichloro-4- (3- (5-fluoro-2, 3-dihydro-1H-inden-1-yl) -4-hydroxybenzyl) phenoxy) acetic acid (phosphonium chloride) Synthesis of Compound 113)

To compound 112(30mg, 74umol) in THF/H₂LiOH. H was added to a room temperature solution of O (1mL/0.3mL)₂O (5mg, 221 umol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (5mL), acidified to pH-3-4 with 1N HCl and extracted with EtOAc (3mL × 3). The combined organic phases were washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC (MeCN/H) ₂O/TFA) to give compound 113 as a white solid (5mg, 17% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.30

LCMS:T＝4.115min；[M-1]＝458.8

¹H NMR(400MHz,DMSO-d₆)δ13.18(s,1H),9.33(s,1H),7.08(d,J＝9.0Hz,1H),7.04(s,2H),6.93–6.85(m,2H),6.79–6.71(m,2H),6.66–6.62(m,1H),4.72(s,2H),4.54(t,J＝8.0Hz,1H),3.94(s,2H),2.87(dt,J＝17.6,9.6Hz,2H),2.47–2.42(m,1H),1.91(dd,J＝12.4,8.0Hz,1H)。

¹⁹F NMR(376MHz,DMSO)δ-117.58(s)。

Example 114

2- (3-chloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -5-methylphenoxy) acetic acid methyl ester (Compound 114) Synthesis of (2)

To a room temperature solution of intermediate C31(138mg, 0.69mmol) in DCE (5mL) was added intermediate A15(60mg, 0.23mmol) and ZnCl₂THF (1M) (0.57mL, 0.58 mmol). The resulting mixture was stirred at 80 ℃ overnight. The mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether/EtOAc: 5/1, v/v) to give compound 114 as a yellow oil (60mg, 61% yield).

TLC petroleum ether/EtOAc (v/v) 1/5, Rf 0.4

¹H NMR:(400MHz,DMSO)δ9.23(s,1H),7.24–7.13(m,2H),7.05(m,2H),6.90(d,J＝2.7Hz,1H),6.79(d,J＝2.5Hz,2H),6.72–6.58(m,2H),4.81(s,2H),3.90(s,2H),3.77(s,2H),3.70(s,3H),2.16(s,3H)。

Example 115

Synthesis of 2- (3-chloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -5-methylphenoxy) acetic acid (Compound 115) Become into

To a room temperature solution of compound 114(60mg, 0.14mmol) in THF/water (5mL/1mL) was added LiOH₂O (17mg, 0.52 mmol); the resulting mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 6-7 with HCl (1N), and the solid was collected by filtration, washed with water and dried to give compound 115(26mg, 45% yield).

TLC, petroleum ether/EtOAc (5/1 (v/v)), Rf (0)

¹H NMR:(400MHz,DMSO)δ9.27(s,1H),7.22–7.14(m,2H),7.05(m,2H),6.80(m,2H),6.72(d,J＝2.6Hz,1H),6.68(d,J＝8.2Hz,1H),6.63(m,1H),4.52(s,2H),3.88(s,2H),3.77(s,2H),2.14(s,3H)。

LCMS:RT＝3.81min；[M-1]＝413。

Example 116

2- (3-chloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -5-methylphenoxy) -N-methylacetamide (compound) 116) Synthesis of (2)

A solution of compound 114(45mg, 104.92umol) and methylamine (2M/THF, 1mL) in THF (3mL) was stirred in a sealed tube at 70 ℃ overnight. Water (30mL) was added and the mixture was extracted with EtOAc (25mL × 2). The combined organic layers were washed with water (20mL x 2), then brine (20mL), over Na₂SO₄Dried and purified by Prep-TLC (DCM/MeOH ═ 20/1) to give compound 116 as a white solid (35mg, 78% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.25

LCMS:RT＝3.754min；[M-1]＝426.1

¹H NMR:(400MHz,DMSO-d₆)δ9.21(s,1H),8.01(d,J＝5.6Hz,1H),7.21–7.14(m,2H),7.08–7.02(m,2H),6.92(d,J＝2.6Hz,1H),6.81–6.78(m,2H),6.69–6.62(m,2H),4.45(s,2H),3.90(s,2H),3.78(s,2H),2.65(d,J＝4.8Hz,3H),2.16(s,3H)。

Example 117

2- (3-chloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -5-methylphenoxy) -N, N-dimethylacetamide (formula) Synthesis of Compound 117)

To a mixture of compound 115(230mg, 554umol) in DCM (5mL) was added oxalyl chloride (211mg, 1.66 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give crude acid chloride (2)30mg, 96% yield), which was added to dimethylamine solution (2M/THF, 2mL) and stirred at room temperature for 5 min. The mixture was concentrated in vacuo; water (30mL) was added and the resulting mixture was extracted with EtOAc (15mL x 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dried and purified by Prep-TLC (DCM/MeOH ═ 20/1) to give compound 117 as a white solid (150mg, 64% yield).

TLC:DCM/MeOH＝20/1(v/v),Rf＝0.4

LCMS:RT＝3.794min；[M-1]＝440.1

¹H NMR:(400MHz,DMSO-d₆)δ9.21(s,1H),7.19-7.16(m,2H),7.06(t,J＝8.8Hz,2H),6.87(d,J＝2.8Hz,1H),6.80–6.75(m,2H),6.69–6.63(m,2H),4.80(s,2H),3.89(s,2H),3.78(s,2H),2.98(s,3H),2.84(s,3H),2.15(s,3H)。

Example 118

2- (3, 5-dichloro-4- (3- (furan-3-ylmethyl) -4-hydroxybenzyl) phenoxy) acetic acid methyl ester (Compound) 118) Synthesis of (2)

Intermediate D4(120mg, 1.03mmol), intermediate A6(703mg, 2.06mmol) and ZnCl₂A mixture of (2.57mmol, 2.57mL 1N/THF) in DCE (5mL) was stirred at 90 deg.C overnight. The mixture was concentrated in vacuo and purified by Prep-TLC to give compound 118 as a colorless oil (40mg, 9% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.38

Example 119

Process for preparing 2- (3, 5-dichloro-4- (3- (furan-3-ylmethyl) -4-hydroxybenzyl) phenoxy) acetic acid (compound 119) Synthesis of

To a solution of compound 118(35mg, 83umol) in MeOH (3mL) and water (1mL) was added lioh₂O (10mg, 249 umol). The mixture was stirred at room temperature for 2 h. The mixture was acidified with 1N HCl to pH 4-5. Water (10mL) was added and the mixture was extracted with DCM (10 mL). The organic layer was concentrated in vacuo and purified by Prep-HPLC to give compound 119 as a white solid (14mg, 41% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝1.609min；[M-1]＝405.0/406.9

HNMR ¹H NMR:(400MHz,DMSO-d₆)δ9.26(s,1H),7.52(t,J＝1.7Hz,1H),7.36(t,J＝1.2Hz,1H),7.09(s,2H),6.86(d,J＝2.2Hz,1H),6.73(dd,J＝8.2,2.2Hz,1H),6.68(d,J＝8.3Hz,1H),6.28(d,J＝1.8Hz,1H),4.77(s,2H),4.00(s,2H),3.57(s,2H)。

Example 120

2- (3, 5-dichloro-4- (4-hydroxy-3- (thiophen-3-ylmethyl) benzyl) phenoxy) acetic acid ethyl ester (Compound) 120) Synthesis of (2)

To a room temperature solution of intermediate C33(150mg, 0.50mmol) in DCE (10mL) was added intermediate A12(287mg, 1.51mmol) and ZnCl₂(206mg, 1.51 mmol). The reaction was heated to 90 ℃ and stirred for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL); the resulting mixture was washed with brine (10mL x 2) and over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 120(50mg, 21% yield) as a colourless oil.

TLC petroleum ether/EtOAc (v/v) 5/1, Rf 0.21

LCMS:RT＝4.284min；[M-1]＝449.0

¹H NMR:(400MHz,DMSO-d₆)δ9.27(s,1H),7.40(dd,J＝4.8,2.8Hz,1H),7.12(s,2H),7.06–7.04(m,1H),6.91(dd,J＝4.8,1.6Hz,1H),6.85(d,J＝2.4Hz,1H),6.73(dd,J＝8.0,2.0Hz,1H),6.69(d,J＝8.4Hz,1H),4.87(s,2H),4.17(q,J＝7.2Hz,2H),4.08–3.96(m,3H),3.78(s,2H),1.21–1.16(m,3H)

Example 121

Process for preparing 2- (3, 5-dichloro-4- (4-hydroxy-3- (thien-3-ylmethyl) benzyl) phenoxy) acetic acid (compound 121) Synthesis of

To a solution of compound 120(50mg, 0.11mmol) in water (1mL) and THF (10mL) was added LiOH. H₂O (14mg, 0.33 mmol). The mixture was stirred at room temperature for 2 h. Water (10mL) was added, the mixture was adjusted to pH-3-4 with 1N HCl and extracted with EtOAc (5mL × 2). The combined organic phases were washed with brine (10mL) and Na₂SO₄Drying and concentration in vacuo afforded compound 121(30mg, 63% yield) as a white solid.

TLC:DCM/MeOH＝15/1(v/v),Rf＝0.23

LCMS:RT＝3.757min；[M-1]＝421.0

¹H NMR:(400MHz,DMSO-d₆)δ9.27(s,1H),7.39(dd,J＝4.8,2.8Hz,1H),7.09–7.03(m,3H),6.91(dd,J＝5.2,1.2Hz,1H),6.86(d,J＝2.0Hz,1H),6.75–6.65(m,2H),4.73(s,2H),3.99(s,2H),3.78(s,2H)。

Example 122

2- (3, 5-dichloro-4- (4-hydroxy-3- (thien-2-ylmethyl) benzyl) phenoxy) acetic acid ethyl ester (Compound) 122) Synthesis of (2)

To a room temperature solution of intermediate C35(200mg, 0.67mmol) in DCE (10mL) was added intermediate A12(384mg, 2.02mmol) and ZnCl₂(275mg, 2.02 mmol). The reaction was heated to 90 ℃ overnight. The reaction was cooled to room temperature and diluted with DCM (20 mL); mixing the raw materialsThe material was washed with brine (10 mL. times.2) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (EtOAc/petroleum ether ═ 1/5) and Prep-HPLC to give compound 122 as a colorless oil (50mg, 16% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.45

¹H NMR:(400MHz,DMSO-d₆)δ9.37(s,1H),7.26(dd,J＝5.2,1.2Hz,1H),7.12(s,2H),6.92–6.87(m,2H),6.79(dd,J＝3.6,1.2Hz,1H),6.74(d,J＝2.4Hz,1H),6.69(d,J＝8.4Hz,1H),4.87(s,2H),4.17(q,J＝7.2Hz,2H),4.02(d,J＝2.0Hz,2H),3.97(s,2H),1.20–1.17(m,3H)。

Example 123

Process for preparing 2- (3, 5-dichloro-4- (4-hydroxy-3- (thien-2-ylmethyl) benzyl) phenoxy) acetic acid (compound 123) Synthesis of

To a room temperature solution of compound 122(40mg, 88.6umol) in water (1mL)/THF (10mL) was added LiOH. H₂O (11mg, 266 umol); the mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH 4-5 with 2N HCl and extracted with EtOAc (5mL × 2); the combined organic phases were washed with brine (5mL x 2) and over Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 123(25mg, 66% yield) as a white solid.

TLC petroleum ether/EtOAc (v/v) 1/1, Rf 0.1

LCMS：RT＝3.80min；[M-1]＝421.0

¹H NMR:(400MHz,DMSO-d₆)δ9.35(s,1H),7.26(dd,J＝5.2,1.2Hz,1H),7.09(s,2H),6.93–6.87(m,2H),6.81–6.78(m,1H),6.76(dd,J＝8.4,2.4Hz,1H),6.69(d,J＝8.4Hz,1H),4.77(s,2H),4.01(s,2H),3.97(s,2H)。

Example 124

2- (3, 5-dichloro-4- (4-hydroxy-3- (2,2, 2-trifluoro-1- (4-fluorophenyl) ethyl) benzyl) phenoxy) ethyl ester Acid(s) Synthesis of Ethyl ester (Compound 124)

To a solution of intermediate C37(300mg, 1.11mmol) and intermediate A12(165mg, 555umol) in DCE (5mL) was added ZnCl₂(1M, 1.39 mL). The mixture was microwaved at 150 ℃ for 2 h. The mixture was cooled to room temperature and concentrated to dryness; water (20mL) was added and the resulting mixture was extracted with DCM (20 mL). The organic layer was washed with Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 124(100mg, 34% yield) as a colorless oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.38

¹H NMR:(400MHz,DMSO-d₆)δ9.77(s,1H),7.36(dd,J＝8.5,5.4Hz,2H),7.27(d,J＝2.1Hz,1H),7.22–7.17(m,2H),7.15(s,2H),6.93(dd,J＝8.4,2.2Hz,1H),6.76(d,J＝8.3Hz,1H),5.27(q,J＝10.7Hz,1H),4.88(s,2H),4.35(t,J＝5.1Hz,2H),4.09(s,2H),1.16(t,J＝6.8Hz,3H)。

Example 125

2- (3, 5-dichloro-4- (4-hydroxy-3- (2,2, 2-trifluoro-1- (4-fluorophenyl) ethyl) benzyl) phenoxy) acetic acid Synthesis of (Compound 125)

To a solution of compound 124(100mg, 188umol) in MeOH (3mL) and water (1mL) was added NaOH (23mg, 565 umol). The mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 4-5 with 1N HCl, water (10mL) was added, and the resulting mixture was extracted with DCM (10 mL). The organic layer was washed with Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 125 as a white solid (30mg, 32% yield).

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0

LCMS:RT＝4.034min；[M-1]＝501.0/502.9

¹H NMR:(400MHz,DMSO-d₆)δ9.78(s,1H),7.38–7.35(m,2H),7.28(s,1H),7.18(t,J＝8.8Hz,2H),7.12(s,2H),6.93(dd,J＝8.3,2.2Hz,1H),6.76(d,J＝8.3Hz,1H),5.27(q,J＝10.8Hz,1H),4.78(s,2H),4.08(s,2H)。

Example 126

2- (3, 5-dichloro-4- (4-hydroxy-3- (3,3, 3-trifluoro-1- (4-fluorophenyl) propyl) benzyl) phenoxy) acetic acid Synthesis of methyl ester (Compound 126)

To a solution of intermediate C38(360mg, 1.3mmol) and intermediate A10(180mg, 650umol) in DCE (5mL) was added ZnCl₂(1M/in THF) (1.6mmol, 1.6 mL). The mixture was stirred at 85 ℃ overnight. Water (10mL) was added and the resulting mixture was extracted with DCM (5mL x 3). The combined organic phases were washed with brine (20mL) and Na₂SO₄Drying, concentration in vacuo, and purification by silica gel column chromatography (EtOAc/petroleum ether 1/30 to 1/10) gave compound 126(120mg, 34% yield) as a colorless oil.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.2

LCMS:RT＝2.196min；[M-1]＝529.0

Example 127

2- (3, 5-dichloro-4- (4-hydroxy-3- (3,3, 3-trifluoro-1- (4-fluorophenyl) propyl) benzyl) phenoxy) acetic acid (Compound 127) Synthesis

To compound 126(120mg, 220umol) in THF/H₂LiOH. H was added to the room temperature mixture in O (3mL/0.5mL)₂O(28mg，660umol)。The reaction was stirred at room temperature for 5 min. The mixture was diluted with water (5mL), acidified to pH-4-5 with 1N HCl and extracted with EtOAc (5mL × 3). The combined organic phases were washed with brine (5mL) and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-HPLC (MeCN/H)₂O) to give compound 127(25mg, 22% yield) as a white solid.

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.30

LCMS:RT＝1.691min；[M-1]＝425.0

¹H NMR:(400MHz,DMSO-d₆)δ9.48(s,1H),7.40–7.34(m,2H),7.17–7.02(m,5H),6.71–6.64(m,2H),4.76(s,2H),4.57(m,1H),4.02(d,J＝2.8Hz,2H),3.09–2.96(m,2H)。

¹⁹F NMR:(376MHz,DMSO-d₆)δ-62.37,-116.81。

Example 128

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) -2-methoxyethyl) -4-hydroxybenzyl) phenoxy) acetic acid ethyl ester Synthesis of ester (Compound 128)

To a room temperature solution of intermediate C41(36mg, 0.12mmol) in DCE (5mL) was added intermediate A12(90mg, 0.36mmol) and ZnCl₂(50mg, 0.36 mmol). The reaction was heated to 90 ℃ and stirred for 2 d. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL); the resulting mixture was washed with brine (10mL x 2) and over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (petroleum ether/EtOAc ═ 5/1) to give compound 128(30mg, 48% yield) as a white solid.

TLC Petroleum Ether/EtOAc-5/1 (v/v), R_f＝0.21

LCMS:RT＝2.13；[M-1]＝505.1。

Example 129

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) -2-methoxyethyl) -4-hydroxybenzyl) phenoxy) Acetic acid (Compound 129) Synthesis

To a room temperature solution of compound 128(30mg, 59.1umol) in THF (5 mL)/water (1mL) was added LiOH. H₂O (8mg, 177 umol); the mixture was stirred at room temperature for 1 h. Water (10mL) was added; the mixture was acidified to pH 4-5 with 2N HCl and extracted with EtOAc (5mL × 2). The combined organic phases were washed with brine (5mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-HPLC gave compound 129 as a white solid (8mg, 28% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.26。

LCMS:RT＝3.84；[M-1]＝447.0。

¹H NMR:(400MHz,DMSO-d₆)δ12.99(s,1H),9.28(s,1H),7.24–7.18(m,2H),7.11–7.02(m,3H),6.96(d,J＝2.4Hz,1H),6.75(dd,J＝8.4,2.4Hz,1H),6.66(d,J＝8.4Hz,1H),4.77(s,2H),4.48(s,1H),4.07–3.95(m,2H),3.74(qd,J＝9.6,7.2Hz,2H),3.20(s,3H)。

¹⁹F NMR:(376MHz,DMSO-d₆)δ-117.31。

Example 130

Ethyl 2- (3-bromo-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) -5-methylphenoxy) acetate Synthesis of Compound 130)

To a room temperature solution of intermediate C43(1.0g, 4.65mmol) in DCE (5mL) was added intermediate A18(500mg, 1.55mmol) and ZnCl₂(3.8mL, 3.80 mmol). The mixture was stirred at 85 ℃ overnight. The reaction mixture was poured into water (20mL) and extracted with DCM (30mL × 3). The combined organic phases were washed with brine (100mL) and Na₂SO₄Drying and vacuumConcentration and purification by silica gel column chromatography (petroleum ether/EtOAc ═ 10/1, v/v) gave compound 130(410mg, 52% yield) as a yellow oil.

TLC EtOAc/petroleum ether 1/5(v/v) and Rf 0.4

¹H NMR:(400MHz,DMSO)δ9.17(s,1H),7.18(m,2H),7.10–6.99(m,3H),6.88(d,J＝2.1Hz,1H),6.82(d,J＝2.7Hz,1H),6.62(m,2H),4.78(s,2H),4.37(d,J＝7.3Hz,1H),4.17(d,J＝7.1Hz,2H),3.95(s,2H),2.16(s,3H),1.43(d,J＝7.3Hz,3H),1.17(m,3H)。

Example 131

2- (3-bromo-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) -5-methylphenoxy) acetic acid (compound) 131) Synthesis of (2)

To a room temperature solution of compound 130(410mg, 0.82mmol) in water (10mL)/THF (5mL) was added LiOH₂O (103mg, 2.46 mmol). The mixture was stirred at room temperature for 1 h. The reaction was acidified to pH-3-4 with 2N HCl, concentrated in vacuo, and purified by reverse phase column chromatography to give compound 131 as a pale yellow solid (260mg, 67% yield).

TLC, petroleum ether/EtOAc (1/5 (v/v)), Rf (0)

LCMS:RT＝4.04min；[M-1]＝471.0

¹H NMR:(400MHz,DMSO)δ9.19(s,1H),7.24–7.13(m,2H),7.05(m,2H),6.96(d,J＝2.7Hz,1H),6.90(d,J＝2.1Hz,1H),6.75(d,J＝2.6Hz,1H),6.68–6.55(m,2H),4.49(s,2H),4.37(m,1H),3.94(s,2H),2.15(s,3H),1.44(d,J＝7.3Hz,3H)。

Example 132

2- (3-bromo-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) -5-methylphenoxy) -N-methylacetoacetyl Synthesis of amine (Compound 132)

To a solution of compound 131(80mg, 0.16mmol) in DCM (15mL) was added oxalyl chloride (62mg, 0.48mmol) and DMF (cat.). After stirring at room temperature for 1h, the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (15mL) and methylamine/THF (1M, 1.6mL) was added. After stirring at room temperature for 2h, the mixture was poured into water (20mL) and extracted with DCM (30mL × 3). The combined organic phases were washed with brine (30mL) and Na₂SO₄Drying, concentration in vacuo, and purification by Prep-TLC afforded compound 132(40mg, 50% yield) as a white solid.

TLC EtOAc/petroleum ether 1/1(v/v) and Rf 0.3

LCMS:RT＝4.0min；[M-1]＝484.1

¹H NMR:(400MHz,DMSO)δ9.17(s,1H),8.02(d,J＝5.2Hz,1H),7.18(m,2H),7.10–7.02(m,3H),6.89(d,J＝2.0Hz,1H),6.85(d,J＝2.6Hz,1H),6.61(m,2H),4.46(d,J＝6.1Hz,2H),4.41–4.34(m,1H),3.96(s,2H),2.65(d,J＝4.5Hz,3H),2.16(s,3H),1.44(d,J＝7.2Hz,2H)。

Example 133

Synthesis of 2- (4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -3, 5-dimethylphenoxy) acetic acid (Compound 133)

Intermediate C31(213mg, 1.05mmol), intermediate A21(100mg, 0.35mmol) and ZnCl₂A solution of (1M, 0.88mL) in DCE (4mL) was stirred at 85 ℃ overnight. The mixture was cooled to room temperature, water (30mL) was added, and the mixture was extracted with EtOAc (25mL × 2). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dried and purified by Prep-TLC (DCM/MeOH ═ 5/1) to give compound 133(30mg, 19% yield) as a white solid.

TLC:DCM/MeOH＝5/1(v/v),Rf＝0.39

LCMS:RT＝3.705min；[M-1]＝392.9

¹H NMR:(400MHz,DMSO-d₆)δ12.90(s,1H),9.17(s,1H),7.19-7.15(m,2H),7.09-7.01(m,2H),6.73(d,J＝2.4Hz,1H),6.66(d,J＝8.0Hz,1H),6.59-6.52(m,3H),4.58(s,2H),3.76(d,J＝8.8Hz,4H),2.11(s,6H)。

Example 134

Process for preparing methyl 2- (3, 5-dichloro-4- (3- (4-fluorophenethyl) -4-hydroxybenzyl) phenoxy) acetate (compound 134) Synthesis of

To a solution of intermediate C45(120mg, 555umol) and intermediate A10(52mg, 185umol) in DCE (2mL) was added ZnCl₂(1M in THF) (463umol, 0.46 mL). The mixture was stirred at 85 ℃ overnight. Water (5mL) was added and the resulting mixture was extracted with DCM (3mL x 3). The combined organic phases were washed with brine (10mL) and Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (EtOAc/petroleum ether ═ 1/5) to give compound 134(40mg, 51% yield) as a white solid.

TLC EtOAc/Petroleum Ether 1/5(v/v), R_f＝0.2

¹H NMR:(400MHz,DMSO)δ9.19(s,1H),7.19–7.15(m,1H),7.14(s,1H),7.13(d,J＝4.0Hz,1H),7.04(dt,J＝4.8,2.0Hz,1H),6.76(s,1H),6.74–6.70(m,1H),6.68(d,J＝8.0Hz,1H),4.90(s,1H),4.00(s,1H),3.71(s,1H),2.74(dt,J＝11.6,6.0Hz,1H)。

Example 135

Synthesis of 2- (3, 5-dichloro-4- (3- (4-fluorophenethyl) -4-hydroxybenzyl) phenoxy) acetic acid (Compound 135)

To compound 134(90mg, 185umol) in THF/H₂LiOH. H was added to the mixture in O (2/0.5mL)₂O(13.3mg，556umol)。The mixture was stirred at room temperature for 2 h. Water (5mL) was added and the pH adjusted to pH 3-4 with 1N HCl. The resulting mixture was extracted with EtOAc (3mL x 3); the combined organic phases were washed with brine (10mL) and Na₂SO₄Dry, concentrate in vacuo, and purify by Prep-TLC (DCM/MeOH ═ 10/1) to give compound 135 as a white solid (25mg, 65% yield).

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.25

LCMS:T＝4.058min；[M-1]＝447.0

¹H NMR:(400MHz,DMSO)δ9.18(s,1H),7.16(dd,J＝8.4,6.4Hz,1H),7.07(d,J＝8.8Hz,1H),7.03(t,J＝8.8Hz,1H),6.76(s,1H),6.73–6.66(m,1H),4.77(s,1H),3.99(s,1H),2.73(dt,J＝12.4,6.0Hz,1H)。

¹⁹F NMR:(376MHz,DMSO)δ-117.77(s)。

Example 136

Synthesis of 2- (3, 5-dichloro-4- (3- (4-fluorobenzoyl) -4-hydroxybenzyl) phenoxy) acetic acid (compound 136) Become into

To a room temperature solution of intermediate A6(500mg, 1.5mmol) and TEA (296mg, 3.0mmol) in DCM (20mL) was added 4-fluorobenzoyl chloride (243mg, 1.5 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (20mL), washed with water (10mL), then brine (10mL), and Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (EtOAc/petroleum ether ═ 1/5) to give 4- (2, 6-dichloro-4- (2-methoxy-2-oxoethoxy) benzyl) phenyl 4-fluorobenzoate (intermediate 136-1) as a white solid (460mg, 68% yield).

TLC:MeOH/DCM＝1/20(v/v),Rf＝0.67

¹H NMR:(400MHz,DMSO-d₆)δ8.18(dd,J＝8.8,5.6Hz,2H),7.43(t,J＝8.8Hz,2H),7.19(s,5H),4.91(s,2H),4.22(s,2H),3.71(s,3H)。

Towards centerAlCl was added to a solution of intermediate 136-1(150mg, 0.3mmol) in DCE (5.0mL)₃(86mg, 0.6 mmol). The mixture was heated to 120 ℃ for 12 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (10 mL). The mixture was extracted with DCM (10mL × 3); the combined organic phases are passed over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (methanol/DCM ═ 1/10) to give compound 136 as a brown solid (11mg, 8% yield).

TLC:MeOH/DCM＝1/20(v/v),Rf＝0.2

LCMS:RT＝3.07min；[M-1]＝447。

¹H NMR:(400MHz,DMSO-d₆)δ13.12(s,1H),10.23(s,1H),7.77–7.71(m,2H),7.37–7.30(m,3H),7.21(dd,J＝8.4,2.4Hz,1H),7.12(s,2H),7.09(d,J＝2.4Hz,1H),6.91(d,J＝8.4Hz,1H),4.78(s,2H),4.11(s,2H)。

Example 137

2- (3, 5-dichloro-4- (3- ((4-fluorophenyl) (hydroxy) methyl) -4-hydroxybenzyl) phenoxy) acetic acid (compound) 137) Synthesis of (2)

To a solution of compound 136(11mg, 24.5umol) in THF (3mL) at 10 deg.C was added NaBH₄(1.1mg, 29.4 umol). The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with water (5mL), acidified to pH-4-5 with aqueous HCl (1N), and extracted with EtOAc (5 x 2 mL). The combined organic phases are passed over Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by Prep-TLC (methanol/DCM ═ 1/10) to give compound 137(9mg, 81% yield) as a brown solid.

TLC:MeOH/DCM＝1/10(v/v),Rf＝0.12

LCMS:RT＝2.54min；[M-1]＝449。

¹H NMR:(400MHz,DMSO-d₆)δ13.20(s,1H),9.28(s,1H),7.35–7.29(m,2H),7.26(d,J＝2.4Hz,1H),7.10–7.04(m,3H),6.74(dd,J＝8.4,2.4Hz,1H),6.64(d,J＝8.4Hz,1H),5.89(d,J＝4.0Hz,1H),5.68(d,J＝4.4Hz,1H),5.32(t,J＝5.2Hz,1H),4.68(s,2H),4.10–3.97(m,2H)。

Example 138

1- (aziridin-1-yl) -2- (3, 5-dichloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]- Synthesis of 3-yl) methyl) phenoxy) ethan-1-one (Compound 138)

Compound 138 was prepared according to the procedure described in example 4, substituting compound 5 for compound 3 and an aqueous aziridine solution for an aqueous methylamine solution.

Example 139

1- (azetidin-1-yl) -2- (3, 5-dichloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl) Base of]Synthesis of (E) -3-yl) methyl) phenoxy) ethan-1-one (Compound 139)

Compound 139 was prepared according to the procedure described in example 4, substituting compound 5 for compound 3 and aqueous azetidine for aqueous methylamine.

Example 140

2- (3, 5-dichloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl) ]-3-yl) methyl) phenoxy Synthesis of 1- (pyrrolidin-1-yl) ethan-1-one (Compound 140)

Compound 140 was prepared following the procedure described in example 4, substituting compound 5 for compound 3 and aqueous pyrrolidine for aqueous methylamine.

Example 141

2- (3, 5-dichloro-4- ((3'- (difluoromethoxy) -6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy Synthesis of 1- (piperidin-1-yl) ethan-1-one (Compound 141)

Compound 141 was prepared according to the procedure described in example 4, substituting compound 5 for compound 3 and aqueous piperidine for aqueous methylamine.

Example 142

2- (3, 5-dichloro-4- ((6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) -acetic acid (compound 142) Synthesis of (2)

Compound 142 is prepared according to the procedure described in example 1, substituting potassium phenyltrifluoroborate for 3-trifluoromethyl-phenylboronic acid and Pd (OAc)₂In place of Pd (dppf) Cl₂。MS(ES-API)m/z 400.9/402.9。

Example 143

2- (3, 5-dichloro-4- ((3 '-cyclopropyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) acetic acid Synthesis of (Compound 143)

Compound 143 was prepared according to the procedure described in example 1, substituting (3-cyclopropylphenyl) boronic acid for 3-trifluoromethyl-phenylboronic acid. MS (ES-API) m/z 440.7/442.8.

Example 144

1- (aziridin-1-yl) -2- (3)5-dichloro-4- ((6-hydroxy-3 '-propyl- [1,1' -biphenyl)]-3-yl) methyl Yl) PHENOXY) ETHAN-1-ONE (COMPOUND 144) SYNTHESIS

Compound 144 was prepared following the procedure described in example 4, substituting compound 16 for compound 3 and an aqueous aziridine solution for an aqueous methylamine solution.

Example 145

1- (azetidin-1-yl) -2- (3, 5-dichloro-4- ((6-hydroxy-3 '-propyl- [1,1' -biphenyl)]-3- Synthesis of (yl) methyl) phenoxy) ethan-1-one (Compound 145)

Compound 145 was prepared following the procedure described in example 4, substituting compound 16 for compound 3 and aqueous azetidine for aqueous methylamine.

Example 146

2- (3, 5-dichloro-4- ((6-hydroxy-3 '-propyl- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) -1- (pir-o-xy) Synthesis of pyrrolidin-1-yl) ethan-1-one (Compound 146)

Compound 146 was prepared following the procedure described in example 4, substituting compound 16 for compound 3 and aqueous pyrrolidine for aqueous methylamine.

Example 147

2- (3, 5-dichloro-4- ((6-hydroxy-3 '-propyl- [1,1' -biphenyl)]-3-yl) methyl) phenoxy) -1- (piperazines Synthesis of pyridin-1-yl) ethan-1-one (Compound 147)

Compound 147 was prepared following the procedure described in example 4, substituting compound 16 for compound 3 and aqueous piperidine for aqueous methylamine.

Example 148

1- (aziridin-1-yl) -2- (3-chloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) - Synthesis of 5-methylphenoxy) ethan-1-one (Compound 148)

Compound 148 was prepared following the procedure described in example 4, substituting compound 60 for compound 3 and an aqueous aziridine solution for an aqueous methylamine solution.

Example 149

1- (azetidin-1-yl) -2- (3-chloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl Synthesis of the radical) -5-methylphenoxy) ethan-1-one (Compound 149)

Compound 149 was prepared following the procedure described in example 4, substituting compound 60 for compound 3 and aqueous azetidine for aqueous methylamine.

Example 150

2- (3-chloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylphenoxy) -1- Synthesis of (pyrrolidin-1-yl) ethan-1-one (Compound 150)

Compound 150 was prepared following the procedure described in example 4, substituting compound 60 for compound 3 and aqueous pyrrolidine for aqueous methylamine.

Example 151

22- (3-chloro-4- ((3 '-ethyl-6-hydroxy- [1,1' -biphenyl)]-3-yl) methyl) -5-methylphenoxy) - Synthesis of 1- (piperidin-1-yl) ethan-1-one (Compound 151)

Compound 151 was prepared according to the procedure described in example 4, substituting compound 60 for compound 3 and aqueous piperidine for aqueous methylamine.

Example 152

1- (aziridin-1-yl) -2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) Yl) Synthesis of ethane-1-one (Compound 152)

Compound 152 was prepared following the procedure described in example 71, substituting compound 72 for compound 69 and aziridine aqueous solution for methylamine aqueous solution.

Example 153

1- (azetidin-1-yl) -2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) benzene Synthesis of oxy) ethan-1-one (Compound 153)

Compound 153 was prepared according to the procedure described in example 71, substituting compound 72 for compound 69 and aqueous azetidine for aqueous methylamine.

Example 154

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) -1- (pyrrolidine-1-) Yl) Synthesis of ethan-1-one (Compound 154)

Compound 154 was prepared following the procedure described in example 71, substituting compound 72 for compound 69 and aqueous pyrrolidine for aqueous methylamine.

Example 155

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) ethyl) -4-hydroxybenzyl) phenoxy) -1- (piperidin-1-yl) Synthesis of ethan-1-one (Compound 155)

Compound 155 was prepared according to the procedure described in example 71, substituting compound 72 for compound 69 and aqueous piperidine for aqueous methylamine.

Example 156

2- (4- (3- (bis (4-fluorophenyl) methyl) -4-hydroxybenzyl) -3, 5-dichlorophenoxy) acetic acid (Compound 156) Synthesis of (2)

Compound 156 was prepared according to the procedure described for examples 70 and 71 substituting 4,4' - (chloromethylene) bis (fluorobenzene) for 4-fluorobenzyl chloride in example 70. MS (ES-API) m/z 526.8/528.8.

Example 157

1- (aziridin-1-yl) -2- (3-chloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -5-methylphenoxy) ethyl ester Synthesis of alk-1-ones (Compound 157)

Compound 157 was prepared according to the procedure described in example 71, substituting compound 114 for compound 69 and aqueous methylamine with aqueous aziridine.

Example 158

1- (azetidin-1-yl) -2- (3-chloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -5-methylphenoxy) Synthesis of ethane-1-one (Compound 158)

Compound 158 was prepared according to the procedure described in example 71, substituting compound 114 for compound 69 and aqueous azetidine for aqueous methylamine.

Example 159

2- (3-chloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -5-methylphenoxy) -1- (pyrrolidin-1-yl) ethyl Synthesis of alk-1-ones (Compound 159)

Compound 159 was prepared according to the procedure described in example 71, substituting compound 114 for compound 69 and aqueous pyrrolidine for aqueous methylamine.

Example 160

2- (3-chloro-4- (3- (4-fluorobenzyl) -4-hydroxybenzyl) -5-methylphenoxy) -1- (piperidin-1-yl) ethane- Synthesis of 1-one (Compound 160)

Compound 160 was prepared according to the procedure described in example 71, substituting compound 114 for compound 69 and aqueous piperidine for aqueous methylamine.

Example 161

Synthesis of 2- (4- (3-benzyl-4-hydroxybenzyl) -3, 5-dichlorophenoxy) acetic acid (Compound 161)

Compound 161 was prepared according to the procedure described for the preparation of examples 114 and 115 substituting intermediate a10 for intermediate a15 and 2-benzylphenol for 2- (4-fluorobenzyl) phenol in example 114. MS (ES-API) m/z 414.9/416.9.

Example 162

1- (aziridin-1-yl) -2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) propyl) -4-hydroxybenzyl) phenoxy) benzene Yl) Synthesis of ethan-1-one (Compound 162)

Compound 162 was prepared following the procedure described in example 4, substituting compound 98 for compound 3 and aziridine aqueous solution for methylamine aqueous solution.

Example 163

1- (azetidin-1-yl) -2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) propyl) -4-hydroxybenzyl) benzene Synthesis of oxy) ethan-1-one (Compound 163)

Compound 163 was prepared following the procedure described in example 4, substituting compound 98 for compound 3 and aqueous azetidine for aqueous methylamine.

Example 164

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) propyl) -4-hydroxybenzyl) phenoxy) -1- (pyrrolidine-1-) Yl) Synthesis of ethan-1-one (Compound 164)

Compound 164 was prepared following the procedure described in example 4, substituting compound 98 for compound 3 and aqueous pyrrolidine for aqueous methylamine.

Example 165

2- (3, 5-dichloro-4- (3- (1- (4-fluorophenyl) propyl) -4-hydroxybenzyl) phenoxy) -1- (piperidin-1-yl) Synthesis of ethane-1-one (Compound 165)

Compound 165 was prepared according to the procedure described in example 4, substituting compound 98 for compound 3 and aqueous piperidine for aqueous methylamine.

Example 166

Thyroid hormone reporter gene assay

Compounds were tested for thyroid hormone receptor activity using the TR receptor reporter assay. The reporter cells used in this assay express a TR receptor hybrid (TR α or TR β) in which the native N-terminal DNA Binding Domain (DBD) has been replaced by the N-terminal DNA binding domain of yeast Gal4 DBD. The reporter firefly luciferase is functionally associated with the Upstream Activation Sequence (UAS) of Gal 4. Both cell lines were derived from human embryonic kidney (HEK 293).

Step 1: a suspension of reporter cells was prepared in cell recovery medium containing 10% charcoal-treated FBS and dispensed into assay plates. The plates were preincubated for 6 hours in a cell culture incubator (37 ℃/5% CO 2/85% humidity).

Step 2: test compound stocks and triiodothyronine were diluted in DMSO to produce "1,000 x concentration" solutions relative to each final treatment concentration. These intermediate stocks were then diluted directly into compound screening media containing 10% charcoal-treated FBS to generate "2 x concentration" treatment media (containing 0.2, 0.4, or 0.8% DMSO).

And step 3: at the end of the pre-incubation period, the medium was discarded from the assay plate and all wells received 100 μ l of compound screening media. 100 μ l of each previously prepared "2 x concentration" treatment medium was dispensed into duplicate assay wells to achieve the desired final treatment concentration. The final concentration of DMSO in all assay wells was 0.1, 0.2 or 0.4%. Assay plates were incubated in a cell culture incubator (37 ℃/5% CO 2/85% humidity) for 24 hours.

And 4, step 4: at the end of the 24 hour assay, the treatment medium was discarded and 100. mu.l/well of luciferase detection reagent was added. Relative photometric units (RLU) were quantified from each assay well. The performance of the TR α and TR β assays was verified using the reference agonist triiodothyronine (T3).

The results of these assays are presented in table 2 below, where the data are reported as EC determined for TR α and TR β receptors₅₀The value, and the Selectivity Index (SI) is calculated as EC₅₀(TRα)/EC₅₀(TR β). To this end, EC₅₀And the SI values are expressed as follows:

efficacy: + EC₅₀>1,000nM

++100nM<EC₅₀≤1,000nM

+++10nM<EC₅₀≤100nM

++++EC₅₀≤10nM

Not determined ND

And (3) selectivity: + T3-SI ≤ 3X

++3X<T3-SI≤30X

+++T3-SI>30X

Not determined ND

TABLE 2

Activity data

As shown in the above experiments, the compounds of the present invention show improved TR β selectivity compared to the natural agonist T3.

Example 167

In vivo Activity

Animal research

Compounds of the invention can be tested for thyroid hormone receptor agonist activity in an in vivo model according to the following protocol.

Male Sprague-Dawley rats (about 6 weeks old) were fed a high cholesterol diet (HC Chow; 1.5% cholesterol, 0.5% choline) for at least 10 days. Animals were weighed on day-1. Test compounds were formulated in 1% NMP/1% solutol and administered orally (PO), Subcutaneously (SC) or Intraperitoneally (IP) for 7 days, each daily dose based on the body weight of the day. On days 1 and 7, blood samples were taken via the saphenous vein approximately 24 hours after the first and last dose, respectively, serum treated, and frozen at-80 ℃. Serum samples were analyzed for total cholesterol, low density lipoprotein cholesterol and/or triglycerides using a clinical chemistry analyzer. The levels of test compound in these same samples can be determined by LCMS comparing the peak areas to authentic standards, if desired. Rats were then anesthetized with isoflurane and additional blood samples were collected from the inferior vena cava or by cardiac puncture. The samples were again serotreated and then analyzed for T3/T4/TSH levels by ELISA. The rats were sacrificed by exsanguination or pneumothorax; organs were harvested and weighed. Organ weight data are reported as absolute values and as a percentage relative to the final body weight.

Compounds of the invention can be tested for thyroid hormone-mediated remyelination according to the following protocol.

Eight week old male and female icako-Myrf mice were treated intraperitoneally with 100 μ L (20mg/mL) of tamoxifen daily for 5 days to induce oligodendrocyte depletion by removing Myrf from mature oligodendrocytes (Koenning et al 2012j. neuroscience). Test compounds were formulated into food or 1% NMP/1% solutol and PO, SC or IP administration was started 2, 5 or 12 weeks after tamoxifen induction. The dosing frequency may be daily (QD), every other day (Q2D), 3 times per week (QIW), or weekly (QW). The functional impact of central demyelination was measured by applying the accelerated rotarod technique to mice, where the time for the mice to fall off the rotarod is indicative of their neuromuscular function. Mice were subjected to the rotarod protocol weekly, every other week, or at specific times during the study. The loss of myelination was associated with a reduction in time such that the lowest point of capacity occurred approximately 12 weeks after tamoxifen treatment. Partial recovery occurs between 12-24 weeks. Mice were sacrificed 24 weeks after tamoxifen induction and examined brain and spinal cord tissue for remyelination using histological analysis.

The compounds of the present invention can be tested for inhibition of thyroid hormone mediated fibrosis according to the following protocol.

Adult male C57Bl/6 mice induced pulmonary fibrosis by a single Oropharyngeal (OP) administration of 1.5-2U/kg bleomycin. The test compounds were formulated in 1% NMP/1% solutol and administered PO, SC or IP, QD, beginning on day-1 (prophylactic) or on day 7 (therapeutic) after bleomycin administration. On day 21, mice were anesthetized and blood was drawn by cardiac puncture. Lungs were excised and weighed, bronchoalveolar lavage, inflated and fixed for histological analysis. Lung specimens were embedded in paraffin and stained with hematoxylin and eosin and masson trichrome stain. The degree of fibrosis was assessed by the pathologist using the Ashcroft score which quantifies fibrosis. At least 10 sites per lung were evaluated and the mean score per lung was reported.

Tissue distribution study

For the tissue concentration study in male C57Bl/6 mice, the test compounds were formulated as NMP/solutol/PBS solutions at a concentration of 0.05mg/mL, administered at 2mL/kg by subcutaneous injection or oral administration, at a target dose of 0.100 mg/kg. Plasma, brain, liver, lung, kidney, heart and other selected tissue samples were collected at 0.5, 2, 8 and 24 hours (for AUC determinations) or 1 hour (single time point) post-dose, three animals per time point. Plasma concentrations of the tissue homogenate and test compound were measured using LC-MS/MS with a lower limit of quantitation of 0.0200ng/mL or 0.100 ng/g. Pharmacokinetic parameters were determined by a non-compartmental method using WinNonlin.

Gene activation

Adult male Sprague-Dawley rats or C57BL/6 mice at up to 3 dose levels (e.g., ED obtained in the cholesterol lowering studies described above₅₀Values 1x, 3x and 10x) of test compound was administered orally. At predetermined times, 4, 8 or 24 hours after test compound administration, rodents are anesthetized and blood is drawn to prepare plasma samples for measurement of drug concentration. Samples of various organs including, but not limited to, liver, brain, kidney, heart, lung, skeletal muscle, pituitary and testis were collected and processed for RNA analysis. Samples are analyzed by RNA-Seq after RNA isolation, or using appropriate platforms that do not require RNA isolation, such as Quantigene^TMAnalysis was performed by targeted gene analysis. Multiple genes are used to represent T3-mediated gene signatures in each tissue; each tissue used a different gene, and all genes were normalized to multiple housekeeping genes, which account for any variability in overall RNA quality.

Transformation study

The amide of formula II can be converted to the active agonist acid of formula IV by the action of an amidase such as FAAH. Similarly, esters of formula III can be converted to active agonist acids of formula IV by the action of various esterases. This in vivo transformation can be demonstrated by pharmacokinetic studies that measure the levels of test compounds as follows:

The pharmacokinetics of the test compounds were evaluated after IV, PO or SC administration in fasted male Sprague-Dawley rats (N ═ 3/route/dose). The test compounds were administered as a clear solution in NMP/solutol/PBS at a concentration of 0.1mg/mL as a single dose by intravenous injection (0.1mg/kg) or oral (1mg/kg) or subcutaneous injection (SC, 0.1 mg/kg). Blood samples were collected at K before, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after dosing₂EDTA tubes. Plasma concentrations of test compounds were determined using LC-MS/MS with a lower limit of quantitation of 0.0200 ng/mL. Pharmacokinetic parameters were determined by a non-compartmental method using WinNonlin.

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the application data sheet, are incorporated herein by reference, in their entirety. Furthermore, the terms used in the following claims should not be construed to be limited to the specific embodiments disclosed in the specification, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled.

This application claims priority from united states provisional application number 62/812,890 filed on 3/1/2019 and united states provisional application number 62/953,100 filed on 12/23/2019, which are incorporated herein by reference in their entirety.