Protein tyrosine kinase 6(PTK6) degradation/disruption compounds and methods of use

文档序号：664425 发布日期：2021-04-27 浏览：17次中文

阅读说明：本技术 蛋白酪氨酸激酶6(ptk6)降解/破坏化合物和使用方法 (Protein tyrosine kinase 6(PTK6) degradation/disruption compounds and methods of use ) 是由金剑 H·艾瑞斯刘静熊燕 J·拜尔里 S·托米塔 J·P·胡于 2019-07-03 设计创作，主要内容包括：本文中公开的是包含PTK6配体、降解/破坏标签和连接基团的蛋白酪氨酸激酶6(PTK6)降解/破坏化合物和在PTK6介导的疾病的治疗中使用此类化合物的方法。(Disclosed herein are protein tyrosine kinase 6(PTK6) degradation/disruption compounds comprising a PTK6 ligand, a degradation/disruption tag, and a linking group and methods of using such compounds in the treatment of PTK 6-mediated diseases.)

1. A divalent compound comprising a protein tyrosine kinase 6(PTK6) ligand conjugated to a degradation/disruption tag through a linking group selected from the group consisting of:

(a)

formula 7

Wherein

A. W and B are independently selected at each occurrence from null, or a divalent moiety selected from: r ' -R ', R ' COR ', R ' CO ₂R”、R’C(O)N(R¹)R”、R’C(S)N(R¹)R”、R’OR”、R’OC(O)R”、R’OC(O)OR”、R’OCON(R¹)R”、R’SR”、R’SOR”、R’SO₂R”、R’SO₂N(R¹)R”、R’N(R¹)R”、R’NR¹COR”、R’NR¹C(O)OR”、R’NR¹CON(R²)R”、R’NR¹C(S)R”、R’NR¹S(O)R”、R’NR¹S(O)₂R ', and R' NR¹S(O)₂N(R²) R' is provided, wherein

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C ₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R¹and R²Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

r 'and R', R¹And R²R' and R¹R' and R²R' and R¹R' and R²Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring; and

m is 0 to 15;

(b)

in the formula (7A), the compound has the structure,

wherein

R¹、R²、R³And R⁴Independently at each occurrence, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C ₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino, and optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 3-to 8-membered cycloalkyloxy, optionally substituted 3-to 10-membered carbocyclylamino, optionally substituted 4-to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹And R²、R³And R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

A. w and B are independently selected at each occurrence from null, or a divalent moiety selected from: r ' -R ', R ' COR ', R ' CO₂R”、R’C(O)N(R⁵)R”、R’C(S)N(R⁵)R”、R’OR”、R’OC(O)R”、R’OC(O)OR”、R’OCONR⁵R”、R’SR”、R’SOR”、R’SO₂R”、R’SO₂N(R⁵)R”、R’N(R⁵)R”、R’NR⁵COR”、R’NR⁵C(O)OR”、R’NR⁵CON(R⁶)R”、R’NR⁵C(S)R”、R’NR⁵S(O)R”、R’NR⁵S(O)₂R ', and R' NR⁵S(O)₂N(R⁶) R' is provided, wherein

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C ₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁵and R⁶Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C ₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

r 'and R', R⁵And R⁶R' and R⁵R' and R⁶R' and R⁵R' and R⁶Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15;

n is 0 to 15 at each occurrence; and

o is 0 to 15;

(c)

in the formula (7B), the compound has the following structure,

wherein

R¹And R²Independently at each occurrence, is selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, and optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical, C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 3-to 8-membered cycloalkyloxy, optionally substituted 3-to 10-membered carbocyclylamino, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹And R²Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl group A ring or a 4-to 20-membered heterocyclyl ring;

a and B are independently selected at each occurrence from null, or a divalent moiety selected from: r ' -R ', R ' COR ', R ' CO₂R”、R’C(O)NR³R”、R’C(S)NR³R”、R’OR”、R’OC(O)R”、R’OC(O)OR”、R’OCON(R³)R”、R’SR”、R’SOR”、R’SO₂R”、R’SO₂N(R³)R”、R’N(R³)R”、R’NR³COR”、R’NR³C(O)OR”、R’NR³CON(R⁴)R’、R’NR³C(S)R”、R’NR³S(O)R”、R’NR³S(O)₂R ', and R' NR³S(O)₂N(R⁴) R' is provided, wherein

R^rSelected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R³and R⁴Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

r 'and R', R³And R⁴R' and R³R' and R⁴R' and R³R' and R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15 at each occurrence; and

n is 0 to 15;

(d)

in the formula (7C), the compound has the structure,

wherein

X is selected from O, NH, and NR⁷；

R¹、R²、R³、R⁴、R⁵And R⁶Independently at each occurrence, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C ₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 3-to 8-membered cycloalkyloxy group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

a and B are independently selected from null, or a divalent moiety selected from: r ' -R ', R ' COR ', R ' CO₂R”、R’C(O)N(R⁸)R”、R’C(S)N(R⁸)R”、R’OR”、R’OC(O)R”、R’OC(O)OR”、R’OCON(R⁸)R”、R’SR”、R’SOR”、R’SO₂R”、R’SO₂N(R⁸)R”、R’N(R⁸)R”、R’NR⁸COR”、R’NR⁸C(O)OR”、R’NR⁸CON(R⁹)R”、R’NR⁸C(S)R”、R’NR⁸S(O)R”、R’NR⁸S(O)₂R ', and R' NR⁸S(O)₂N(R⁹) R' is provided, wherein

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl radicalOptionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C ₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁷、R⁸and R⁹Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C ₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

r 'and R', R⁸And R⁹R' and R⁸R' and R⁹R' and R⁸R' and R⁹Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15 at each occurrence;

n is 0 to 15 at each occurrence;

o is 0 to 15; and

p is 0 to 15;

(e) the linking group comprises a ring selected from the group consisting of a 3-to 13-membered ring, a 3-to 13-membered fused ring, a 3-to 13-membered bridged ring, and a 3-to 13-membered spiro ring;

(f)

wherein X is C ═ O or CH₂，

Y is C ═ O or CH₂And are and

n is 0 to 15;

(g)

wherein X is C ═ O or CH₂，

Y is C ═ O or CH₂，

m is 0 to 15, and m is,

n is 0 to 6, and

o is 0 to 15; or

(h)

Wherein

X is C ═ O or CH₂，

Y is C ═ O or CH₂，

R is-CH₂–、–CF₂–、–CH(C_1-3Alkyl) -, -C (C)_1-3Alkyl) (C_1-3Alkyl) -, -CH ═ CH-, -C (C)_1-3Alkyl) ═ C (C)_1-3Alkyl) -, -C ═ C-, -O-, -NH-, -N (C)_1-3Alkyl) -, -C (O) NH-, -C (O) N (C)_1-3Alkyl) -, 3-to 13-membered rings, 3-to 13-membered fused rings, 3-to 13-membered bridged rings, and/or 3-to 13-membered spiro rings,

m is 0 to 15, and

n is 0 to 15.

2. The divalent compound of claim 1 wherein the linking group comprises:

wherein

A. W and B are independently selected at each occurrence from null, or a divalent moiety selected from: r ' -R ', R ' COR ', R ' CO₂R”、R’C(O)N(R¹)R”、R’C(S)N(R¹)R”、R’OR”、R’OC(O)R”、R’OC(O)OR”、R’OCON(R¹)R”、R’SR”、R’SOR”、R’SO₂R”、R’SO₂N(R¹)R”、R’N(R¹)R”、R’NR¹COR”、R’NR¹C(O)OR”、R’NR¹CON(R²)R”、R’NR¹C(S)R”、R’NR¹S(O)R”、R’NR¹S(O)₂R ', and R' NR¹S(O)₂N(R²) R' is provided, wherein

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally, theSubstituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C ₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R¹and R²Independently selected from hydrogen,Optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

r 'and R', R¹And R²R' and R¹R' and R²R' and R¹R' and R²Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring; and

m is 0 to 15.

3. The divalent compound according to claim 1 or 2, wherein the linking group comprises:

wherein

A is R 'C (O) NR' R¹Wherein R 'and R' are each optionally substituted C₁-C₈An alkylene group;

w is R 'OR ", wherein R' and R" are each null;

b is optionally substituted C₁-C₈An alkylene group;

R¹is hydrogen; and

m is 2 to 5.

4. A divalent compound according to claim 3 wherein

A is R 'C (O) NR' R¹Wherein R 'and R' are each-CH₂CH₂-；

W is-O-;

b is-CH₂CH₂-；

R¹Is hydrogen; and

m is 2 to 5.

5. A divalent compound according to claim 3 wherein

A is R 'C (O) NR' R¹Wherein R 'and R' are each-CH₂CH₂-；

W is-O-;

b is-CH₂CH₂-；

R¹Is hydrogen; and

m is 4 or 5.

6. The divalent compound according to claim 1 or 2, wherein the linking group comprises:

wherein

A is R 'C (O) R' where R 'is an optionally substituted 4-to 10-membered heterocyclyl and R' is optionally substituted C₁-C₈An alkylene group;

w is R 'OR ", wherein R' and R" are each null;

b is optionally substituted C₁-C₈An alkylene group; and

m is 2 to 9.

7. The divalent compound according to claim 6, wherein

A is R 'C (O) R' where R 'is piperazine and R' is-CH ₂CH₂-；

W is-O-;

b is-CH₂CH₂-；

R¹Is hydrogen; and

m is 2 to 7 or 9.

8. The divalent compound according to claim 6, wherein

A is R ' C (O) R ' where R ' isPiperazine and R' is-CH₂CH₂-；

W is-O-;

b is-CH₂CH₂-；

R¹Is hydrogen; and

m is 4-6, 8 or 9.

9. The divalent compound according to claim 1 or 2, wherein the linking group comprises:

wherein

A is R 'C (O) R' where R 'is an optionally substituted 4-to 10-membered heterocyclyl and R' is optionally substituted C₁-C₈An alkylene group;

w is R 'OR' where R 'is empty and R' is optionally substituted C₁-C₈An alkylene group;

b is R ' C (O) R ' wherein R ' is empty or optionally substituted C₁-C₈An alkylene group; and

m is 1.

10. The divalent compound according to claim 9, wherein

A is R 'C (O) NR' R¹Wherein R 'is piperazine and R' is-CH₂-；

W is-OCH₂-；

B is-C (O) -; and

m is 1.

11. The divalent compound according to claim 9, wherein

A is R 'C (O) NR' R¹Wherein R 'is piperazine and R' is-CH₂-；

W is-OCH₂CH₂O-；

B is-CH₂C (O) -; and

m is 1.

12. The divalent compound of claim 1 wherein the linking group comprises:

wherein

R¹、R²、R³And R⁴Independently at each occurrence, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C ₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino, and optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 3-to 8-membered cycloalkyloxy, optionally substituted 3-to 10-membered carbocyclylamino, optionally substituted 4-to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹And R²、R³And R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C ₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁵and R⁶Independently selected from hydrogen, optionally substituted C ₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

r 'and R', R⁵And R⁶R' and R⁵R' and R⁶R' and R⁵R' and R⁶Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15;

n is 0 to 15 at each occurrence; and

o is 0 to 15.

13. The divalent compound of claim 1 wherein the linking group comprises:

wherein

R¹And R²Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C ₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

r 'and R', R³And R⁴R' and R³R' and R⁴R' and R³R' and R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15 at each occurrence; and

n is 0 to 15.

14. The divalent compound of claim 1 wherein the linking group comprises:

wherein

R¹And R²Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C ₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclic groupsOptionally substituted 4-to 10-membered heterocyclic group, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C ₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

r 'and R', R³And R⁴R' and R³R' and R⁴R' and R³R' and R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15 at each occurrence; and

n is 0 to 15.

15. The divalent compound of claim 14 wherein the linking group comprises:

wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R 'C (O) NR' R¹Or R' NR¹C (O) R 'wherein R' is optionally substituted C₁-C₈Alkylene and R "is null;

b is R 'C (O) R ", wherein R' and R" are both null, or B is null;

R¹is hydrogen; and

o is 6 to 10; and

p is 0.

16. The divalent compound according to claim 15 wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R 'C (O) NR' R¹Or R' NR¹C (O) R 'where R' is-CH₂CH₂CH₂-and R "is empty;

b is-C (O) -;

R¹is hydrogen; and

o is 7 to 10; and

p is 0.

17. The divalent compound according to claim 15 wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R 'C (O) NR' R¹Or R' NR¹C (O) R 'where R' is-CH₂CH₂-and R "is empty;

b is-C (O) -;

R¹is hydrogen; and

o is 6 to 10; and

p is 0.

18. The divalent compound according to claim 15 wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R'C(O)NR”R¹Wherein R' is-CH₂CH₂-and R "is empty;

b is-C (O) -;

R¹is hydrogen; and

o is 6, 9 or 10; and

p is 0.

19. The divalent compound according to claim 15 wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R' NR¹C (O) R 'where R' is-CH₂CH₂-and R "is empty;

b is-C (O) -;

R¹is hydrogen; and

o is 6 to 10; and

p is 0.

20. The divalent compound according to claim 15 wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R 'C (O) NR' R¹Wherein R' is-CH₂CH₂CH₂-and R "is empty;

b is null;

R¹is hydrogen; and

o is 7 or 8; and

p is 0.

21. The divalent compound according to claim 15 wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R 'C (O) NR' R¹Wherein R' is-CH₂CH₂-and R "is empty;

b is null;

R¹is hydrogen; and

o is 6 to 8; and

p is 0.

22. The divalent compound according to claim 15 wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R 'C (O) NR' R¹Wherein R' is-CH₂CH₂-and R "is empty;

b is null;

R¹is hydrogen; and

o is 8; and

p is 0.

23. The divalent compound of claim 14 wherein the linking group comprises:

wherein

R⁵And R⁶At each occurrence is hydrogen;

a is R 'C (O) R' where R 'is an optionally substituted 4-to 10-membered heterocyclyl and R' is optionally substituted C₁-C₈An alkylene group;

b is R 'C (O) R' wherein R 'and R' are each null;

o is 4 to 12; and

p is 0.

24. The divalent compound according to claim 23 wherein

A is R 'C (O) R' where R 'is piperazine and R' is-CH₂CH₂-；

W is-O-;

b is-C (O) -;

o is 4 to 11; and

p is 0.

25. The divalent compound according to claim 23 wherein

A is R 'C (O) R' where R 'is piperazine and R' is-CH₂CH₂-；

W is-O-;

b is-C (O) -;

o is 9 to 12; and

p is 0.

26. The divalent compound according to any one of claims 1, 2, 12, 13 or 14 wherein a and B are independently at each occurrence selected from the group consisting of null, CO, NH-CO, CO-NH, CH ₂-NH-CO、CH₂-CO-NH、NH-CO-CH₂、CO-NH-CH₂、CH₂-NH-CH₂-CO-NH、CH₂-NH-CH₂-NH-CO、-CO-NH、CO-NH-CH₂-NH-CH₂And CH₂-NH-CH₂。

27. The divalent compound according to any one of claims 1, 2, 12, 13 or 14 wherein o is 0 to 5.

28. The divalent compound according to any one of claims 1, 2, 12, 13 or 14 wherein the linking group comprises one or more rings selected from the group consisting of 3-to 13-membered rings, 3-to 13-membered fused rings, 3-to 13-membered bridged rings and 3-to 13-membered spirorings.

29. The divalent compound according to any one of claims 1, 2, 12, 13 or 14 wherein the linking group comprises one or more rings selected from the group consisting of:

(a)

(b)

(c)

(d)and

(e)

30. the divalent compound of claim 1 wherein the linking group comprises:

wherein

X is C ═ O or CH₂，

Y is C ═ O or CH₂And are and

n is 0 to 15.

31. The divalent compound of claim 1 wherein the linking group comprises:

wherein

X is C ═ O or CH₂，

Y is C ═ O or CH₂，

m is 0 to 15, and m is,

n is 0 to 6, and

o is 0 to 15.

32. The divalent compound of claim 1 wherein the linking group comprises:

wherein

X is C ═ O or CH₂，

Y is C ═ O or CH₂，

R is-CH₂–、–CF₂–、–CH(C_1-3Alkyl) -, -C (C)_1-3Alkyl) (C_1-3Alkyl) -, -CH ═ CH-, -C (C)_1-3Alkyl) ═ C (C)_1-3Alkyl) -, -C ═ C-, -O-, -NH-, -N (C) _1-3Alkyl) -, -C (O) NH-, -C (O) N (C)_1-3Alkyl) -, 3-to 13-membered rings, 3-to 13-membered fused rings, 3-to 13-membered bridged rings, and/or 3-to 13-membered spiro rings,

m is 0 to 15, and

n is 0 to 15.

33. The divalent compound of claim 1 wherein the linking group comprises:

wherein

X is C ═ O,

y is C ═ O,

r is-NH-,

m is 0, and

n is 0 to 15.

34. The divalent compound according to claim 1, subpart (h), or claim 32 wherein

R is a 3-to 13-membered ring, a 3-to 13-membered fused ring, a 3-to 13-membered bridged ring, and/or a 3-to 13-membered spirocyclic ring, one or more of which may contain one or more heteroatoms.

35. The divalent compound according to claim 1, subpart (h), or claim 32 wherein R has the structure:

(a)

(b)

(c)

(d)or

(e)

36. The divalent compound according to any one of claims 1 to 35 wherein the linking group is covalently bonded to the PTK6 ligand.

37. The divalent compound of claim 36 wherein the covalent bond is an amide or amino bond.

38. The divalent compound according to any one of claims 1 to 37 wherein the PTK6 ligand is selected from the group consisting of:

Wherein

R is selected from H, halogen, or unsubstituted or optionally substituted C_1-8Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C₁-C₈Alkylene radical OR⁴、C₁-C₈Alkylene SR⁵、C₁-C₈Alkylene radical NR⁶R⁷、C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, OR⁴、SR⁵、NR⁶R⁷；

R¹Selected from H, C_1-8Alkyl radical, C₁-C₈Hydroxyalkyl radical, C₁-C₈An alkoxyalkyl group,C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, OR⁸、SR⁹、NR¹⁰R¹¹；

R²Is selected from C₆-C₁₀Aryl or C₅-C₁₀Heteroaryl radical, R²Is unsubstituted or optionally substituted with one or more groups selected from: halogen, ═ O, ═ S, CN, NO₂、C_1-8Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C₁-C₈Alkylene radical OR¹²、C₁-C₈Alkylene SR¹³、C₁-C₈Alkylene radical NR¹⁴R¹⁵、C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, OR¹²、SR¹³、NR¹⁴R¹⁵；

R³Is selected from C₆-C₁₀Aryl or C₅-C₁₀Heteroaryl radical, R³Is unsubstituted or substituted by one or more groups selected from: c₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₁-C₈Alkoxyalkyl group, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, halogen, CN, NO₂、＝O、＝S、R¹⁶、OR¹⁶、SR¹⁷、SO₂R¹⁸、NR¹⁹R²⁰、C(O)R¹⁶、C(O)OR¹⁶、C(S)OR^16、C(O)NR¹⁹R²⁰、C(S)NR¹⁹R²⁰、NR¹⁹C(O)R¹⁶、NR¹⁹C(O)OR¹⁶、NR¹⁹S(O)R¹⁶、NR¹⁹S(O)OR¹⁶、S(O)R¹⁶、S(O)OR¹⁶And S (O) ONR¹⁹R²⁰；

R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵Independently selected from H, C₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₃-C₁₀Cycloalkyl, and C (O) C₃-C₁₀Heterocyclyl group, or R⁶And R⁷、R¹⁰And R ¹¹、R¹⁴And R¹⁵Together with the nitrogen atom to which they are attached may independently form a 3-to 10-membered heterocyclyl ring;

R¹⁶、R¹⁷and R¹⁸Independently selected from H, C₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Alkoxyalkyl group, C₁-C₈Hydroxyalkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₇Heterocycloalkyl radical, C₆-C₁₀Aryl radical, C₅-C₁₀Heteroaryl, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₁-C₈Alkoxyalkyl group, C (O) C₃-C₁₀Cycloalkyl, C (O) C₃-C₁₀Heterocyclic group, C (O) C₆-C₁₀Aryl, C (O) C₅-C₁₀Heteroaryl group, C₁-C₈Alkylene radical C₃-C₁₀Cycloalkyl radical, C₁-C₈Alkylene radical C₃-C₁₀Heterocycloalkyl radical, C₁-C₈Alkylene radical C₆-C₁₀Aryl radical, C₁-C₈Alkylene, or C₅-C₁₀A heteroaryl group;

R¹⁹and R²⁰Independently selected from H, C₁-C₈Alkyl radical, C₁-C₈A halogenated alkyl group,C₁-C₈Alkoxyalkyl group, C₁-C₈Hydroxyalkyl radical, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl radical, C₅-C₁₀Heteroaryl, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₁-C₈Alkoxyalkyl group, C (O) C₃-C₁₀Cycloalkyl, C (O) C₃-C₁₀Heterocycloalkyl, C (O) C₆-C₁₀Aryl, C (O) C₅-C₁₀Heteroaryl, C (O) OC₁-C₈Alkyl, C (O) OC₁-C₈Haloalkyl, C (O) OC₁-C₈Hydroxyalkyl, C (O) OC₁-C₈Alkoxyalkyl group, C (O) OC₃-C₁₀Cycloalkyl, C (O) OC₃-C₁₀Heterocyclic group, C (O) OC₆-C₁₀Aryl, C (O) OC₅-C₁₀Heteroaryl, C (O) NC₁-C₈Alkyl, C (O) NC₁-C₈Haloalkyl, C (O) NC₁-C₈Hydroxyalkyl, C (O) NC₁-C₈Alkoxyalkyl group, C (O) NC ₃-C₁₀Cycloalkyl, C (O) NC₃-C₁₀Heterocyclic group, C (O) NC₆-C₁₀Aryl, C (O) NC₅-C₁₀Heteroaryl, SO₂C₁-C₈Alkyl, SO₂C₁-C₈Halogenated alkyl, SO₂C₁-C₈Hydroxyalkyl, SO₂C₁-C₈Alkoxyalkyl group, SO₂C₃-C₁₀Cycloalkyl, SO₂C₃-C₁₀Heterocyclic radical, SO₂C₆-C₁₀Aryl, SO₂C₅-C₁₀Heteroaryl group, C₁-C₈Alkylene radical C₃-C₁₀Cycloalkyl radical, C₁-C₈Alkylene radical C₃-C₁₀Heterocycloalkyl radical, C₁-C₈Alkylene radical C₆-C₁₀Aryl radical, C₁-C₈Alkylene radical C₅-C₁₀Heteroaryl, or R¹⁹And R²⁰Together with the nitrogen atom to which they are attached may independently form a 3-to 10-membered heterocyclyl ring; and

x is selected from CH or N.

39. The divalent compound according to claim 38 wherein R is selected from H, halogen, optionally substituted C_1-3Alkyl, and optionally substituted C_1-3An alkoxy group.

40. The divalent compound according to claim 38 wherein R is selected from H, F, CH₃、CH₂F、CHF₂、CF₃、CH₂CH₃、CH₂CF₃、i-Pr、c-Pr、OCH₃、OCH₂F、OCHF₂、OCF₃、OCH₂CH₃、OCH₂CF₃Oi-Pr and Oc-Pr.

41. The divalent compound according to claim 38 wherein R is selected from CH₃、CF₃、CH₂CH₃、CH₂CF₃And c-Pr.

42. The divalent compound according to claim 38 wherein R is selected from CH₃And c-Pr.

43. The divalent compound according to claim 38 wherein R is c-Pr.

44. The divalent compound according to claim 38 wherein R¹Selected from H, halogen, optionally substituted C_1-3Alkyl, and optionally substituted C_1-3An alkoxy group.

45. The divalent compound of claim 38 wherein R ¹Selected from H, F, CH₃、CH₂F、CHF₂、CF₃、CH₂CH₃、CH₂CF₃、i-Pr、c-Pr、OCH₃、OCH₂F、OCHF₂、OCF₃、OCH₂CH₃、OCH₂CF₃Oi-Pr, and Oc-Pr.

46. The divalent compound according to claim 38 wherein R¹Selected from H, F, CH₃And CF₃。

47. The divalent compound according to claim 38 wherein R¹Is H.

48. The divalent compound according to claim 38 wherein R²Selected from phenyl and 5-to 6-membered heteroaryl, said phenyl and 5-to 6-membered heteroaryl being optionally substituted by a group selected from halogen, optionally substituted C_1-3Alkyl and optionally substituted C_1-3One or more groups of alkoxy groups.

49. The divalent compound according to claim 38 wherein R²Is a 5-to 6-membered heteroaryl, said 5-to 6-membered heteroaryl being optionally substituted by a group selected from halogen, optionally substituted C_1-3Alkyl and optionally substituted C_1-3One or more groups of alkoxy groups.

50. The divalent compound according to claim 38 wherein R²Selected from phenyl,

51. The divalent compound according to claim 38 wherein R²Is composed of

52. The divalent compound according to claim 38 wherein R³Selected from phenyl and 5-to 6-membered heteroaryl, optionally substituted with one or more groups selected from: halogen, optionally substituted C_1-8Alkyl, and optionally substituted C _1-8Alkoxy, optionally substituted C_1-8Alkylene, optionally substituted 3-to 8-membered carbocyclyl, optionally substituted 4-to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted 5-to 6-membered heteroaryl, -CO-, -C (O) - (C)_1-8Alkylene) -, -C (O) -NH (C)_1-8Alkylene) -, -C (O) -N (C)_1-8Alkylene) (C_1-8Alkylene) -, -C (O) - (3-to 8-membered carbocyclyl) -, -C (O) - (4-to 8-membered heterocyclyl) -, -C (O) - (5-to 6-membered heteroaryl) -, -NH (C)_1-8Alkylene) -, -N (C)_1-8Alkylene) (C_1-8Alkylene) -, -CH₂- (3-to 8-membered carbocyclyl) -, -CH₂- (4-to 8-membered heterocyclyl) -, and-CH₂- (5-to 6-membered heteroaryl) -.

53. The divalent compound according to claim 38 wherein R³Selected from phenyl and 5-to 6-membered heteroaryl, optionally substituted with one or more groups selected from: F. cl, CH₃、CF₃、OCH₃、OCF₃、CH₂CH₃、CH₂CF₃、OCH₂CH₃、OCH₂CF₃i-Pr, c-Pr, i-PrO, c-PrO, -CO-, optionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substituted Is/are as followsOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedAnd optionally substituted

54. The divalent compound according to claim 38 wherein R³Selected from phenyl, thiophene, thiazole, isothiazole, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, and pyrazinyl, said phenyl, thiophene, thiazole, isothiazole, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, and pyrazinyl being optionally substituted with one or more groups selected from: F. cl, CH₃、CF₃、OCH₃、OCF₃、CH₂CH₃、CH₂CF₃、OCH₂CH₃、OCH₂CF₃i-Pr, c-Pr, i-PrO, c-PrO, -CO-, optionally substitutedOptionally substitutedOptionally substitutedOptionally substituted Optionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedAnd optionally substituted

55. The divalent compound according to claim 38 wherein R³Is selected from

56. The divalent compound according to claim 38 wherein R³Is selected from

57. The divalent compound according to claim 38 wherein R³Is composed of

58. The divalent compound according to claim 38 wherein X is N.

59. The divalent compound according to any one of claims 1 to 37 wherein the PTK6 ligand is selected from the group consisting of:

Wherein

X, Y and Z are independently selected from null, CR⁵And N, wherein

R⁵Selected from hydrogen, halogen, or optionally substituted C_1-3An alkyl group;

a is selected from null or-R⁶-R⁷-, wherein

R⁶And R⁷Independently selected from null, NR⁸、O、S、C(O)、C(O)NR⁸、NR⁸C(O)、NR⁸C(O)NR⁹、OC(O)NR⁹、NR⁸C(O)O、S(O)、S(O)NR⁸、NR⁸S(O)、NR⁸S(O)NR⁹、OS(O)NR⁹、NR⁸S(O)O、S(O)₂、S(O)₂NR⁸、NR⁸S(O)₂、NR⁸S(O)₂NR⁹、OS(O)₂NR⁹、NR⁸S(O)₂O, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸And R⁹Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl C₁-C₈Alkyl, optionally substituted 4-to 10-membered heterocyclyl C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R⁸And R⁹Together with the atoms to which they are attached form a 4-to 20-membered heterocyclyl ring;

b and D are independently selected from CR¹⁰R¹¹、NR¹⁰O, SO, or SO₂Wherein R is¹⁰And R¹¹Independently selected from hydrogen, halogen, hydroxy, cyano, nitro, and optionally substituted C₁-C₃Alkyl, or R ¹⁰And R¹¹Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic ring or a 4-to 6-membered heterocyclic ring;

R¹and R²Independently selected from hydrogen and optionally substituted C₁-C₃Alkyl, or

R¹And R²Together with the atoms to which they are attached form a 4-to 6-membered heterocyclyl ring;

R³and R⁴Independently at each occurrence, is selected from hydrogen, fluoro, hydroxy, cyano, amino, nitro, optionally substituted C₁-C₃Alkyl, optionally substituted C₁-C₃Alkoxy, and optionally substituted C₁-C₃An alkylamino group;

m and n are independently selected from 0, 1, 2, 3 and 4; and

ar is selected from aryl and heteroaryl, which are optionally substituted with one or more substituents independently selected from: hydrogen, halogen, oxo, CN, NO₂、OR¹²、SR¹²、NR¹²R¹³、OCOR¹²、OCO₂R¹²、OCON(R¹²)R¹³、COR¹²、CO₂R¹²、CON(R¹²)R¹³、SOR¹²、SO₂R¹²、SO₂N(R¹²)R¹³、NR¹⁴CO₂R¹²、NR¹⁴COR¹²、NR¹⁴C(O)N(R¹²)R¹³、NR¹⁴SOR¹²、NR¹⁴SO₂R¹²、NR¹⁴SO₂N(R¹²)R¹³Optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 4-to 10-membered heterocyclyl C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, wherein R is¹²、R¹³And R¹⁴Independently selected from hydrogen, optionally substituted C ₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl C₁-C₈Alkyl, optionally substituted 4-to 10-membered heterocyclyl C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R¹²And R¹³、R¹²And R¹⁴Together with the atoms to which they are attached form a 4-to 20-membered heterocyclyl ring.

60. The divalent compound according to claim 59 wherein X, Y and Z are independently selected from CH, CF and N.

61. The divalent compound according to claim 59 wherein X is N; and Y and Z are independently selected from CH, CF and N.

62. The divalent compound according to claim 59 wherein X is N; and Y and Z are CH.

63. The divalent compound according to claim 59 wherein A is empty or selected from optionally substituted 3-to 8-membered carbocyclyl, optionally substituted 4-to 8-membered heterocyclyl, optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, fused ring, bridged ring, and spiro ring.

64. The divalent compound according to claim 59 wherein A is null, phenyl, 4-to 8-membered heterocyclyl, and 5-to 6-membered heteroaryl, said phenyl, 4-to 8-membered heterocyclyl, and 5-to 6-membered heteroaryl being optionally substituted with: F. OH, CN, NO ₂、NH₂Optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Alkoxy, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

65. The divalent compound according to claim 59 wherein A is null, phenyl, 4-to 8-membered heterocyclyl, and 5-to 6-membered heteroaryl, said phenyl, 4-to 8-membered heterocyclyl, and 5-to 6-membered heteroaryl being optionally substituted with: F. OH, CN, NO₂、NH₂、CH₃、CF₃i-Pr, and c-Pr.

66. The divalent compound according to claim 59 wherein A is

67. The divalent compound according to claim 59 wherein B and D are independently selected from CH₂、CHOH、CHCH₃、C(CH₃)₂、CHF、CF₂O, NH, and NCH₃。

68. The divalent compound according to claim 59 wherein B is O.

69. According to claimThe divalent compound of claim 59 wherein D is CH₂。

70. The divalent compound according to claim 59 wherein R¹And R²Independently selected from H and optionally substituted C₁-C₃Alkyl, provided that R is¹And R²At least one of which is H.

71. The divalent compound according to claim 59 wherein R¹And R²Independently selected from H and CH₃Provided that R is¹And R²At least one of which is H.

72. The divalent compound according to claim 59 wherein R ¹And R²Is H.

73. The divalent compound according to claim 59 wherein R³And R⁴Independently at each occurrence, selected from H, F, OH, CN, NH₂、NO₂、CH₃、CF₃i-Pr, and c-Pr.

74. The divalent compound according to claim 59 wherein R³And R⁴Independently at each occurrence, selected from H and F.

75. The divalent compound according to claim 59 wherein m and n are independently selected from 0, 1 and 2.

76. The divalent compound according to claim 59 wherein m and n are 1.

77. The divalent compound according to claim 59 wherein Ar is selected from aryl and heteroaryl, said aryl and heteroaryl being optionally substituted with one or more substituents independently selected from: H. f, ═ O, CN, NO₂、CH₃、OCH₃、CH₂F、CHF₂、CF₃、OCH₂F、OCHF₂、OCF₃i-Pr, and c-Pr.

78. The divalent compound according to claim 59 wherein Ar is 4-OCF₃A substituted phenyl group.

79. The divalent compound according to any one of claims 1 to 37 wherein the PTK6 ligand is selected from the group consisting of:

80. the divalent compound according to any one of claims 1 to 37 wherein the PTK6 ligand is selected from the group consisting of:

81. the divalent compound according to any one of claims 1 to 80, wherein said degradation/disruption label is selected from the group consisting of:

Wherein

V, W and X are independently selected from CR²And N;

y is selected from CO and CR³R⁴And N ═ N;

z is selected from among null, CO, CR⁵R⁶、NR⁵O, optionally substituted C₁-C₁₀Alkylene, optionally substituted C₁-C₁₀Alkenylene, optionally substituted C₁-C₁₀Alkynylene, optionally substituted 3-to 10-membered carbocyclylOptionally substituted 4-to 10-membered heterocyclic group, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH₂CH ═ CH, C ≡ C, NH, and O;

R¹and R²Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C₁-C₆An alkyl group, an optionally substituted 3-to 6-membered carbocyclyl group, and an optionally substituted 4-to 6-membered heterocyclyl group;

R³and R⁴Independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C₁-C₆An alkyl group, an optionally substituted 3-to 6-membered carbocyclyl group, and an optionally substituted 4-to 6-membered heterocyclyl group; or R³And R⁴Together with the atoms to which they are attached form a 3-to 6-membered carbocyclyl, or a 4-to 6-membered heterocyclyl; and

R⁵and R⁶Independently selected from the group consisting of empty, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C ₁-C₆An alkyl group, an optionally substituted 3-to 6-membered carbocyclyl group, and an optionally substituted 4-to 6-membered heterocyclyl group; or R⁵And R⁶Together with the atoms to which they are attached form a 3-to 6-membered carbocyclyl, or a 4-to 6-membered heterocyclyl.

82. The divalent compound according to claim 81 wherein

V, W and X are independently CR²Or the number of N is greater than the number of N,

y is CO or CH₂，

Z is CH₂The content of the nitrogen is NH or O,

R¹is hydrogen, methyl or fluorine, and

R²is hydrogen, halogen or C₁-C₅An alkyl group.

83. The divalent compound according to any one of claims 1 to 80, wherein said degradation/disruption label is selected from the group consisting of:

wherein

U, V, W and X are independently selected from CR²And N;

y is selected from CR³R⁴、NR³And O; optionally, Y is selected from CH₂、NH、NCH₃And O;

z is selected from among null, CO, CR⁵R⁶、NR⁵O, optionally substituted C₁-C₁₀Alkylene, optionally substituted C₁-C₁₀Alkenylene, optionally substituted C₁-C₁₀Alkynylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH ₂CH ═ CH, C ≡ C, NH, and O;

R⁵and R⁶Independently selected from the group consisting of empty, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₆An alkyl group, an optionally substituted 3-to 6-membered carbocyclyl group, and an optionally substituted 4-to 6-membered heterocyclyl group; or R⁵And R⁶Together with the atoms to which they are attached form a 3-to 6-membered carbocyclyl, or a 4-to 6-membered heterocyclyl.

84. The divalent compound according to any one of claims 1 to 80, wherein said degradation/disruption label is selected from the group consisting of:

wherein

R¹And R²Independently of one another is hydrogen, C₁-C₈Alkyl radical, C₁-C₈Alkoxyalkyl group, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₁-C₈Aminoalkyl radical, C₁-C₈Alkylaminoalkyl, C₃-C₇Cycloalkyl radical, C ₃-C₇Heterocyclic group, C₂-C₈Alkenyl, or C₂-C₈An alkynyl group;

R³is H, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Alkoxyalkyl group, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₁-C₈Aminoalkyl radical, C (O) C₁-C₈Alkylaminoalkyl, C (O) C₃-C₇Cycloalkyl, C (O) C₃-C₇Heterocyclic group, C (O) C₂-C₈Alkenyl, C (O) C₂-C₈Alkynyl, C (O) OC₁-C₈Alkoxyalkyl group, C (O) OC₁-C₈HalogenatedAlkyl, C (O) OC₁-C₈Hydroxyalkyl, C (O) OC₁-C₈Aminoalkyl, C (O) OC₁-C₈Alkylaminoalkyl, C (O) OC₃-C₇Cycloalkyl, C (O) OC₃-C₇Heterocyclic group, C (O) OC₂-C₈Alkenyl, C (O) OC₂-C₈Alkynyl, C (O) NC₁-C₈Alkoxyalkyl group, C (O) NC₁-C₈Haloalkyl, C (O) NC₁-C₈Hydroxyalkyl, C (O) NC₁-C₈Aminoalkyl, C (O) NC₁-C₈Alkylaminoalkyl, C (O) NC₃-C₇Cycloalkyl, C (O) NC₃-C₇Heterocyclic group, C (O) NC₂-C₈Alkenyl, C (O) NC₂-C₈Alkynyl, P (O) (OH)₂、P(O)(OC₁-C₈Alkyl radical)₂Or P (O) (OC)₁-C₈Aryl radical)₂。

85. The divalent compound according to any one of claims 1 to 80, wherein said degradation/disruption label is selected from the group consisting of:

wherein

R¹And R²Independently selected from hydrogen, halogen, OH, NH₂CN, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Aminoalkyl, optionally substituted C₁-C₈Alkylamino radical C ₁-C₈Alkyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted C₂-C₈Alkenyl, and optionally substituted C₂-C₈Alkynyl radical(ii) a (preferably, R)¹Selected from isopropyl or tert-butyl; and R is²Selected from hydrogen or methyl);

R³is hydrogen, optionally substituted C (O) C₁-C₈Alkyl, optionally substituted C (O) C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) C₁-C₈Haloalkyl, optionally substituted C (O) C₁-C₈Hydroxyalkyl, optionally substituted C (O) C₁-C₈Aminoalkyl, optionally substituted C (O) C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C (O) C₃-C₇Cycloalkyl, optionally substituted C (O) (3-to 7-membered heterocyclyl), optionally substituted C (O) C₂-C₈Alkenyl, optionally substituted C (O) C₂-C₈Alkynyl, optionally substituted C (O) OC₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) OC₁-C₈Haloalkyl, optionally substituted C (O) OC₁-C₈Hydroxyalkyl, optionally substituted C (O) OC₁-C₈Aminoalkyl, optionally substituted C (O) OC₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C (O) OC₃-C₇Cycloalkyl, optionally substituted C (O) O (3-to 7-membered heterocyclyl), optionally substituted C (O) OC₂-C₈Alkenyl, optionally substituted C (O) OC₂-C₈Alkynyl, optionally substituted C (O) NC₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) NC₁-C₈Haloalkyl, optionally substituted C (O) NC₁-C₈Hydroxyalkyl, optionally substituted C (O) NC ₁-C₈Aminoalkyl, optionally substituted C (O) NC₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C (O) NC₃-C₇Cycloalkyl, optionally substituted C (O) N (3-to 7-membered heterocyclyl), optionally substituted C (O) NC₂-C₈Alkenyl, optionally substituted C (O) NC₂-C₈Alkynyl, optionally substituted P (O) (OH)₂Optionally substituted P (O) (OC)₁-C₈Alkyl radical)₂And optionally substituted P (O) (OC)₁-C₈Aryl radical)₂(ii) a And

R⁴and R⁵Independently selected from hydrogen, COR⁶、CO₂R⁶、CONR⁶R⁷、SOR⁶、SO₂R⁶、SO₂NR⁶R⁷Optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 8-membered cycloalkyl group, an optionally substituted 3-to 8-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, wherein

R⁶And R⁷Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 8-membered cycloalkyl, optionally substituted 3-to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁴And R⁵、R⁶And R⁷Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring;

ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: F. cl, CN, NO ₂、OR⁸、NR⁸R⁹、COR⁸、CO₂R⁸、CONR⁸R⁹、SOR⁸、SO₂R⁸、SO₂NR⁹R¹⁰、NR⁹COR¹⁰、NR⁸C(O)NR⁹R¹⁰、NR⁹SOR¹⁰、NR⁹SO₂R¹⁰Optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Alkoxyalkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted C₁-C₆Hydroxyalkyl, optionally substituted C₁-C₆Alkylamino radical C₁-C₆Alkyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted C₂-C₆Alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted aryl, and optionally substituted C₄-C₅Heteroaryl group of which

R⁸、R⁹And R¹⁰Independently selected from the group consisting of empty, hydrogen, optionally substituted C₁-C₆Alkyl, optionally substituted C₂-C₆Alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁸And R⁹、R⁹And R¹⁰Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring.

86. The divalent compound according to any one of claims 1 to 80, wherein said degradation/disruption label is selected from the group consisting of:

wherein

R¹、R²、R³And R⁴Independently of one another is hydrogen, C₁-C₈Alkyl radical, C₁-C₈Alkoxyalkyl group, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₃-C₇Cycloalkyl radical, C₃-C₇Heterocyclic group, C₂-C₈Alkenyl, or C₂-C₈Alkynyl, and

v, W, X and Z are independentEarth is CR⁴Or N.

87. The divalent compound according to any one of claims 1 to 80, wherein said degradation/disruption label is selected from the group consisting of:

Wherein

R¹、R²And R³Independently selected from hydrogen, halogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted C₂-C₈Alkenyl, and optionally substituted C₂-C₈An alkynyl group;

R⁴and R⁵Independently selected from hydrogen, COR⁶、CO₂R⁶、CONR⁶R⁷、SOR⁶、SO₂R⁶、SO₂NR⁶R⁷Optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted aryl-C₁-C₈An alkyl group, an optionally substituted 3-to 8-membered cycloalkyl group, an optionally substituted 3-to 8-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, wherein

R⁶And R⁷Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substitutedA 3-to 8-membered cycloalkyl group, an optionally substituted 3-to 8-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, or

R⁶And R⁷Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring.

88. The divalent compound according to any one of claims 1 to 63, wherein said degradation/disruption label is selected from the group consisting of:

89. The divalent compound according to any one of claims 1 to 80 wherein said degradation/disruption tag binds to ubiquitin ligase and/or acts as a hydrophobic group leading to misfolding of PTK6 protein.

90. The divalent compound of claim 89 wherein said ubiquitin ligase is E3 ligase.

91. The divalent compound according to claim 90 wherein said E3 ligase is selected from the group consisting of cereblon E3 ligase, VHL E3 ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP1 ligase and IAP ligase.

92. A divalent compound selected from the group consisting of:

YX39-86, YX39-89, YX39-90, YX39-91, YX39-92, YX39-93, YX39-94, YX39-96, YX39-97, YX39-98, YX39-99, YX39-100, YX39-101, YX39-102, YX39-103, YX39-104, YX39-105, YX39-106, YX39-107, YX39-127, YX39-128, YX39-129, YX 39-158, YX 39-172, YX 39-184, YX 39-7-2, YX39-8, YX39-9, YX39-10, YX 39-11, YX 39-72, YX 39-184, YX 39-157, YX 39-72, YX 39-157, YX 39-72, YX 39-39, YX 39-72, YX 39-157, YX 39-39, YX 39-72, YX39, YX 36, YX79-3, YX79-4, YX79-5, YX79-6, YX79-10, YX79-11, YX79-12, YX79-13, YX79-14, YX79-15, YX79-16, YX79-17, YX79-18, YX79-19, YX79-20, YX79-21, YX79-22, YX79-23, YX79-24, YX79-25, YX79-29, YX79-30, YX79-34, YX79-35, YX79-36, YX79-37, YX79-38, YX79-39, YX79-40, YX79-41, YX79-42, YX 79-72, YX79, YX79-67, YX79-68, YX79-69, YX79-70, YX79-86, YX79-87, YX79-88, YX79-89, YX79-90, YX79-91, YX79-92, YX79-93, YX79-94, YX79-95, YX79-967, YX79-97, YX79-131, YX79-132, YX79-133, YX79-134, YX79-135, YX79-136, YX79-137, YX79-138, YX79-139, YX79-140, YX79-141, YX79-142, YX79-143, YX79-144, YX79-145, YX79-149, YX79-145, YX79-157, YX79-157, YX 79-79, YX-36, YX79-158, YX79-159, YX79-160, YX79-161, YX79-162, YX79-164, YX79-165, JH077-29, JH077-30, JH077-31, JH077-32, JH077-33, JH077-34, JH077-35, JH077-36, JH077-37, JH077-38, JH077-39, JH077-40, JH077-41, JH077-47, JH077-48, JH077-49, JH077-51, JH077-52, JH077-53, JH077-54, JH 7-55, JH077-56, JH077-57, JH077-74, JH077-73, JH077-55, JH077-56, JH077-73, JH077-54, JH077-55, JH077-73, JH-077-73, JH077-73, JH077-76, JH077-77, JH077-78, JH077-79, JH077-80, JH077-81, JH077-82, JH077-83, JH077-84, JH077-85, JH077-86, JH077-87, JH077-88, JH077-89, JH077-90, JH077-91, JH077-92, JH077-93, and the like.

93. A divalent compound selected from the group consisting of:

94. A divalent compound selected from the group consisting of compounds 190 to 280 of table 1.

95. A divalent compound selected from the group consisting of: YX39-101, YX39-102, YX39-103, YX39-104, YX39-105, YX39-106, YX39-107, YX-49-24, YX49-99, YX49-100, YX49-101, YX49-102, YX69-157, YX69-158, YX69-159, YX79-10, YX79-11, YX79-12, YX79-15, YX79-36, YX79-37, YX79-40, YX79-42, YX79-59, and YX-79-65.

96.(2S,4R) -1- ((S) -2- (5- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) pentanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 39-101).

(2S,4R) -1- ((S) -2- (6- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) hexanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 39-102).

98.(2S,4R) -1- ((S) -2- (7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) heptanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 39-103).

99.(2S,4R) -1- ((S) -2- (8- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) octanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 39-104).

(2S,4R) -1- ((S) -2- (9- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) nonanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 39-105).

(2S,4R) -1- ((S) -2- (10- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) decanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 39-106).

(2S,4R) -1- ((S) -2- (11- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) undecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 39-107).

(2S,4R) -1- ((S) -2- (12- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -12-oxododecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 49-24).

(2S,4R) -1- ((S) -2- (12- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -12-oxododecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (YX 49-99).

(2S,4R) -1- ((S) -2- (13- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -13-oxotridecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 49-100).

(2S,4R) -1- ((S) -2- (14- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -14-oxotetradecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 49-101).

(2S,4R) -1- ((S) -2- (tert-butyl) -17- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-heptadiazanyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 49-102).

(2S,4R) -1- ((S) -2- (7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) heptanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (YX 69-157).

(2S,4R) -1- ((S) -2- (9- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) nonanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (YX 69-158).

(2S,4R) -1- ((S) -2- (tert-butyl) -17- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-heptadiazanyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (YX 69-159).

(2S,4R) -1- ((S) -2- (5- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -5-oxopentanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 79-10).

(2S,4R) -1- ((S) -2- (6- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -6-oxohexanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 79-11).

(2S,4R) -1- ((S) -2- (7- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -7-oxoheptanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 79-12).

(2S,4R) -1- ((S) -2- (3- (3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropoxy) propionylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 79-15).

115.4- ((2- (2- (3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (YX 79-36).

4- ((2- (2- (2- (3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (YX 79-37).

117. [ 2S,4R) -1- ((S) -2- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2-oxoethoxy) acetylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 79-40).

(2S,4R) -1- ((S) -2- (tert-butyl) -14- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 14-dioxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 79-42).

119.N¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N⁸- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) octanediamide (YX 79-59).

(2S,4R) -1- ((S) -2- (tert-butyl) -14- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 11-dioxo-6, 9-dioxa-3, 12-diazadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (YX 79-65).

121. A method of treating a protein tyrosine kinase 6(PTK6) -mediated disease comprising administering to a subject having a PTK 6-mediated disease a divalent compound comprising a PTK6 ligand conjugated to a degradation/disruption tag through a linking group.

122. The method of claim 121, wherein the PTK6 mediated disease is caused by PTK6 expression or mutation.

123. The method of claim 121 or 122, wherein tissue from the subject has increased PTK6 function relative to wild-type tissue of the same species and tissue type.

124. The method according to any one of claims 121 to 123, wherein the divalent compound is selected from the group consisting of: YX39-101, YX39-102, YX39-103, YX39-104, YX39-105, YX39-106, YX39-107, YX-49-24, YX49-99, YX49-100, YX49-101, YX49-102, YX69-157, YX69-158, YX69-159, YX79-10, YX79-11, YX79-12, YX79-15, YX79-36, YX79-37, YX79-40, YX79-42, YX79-59, and YX-79-65.

125. The method according to any one of claims 121-124, wherein the divalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

126. The method of any one of claims 121-125, further comprising treating the subject with an additional therapeutic regimen for treating cancer.

127. The method of claim 126, wherein the additional treatment regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormonal therapy and immunotherapy.

128. The method of any one of claims 121-127, wherein the PKT 6-mediated disease is selected from the group consisting of: leukemia, lymphoma, ovarian cancer, gastric tumors, cervical cancer, uterine cancer, gastric cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), colorectal cancer (CRC), lung cancer, pancreatic cancer, bladder cancer, breast cancer, and neuroblastoma.

129. The method of any one of claims 121-128, wherein the PTK 6-mediated disease is recurrent cancer.

130. The method of any one of claims 121-129, wherein the PTK 6-mediated disease is refractory to one or more prior treatments.

131. A method for identifying a bivalent compound that mediates degradation/destruction of PKT6, the method comprising:

providing a heterobifunctional test compound comprising a PKT6 ligand conjugated to a degradation/disruption tag through a linking group;

contacting said heterobifunctional test compound with a cell comprising ubiquitin ligase and PKT 6;

determining whether the level of PKT6 in the cell is decreased; and

identifying said heterobifunctional test compound as a bivalent compound that mediates a degradation/reduction of a reduced level of PKT6 in said cell.

132. The method of claim 131, wherein the cell is a cancer cell.

133. The method of claim 132, wherein the cancer cell is a PKT 6-mediated cancer cell.

Technical Field

The present disclosure relates to bivalent compounds (e.g., bifunctional small molecule compounds) that degrade and/or destroy protein tyrosine kinase 6(PTK6, also known as breast tumor kinase or Brk), compositions comprising one or more of the bivalent compounds, and methods of use thereof for treating PTK6 mediated diseases in a subject in need thereof. The present disclosure also relates to methods for designing such divalent compounds.

Background

PTK6, a member of a unique family of non-receptor tyrosine kinases that are distantly related to Src kinases (distantrelated), is expressed in breast cancer and a variety of other cancer types (Brauer and Tyner, 2010; Derry et al, 2003; Mitchell et al, 1994; Ostrander et al, 2010; Schmantt et al, 2006). PTK6 promotes oncogenic phenotypes via kinase activity-dependent and/or independent mechanisms, including enhanced proliferation, enhanced anoikis resistance (anoikis resistance), regulation of autophagy, epithelial-mesenchymal transition (epithelial-mesenchymal transition), and migration/invasion (Brauer and Tyner, 2010; Castro and Lange, 2010; Harvey and Crompton, 2003; Harvey et al, 2009; Ito et al, 2016; Ostrander et al, 2010; Park et al, 2015; Zheng et al, 2013). Unlike distant related src kinases, PTK6 lacks the myristoylation sequence. Thus, PTK6 shows a broader range of cellular localization that can affect its activity; the PTK6 protein has been detected in the nucleus, cytoplasm and membrane of cells (Derry et al, 2003).

PTK6 plays a role in a variety of cancer types including prostate, pancreatic, bladder, ovarian, liver, and cervical cancer. Specifically, it was reported that down-regulation of PTK6 expression (via siRNA/shRNA) in pancreatic and liver cancer cells attenuated their viability (Chen et al, 2016; Ono et al, 2014). In addition to its role in the regulation of cancer cell survival, PTK6 promotes epithelial-to-mesenchymal transition (EMT), a developmental process commonly utilized by cancer cells to promote invasion/migration, chemotherapy resistance, and metastasis. The inventors have demonstrated that PTK6 promotes EMT and enhances their ability to invade and metastasize triple-negative breast cancer cells by modulating the stability of Snail, a transcription factor (Ito et al, 2016). shRNA-mediated down-regulation of PTK6 expression inhibited 3D growth, migration and metastasis of triple negative breast cancer cells (Ito et al, 2016).

Reduction of PTK6 protein levels is unlikely to have significant side effects on the host/patient. Genetically engineered PTK6 knockout mice survive, mature, and reproduce normally. The only phenotype observed to date is the hyperproliferation of cells in the small intestine, which is consistent with the role of PTK6 in intestinal epithelial cell differentiation (haegbarth et al, 2006). Hybridization of these PTK 6-/-mice with mammary tumor-developing ErbB2(Her2) transgenic mice resulted in reduced lung metastasis, again confirming the critical role of PTK6 protein in cancer metastasis (Peng et al, 2015).

Several PTK6 inhibitors are known, including compound 21d (Zeng et al, 2011), compound 4f (Mahmoud et al, 2014), compound 1(Yamamoto, 2016), XMU-MP-2(Jiang et al, 2017), and compound 3s (Cardenas et al, 2018). Recently, compound 21d was validated (Ito et al, 2017; Ito et al, 2016). For EMT modulation by TNBC cells, compound 21d treated phenocopy (phenocopy) PTK6 shRNA effects. However, treatment with compound 21D did not consistently phenotypically mimic the effect of shRNA on all cell lines evaluated with respect to 3D growth. Indeed, kinase-independent oncogenic activity of PTK6 has been reported (Harvey and Crompton, 2003) and the kinase-independent oncogenic activity of PTK6 may account for these differences and may limit the general use of kinase inhibition as a therapeutic strategy. Thus, PTK6 degrading agents that reduce PTK6 protein levels will more consistently mimic the effects of PTK6 knockdown via RNA interference and overcome the kinase-independent activity of PTK 6.

Disclosure of Invention

Unlike PTK6 inhibitors, which inhibit the kinase activity of PTK6, the PTK6 degradation/disruption compounds disclosed herein ("PTK 6 degraders") bind and induce degradation of PTK6, thus eliminating any scaffolding function (scaffold) of PTK6 in addition to the kinase activity of PTK 6. The PTK6 degrading agents disclosed herein are divalent compounds comprising a PTK6 ligand conjugated to a degradation/disruption tag via a linking group.

PTK6 degrading agents disclosed herein provide novel mechanisms for treating PTK6 mediated diseases. In particular, this PTK6 degradant has the ability to target PTK6 for degradation, as opposed to inhibiting only the kinase activity of PTK 6.

In one aspect, the present disclosure provides a method of treating a PTK 6-mediated disease, the method comprising administering to a subject having a PTK 6-mediated disease one or more PTK6 degrading agents, the PTK6 degrading agent being a divalent compound comprising a PTK6 ligand conjugated to a degradation/disruption tag via a linking group. The PTK 6-mediated disease may be a disease caused by expression of PTK 6. PTK 6-mediated diseases may have increased expression of PTK6 relative to wild-type tissue of the same species and tissue type. Non-limiting examples of PTK 6-mediated diseases include breast cancer, ovarian cancer, prostate cancer, colon cancer, pancreatic cancer, bladder cancer, liver cancer, and cervical cancer.

PTK 6-mediated cancer may include, for example, recurrent cancer. PTK 6-mediated cancer may be refractory to one or more prior treatments, for example.

The present disclosure relates generally to bivalent compounds (e.g., bifunctional small molecule compounds) that degrade and/or destroy PTK6, and to methods for treating PTK 6-mediated cancers (i.e., cancers that rely on PTK6 protein; or cancers that have elevated PTK6 levels, or PTK6 activity, relative to wild-type tissue of the same species and tissue type). Since PTK6 degradants/disruptors have a dual function (inhibition of kinase activity plus protein degradation/disruption), the bivalent compounds of the present disclosure would be significantly more effective therapeutic agents than existing PTK6 inhibitors that inhibit the kinase activity of PTK6 but do not affect the protein level of PTK 6. The present disclosure further provides methods for identifying PTK6 degraders/disruptors as described herein.

More specifically, the present disclosure provides divalent compounds comprising PTK6 ligand conjugated to a degradation/disruption tag via a linking group.

In some aspects, the PTK6 degrader/disrupter has the form "PI-linker-EL" as shown below:

wherein the PI ("target protein" (i.e., ligand of the protein to be degraded) comprises a PTK6 ligand (e.g., PTK6 kinase inhibitor) and the EL (e.g., ligand of E3 ligase) comprises a degradation/disruption tag (e.g., E3 ligase ligand). Exemplary PTK6 ligands (PI), exemplary degradation/disruption tags (EL), and exemplary linking groups (Linker) are illustrated below:

PTK6 ligand

PTK6 ligands include, but are not limited to:

wherein

R¹Selected from H, C_1-8Alkyl radical, C₁-C₈Hydroxyalkyl radical, C₁-C₈Alkoxyalkyl group, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, OR⁸、SR⁹And NR¹⁰R¹¹；

R²Is selected from C₆-C₁₀Aryl or C₅-C₁₀A heteroaryl group. R²Is unsubstituted or optionally substituted with one or more groups selected from: halogen, ═ O, ═ S, CN, NO₂、C_1-8Alkyl radical, C ₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C₁-C₈Alkylene radical OR¹²、C₁-C₈Alkylene SR¹³、C₁-C₈Alkylene radical NR¹⁴R¹⁵、C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, OR¹²、SR¹³And NR¹⁴R¹⁵；

R³Is selected from C₆-C₁₀Aryl or C₅-C₁₀A heteroaryl group. R³Is unsubstituted or substituted by one or more groups selected from: c₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₁-C₈Alkoxyalkyl group, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, halogen, CN, NO₂、＝O、＝S、R¹⁶、OR¹⁶、SR¹⁷、SO₂R¹⁸、NR¹⁹R²⁰、C(O)R¹⁶、C(O)OR¹⁶、C(S)OR¹⁶、C(O)NR¹⁹R²⁰、C(S)NR¹⁹R²⁰、NR¹⁹C(O)R¹⁶、NR¹⁹C(O)OR¹⁶、NR¹⁹S(O)R¹⁶、NR¹⁹S(O)OR¹⁶、S(O)R¹⁶、S(O)OR¹⁶And S (O) ONR¹⁹R²⁰；

R⁶And R⁷、R¹⁰And R¹¹、R¹⁴And R¹⁵Together with the nitrogen atom to which they are attached may independently form a 3-to 10-membered heterocyclyl ring;

R¹⁶、R¹⁷and R¹⁸Independently selected from H, C₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Alkoxyalkyl group, C₁-C₈Hydroxyalkyl radical, C₃-C₈Cycloalkyl radical, C₃-C₇Heterocycloalkyl radical, C₆-C₁₀Aryl radical, C₅-C₁₀Heteroaryl, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₁-C₈Alkoxyalkyl group, C (O) C₃-C₁₀Cycloalkyl, C (O) C₃-C₁₀Heterocyclic group, C (O) C₆-C₁₀Aryl, C (O) C₅-C₁₀Heteroaryl group, C₁-C₈Alkylene radical C₃-C₁₀Cycloalkyl radical, C₁-C₈Alkylene radical C₃-C₁₀Heterocycloalkyl radical, C ₁-C₈Alkylene radical C₆-C₁₀Aryl radical, C₁-C₈Alkylene, and C₅-C₁₀A heteroaryl group;

R¹⁹and R²⁰Independently selected from H, C₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Alkoxyalkyl group, C₁-C₈Hydroxyalkyl radical, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl radical, C₅-C₁₀Heteroaryl, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₁-C₈Alkoxyalkyl group, C (O) C₃-C₁₀Cycloalkyl, C (O) C₃-C₁₀Heterocycloalkyl, C (O) C₆-C₁₀Aryl, C (O) C₅-C₁₀Heteroaryl, C (O) OC₁-C₈Alkyl, C (O) OC₁-C₈Haloalkyl, C (O) OC₁-C₈Hydroxyalkyl, C (O) OC₁-C₈Alkoxyalkyl group, C (O) OC₃-C₁₀Cycloalkyl, C (O) OC₃-C₁₀Heterocyclic group, C (O) OC₆-C₁₀Aryl, C (O) OC₅-C₁₀Heteroaryl, C (O) NC₁-C₈Alkyl, C (O) NC₁-C₈Haloalkyl, C (O) NC₁-C₈Hydroxyalkyl, C (O) NC₁-C₈Alkoxyalkyl group, C (O) NC₃-C₁₀Cycloalkyl, C (O) NC₃-C₁₀Heterocyclic group, C (O) NC₆-C₁₀Aryl, C (O) NC₅-C₁₀Heteroaryl, SO₂C₁-C₈Alkyl, SO₂C₁-C₈Halogenated alkyl, SO₂C₁-C₈Hydroxyalkyl, SO₂C₁-C₈Alkoxyalkyl group, SO₂C₃-C₁₀Cycloalkyl, SO₂C₃-C₁₀Heterocyclic radical, SO₂C₆-C₁₀Aryl, SO₂C₅-C₁₀Heteroaryl group, C₁-C₈Alkylene radical C₃-C₁₀Cycloalkyl radical, C₁-C₈Alkylene radical C₃-C₁₀Heterocycloalkyl radical, C₁-C₈Alkylene radical C₆-C₁₀Aryl radical, C₁-C₈Alkylene radical C₅-C₁₀Heteroaryl, or

R¹⁹And R²⁰Together with the nitrogen atom to which they are attached may independently form a 3-to 10-membered heterocyclyl ring; and

x is selected from CH or N.

In some aspects of formula 1, R is selected from H, halogen, optionally substituted C _1-3Alkyl, and optionally substituted C_1-3An alkoxy group.

In some aspects of formula 1, R is selected from H, F, CH₃、CH₂F、CHF₂、CF₃、CH₂CH₃、CH₂CF₃、i-Pr、c-Pr、OCH₃、OCH₂F、OCHF₂、OCF₃、OCH₂CH₃、OCH₂CF₃Oi-Pr, and Oc-Pr.

In some aspects of formula 1, R is selected from CH₃、CF₃、CH₂CH₃、CH₂CF₃And c-Pr.

In some aspects of formula 1, R is selected from CH₃And c-Pr.

In some aspects of formula 1, R is c-Pr.

In some aspects of formula 1, R¹Selected from H, halogen, optionally substituted C_1-3Alkyl, and optionally substituted C_1-3An alkoxy group.

In some aspects of formula 1, R¹Selected from H, F, CH₃、CH₂F、CHF₂、CF₃、CH₂CH₃、CH₂CF₃、i-Pr、c-Pr、OCH₃、OCH₂F、OCHF₂、OCF₃、OCH₂CH₃、OCH₂CF₃Oi-Pr, and Oc-Pr.

In some aspects of formula 1, R¹Selected from H, F, CH₃And CF₃。

In some aspects of formula 1, R¹Is H.

In some aspects of formula 1, R²Selected from phenyl and 5-to 6-membered heteroaryl, said phenyl and 5-to 6-membered heteroaryl being optionally substituted by a group selected from halogen, optionally substituted C_1-3Alkyl and optionally substituted C_1-3One or more groups of alkoxy groups.

In some aspects of formula 1, R²Is a 5-to 6-membered heteroaryl, said 5-to 6-membered heteroaryl being optionally substituted by a group selected from halogen, optionally substituted C_1-3Alkyl and optionally substituted C_1-3One or more groups of alkoxy groups.

In some aspects of formula 1, R²Selected from phenyl,

In some aspects of formula 1, R²Is composed of

In some aspects of formula 1, R³Selected from phenyl and 5-to 6-membered heteroaryl, optionally substituted with one or more groups selected from: halogen, optionally substituted C _1-8Alkyl, and optionally substituted C_1-8Alkoxy, optionally substituted C_1-8Alkylene, optionally substituted 3-to 8-membered carbocyclyl, optionally substituted 4-to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted 5-to 6-membered heteroaryl, -CO-, -C (O) - (C)_1-8Alkylene) -, -C (O) -NH (C)_1-8Alkylene) -, -C (O) -N (C)_1-8Alkylene) (C_1-8Alkylene) -, -C (O) - (3-to 8-membered carbocyclyl) -, -C (O) - (4-to 8-membered heterocyclyl) -, -C (O) - (5-to 6-membered heteroaryl) -, -NH (C)_1-8Alkylene) -, -N (C)_1-8Alkylene) (C_1-8Alkylene) -, -CH₂- (3-to 8-membered carbocyclyl) -, -CH₂- (4-to 8-membered heterocyclyl) -, and-CH₂- (5-to 6-membered heteroaryl) -.

In some aspects of formula 1, R³Selected from phenyl and 5-to 6-membered heteroaryl, optionally substituted with one or more groups selected from: F. cl, CH₃、CF₃、OCH₃、OCF₃、CH₂CH₃、CH₂CF₃、OCH₂CH₃、OCH₂CF₃i-Pr, c-Pr, i-PrO, c-PrO, -CO-, optionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substituted Optionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedAnd optionally substituted

In some aspects of formula 1, R³Selected from phenyl, thiophene, thiazole, isothiazole, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, and pyrazinyl, said phenyl, thiophene, thiazole, isothiazole, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, and pyrazinyl being optionally substituted with one or more groups selected from: F. cl, CH₃、CF₃、OCH₃、OCF₃、CH₂CH₃、CH₂CF₃、OCH₂CH₃、OCH₂CF₃i-Pr, c-Pr, i-PrO, c-PrO, -CO-, optionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substituted Optionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedOptionally substitutedAnd optionally substituted

In some aspects of formula 1, R³Is selected from

In some aspects of formula 1, R³Is composed of

In some aspects of formula 1, X is N.

PTK6 ligands also include, but are not limited to:

wherein

X, Y and Z are independently selected from null, CR⁵And N, wherein

R⁵Selected from hydrogen, halogen, or optionally substituted C_1-3An alkyl group;

a is selected from null or-R⁶-R⁷-, wherein

R⁶And R⁷Independently selected from null, NR ⁸、O、S、C(O)、C(O)NR⁸、NR⁸C(O)、NR⁸C(O)NR⁹、OC(O)NR⁹、NR⁸C(O)O、S(O)、S(O)NR⁸、NR⁸S(O)、NR⁸S(O)NR⁹、OS(O)NR⁹、NR⁸S(O)O、S(O)₂、S(O)₂NR⁸、NR⁸S(O)₂、NR⁸S(O)₂NR⁹、OS(O)₂NR⁹、NR⁸S(O)₂O, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸And R⁹Together with the atoms to which they are attached form a 4-to 20-membered heterocyclyl ring;

b and D are independently selected from CR¹⁰R¹¹、NR¹⁰O, SO, or SO₂Wherein

R¹⁰And R¹¹Independently selected from hydrogen, halogen, hydroxy, cyano, nitro, and optionally substituted C₁-C₃Alkyl, or

R¹⁰And R¹¹Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic ring or a 4-to 6-membered heterocyclic ring;

R¹and R²Independently selected from hydrogen and optionally substituted C₁-C₃Alkyl, or

R¹And R ²Together with the atoms to which they are attached form a 4-to 6-membered heterocyclyl ring;

R³and R⁴Independently at each occurrence, is selected from hydrogen, fluoro, hydroxy, cyano, amino, nitro, optionally substitutedSubstituted C₁-C₃Alkyl, optionally substituted C₁-C₃Alkoxy, and optionally substituted C₁-C₃An alkylamino group.

m and n are independently selected from 0, 1, 2, 3 and 4.

Ar is selected from aryl and heteroaryl, which are optionally substituted with one or more substituents independently selected from: hydrogen, halogen, oxo, CN, NO₂、OR¹²、SR¹²、NR¹²R¹³、OCOR¹²、OCO₂R¹²、OCON(R¹²)R¹³、COR¹²、CO₂R¹²、CON(R¹²)R¹³、SOR¹²、SO₂R¹²、SO₂N(R¹²)R¹³、NR¹⁴CO₂R¹²、NR¹⁴COR¹²、NR¹⁴C(O)N(R¹²)R¹³、NR¹⁴SOR¹²、NR¹⁴SO₂R¹²、NR¹⁴SO₂N(R¹²)R¹³Optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 4-to 10-membered heterocyclyl C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, wherein

R¹²、R¹³And R¹⁴Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C ₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl C₁-C₈Alkyl, optionally substituted 4-to 10-membered heterocyclyl C₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹²And R¹³、R¹²And R¹⁴Together with the atoms to which they are attached form a 4-to 20-membered heterocyclyl ring;

in some aspects of formula 2, X, Y and Z are independently selected from CH, CF, and N.

In some aspects of formula 2, X is N; y and Z are independently selected from CH, CF and N.

In some aspects of formula 2, X is N; y and Z are CH.

In some aspects of formula 2, a is empty or selected from optionally substituted 3-to 8-membered carbocyclyl, optionally substituted 4-to 8-membered heterocyclyl, optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, fused ring, bridged ring, and spiro ring.

In some aspects of formula 2, a is empty, phenyl, 4-to 8-membered heterocyclyl, and 5-to 6-membered heteroaryl, the phenyl, 4-to 8-membered heterocyclyl, and 5-to 6-membered heteroaryl optionally substituted with: F. OH, CN, NO₂、NH₂Optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Alkoxy, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

In some aspects of formula 2, A is

In some aspects of formula 2, B and D are independently selected from CH₂、CHOH、CHCH₃、C(CH₃)₂、CHF、CF₂O, NH, and NCH₃。

In some aspects of formula 2, B is O.

In some aspects of formula 2, D is CH₂。

In some aspects of formula 2, R¹And R²Independently selected from H and optionally substituted C₁-C₃Alkyl, provided that R is¹And R²At least one of which is H.

In some aspects of formula 2, R¹And R²Independently selected from H and CH₃Provided that R is¹And R²At least one of which is H.

In some aspects of formula 2, R¹And R²Is H.

In some aspects of formula 2, R³And R⁴Independently at each occurrence, selected from H, F, OH, CN, NH₂、NO₂、CH₃、CH₂F、CHF₂、CF₃i-Pr, and c-Pr.

In some aspects of formula 2, R³And R⁴Independently at each occurrence, selected from H and F.

In some aspects of formula 2, m and n are independently selected from 0, 1 and 2.

In some aspects of formula 2, m and n are 1.

In some aspects of formula 2, Ar is selected from aryl and heteroaryl, which are optionally substituted with one or more substituents independently selected from the group consisting of: H. f, ═ O, CN, NO ₂、CH₃、OCH₃、CH₂F、CHF₂、CF₃、OCH₂F、OCHF₂、OCF₃i-Pr, and c-Pr.

In some aspects of formula 2, Ar is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of: H. f, ═ O, CN, NO₂、CH₃、OCH₃、CH₂F、CHF₂、CF₃、OCH₂F、OCHF₂、OCF₃i-Pr, and c-Pr.

In some aspects of formula 2, Ar is 4-OCF₃A substituted phenyl group.

In some aspects, the PTK6 ligand may be a derivative of the following compounds:

in some aspects, the PTK6 ligand may be, for example:

PTK6 ligand may bind to PTK6 and/or PTK6 muteins.

Degradation/destruction label

Degradation/destruction labels (EL) include, but are not limited to:

wherein

V, W and X are independently selected from CR²And N;

y is selected from CO and CR³R⁴And N ═ N;

z is selected from among null, CO, CR⁵R⁶、NR⁵O, optionally substituted C₁-C₁₀Alkylene, optionally substituted C₁-C₁₀Alkenylene, optionally substituted C₁-C₁₀Alkynylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH ₂CH ═ CH, C ≡ C, NH, and O;

R⁵and R⁶Independently selected from the group consisting of empty, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₆An alkyl group, an optionally substituted 3-to 6-membered carbocyclyl group, and an optionally substituted 4-to 6-membered heterocyclyl group; or R⁵And R⁶Together with the atoms to which they are attached form a 3-to 6-membered carbocyclyl, or a 4-to 6-membered heterocyclyl.

Wherein

V, W and X are independently CR²Or the number of N is greater than the number of N,

y is CO or CH₂，

Z is CH₂The content of the nitrogen is NH or O,

R¹is hydrogen, methyl or fluorine, and

R²is hydrogen or halogenOr C₁-C₅An alkyl group;

wherein

U, V, W and X are independently selected from CR²And N;

y is selected from CR³R⁴、NR³And O; preferably, Y is selected from CH₂、NH、NCH₃And O;

z is selected from among null, CO, CR⁵R⁶、NR⁵O, optionally substituted C₁-C₁₀Alkylene, optionally substituted C ₁-C₁₀Alkenylene, optionally substituted C₁-C₁₀Alkynylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH₂CH ═ CH, C ≡ C, NH, and O;

R⁵and R⁶Is independently selected fromEmpty, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₆An alkyl group, an optionally substituted 3-to 6-membered carbocyclyl group, and an optionally substituted 4-to 6-membered heterocyclyl group; or R ⁵And R⁶Together with the atoms to which they are attached form a 3-to 6-membered carbocyclyl, or a 4-to 6-membered heterocyclyl.

Wherein

R¹And R²Independently of one another is hydrogen, C₁-C₈Alkyl radical, C₁-C₈Alkoxyalkyl group, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₁-C₈Aminoalkyl radical, C₁-C₈Alkylaminoalkyl, C₃-C₇Cycloalkyl radical, C₃-C₇Heterocyclic group, C₂-C₈Alkenyl, or C₂-C₈An alkynyl group;

R³is H, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Alkoxyalkyl group, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₁-C₈Aminoalkyl radical, C (O) C₁-C₈Alkylaminoalkyl, C (O) C₃-C₇Cycloalkyl, C (O) C₃-C₇Heterocyclic group, C (O) C₂-C₈Alkenyl, C (O) C₂-C₈Alkynyl, C (O) OC₁-C₈Alkoxyalkyl group, C (O) OC₁-C₈Haloalkyl, C (O) OC₁-C₈Hydroxyalkyl, C (O) OC₁-C₈Aminoalkyl, C (O) OC₁-C₈Alkylaminoalkyl, C (O) OC₃-C₇Cycloalkyl, C (O) OC₃-C₇Heterocyclic group, C (O) OC₂-C₈Alkenyl, C (O) OC₂-C₈Alkynyl, C (O) NC₁-C₈Alkoxyalkyl group, C (O) NC₁-C₈HalogenatedAlkyl, C (O) NC₁-C₈Hydroxyalkyl, C (O) NC₁-C₈Aminoalkyl, C (O) NC₁-C₈Alkylaminoalkyl, C (O) NC₃-C₇Cycloalkyl, C (O) NC₃-C₇Heterocyclic group, C (O) NC₂-C₈Alkenyl, C (O) NC₂-C₈Alkynyl, P (O) (OH)₂、P(O)(OC₁-C₈Alkyl radical)₂Or P (O) (OC)₁-C₈Aryl radical)₂，

Wherein

R¹And R²Independently selected from hydrogen, halogen, OH, NH₂CN, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C ₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Aminoalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted C₂-C₈Alkenyl, and optionally substituted C₂-C₈An alkynyl group; (preferably, R)¹Selected from isopropyl or tert-butyl; and R is²Selected from hydrogen or methyl);

R³is hydrogen, optionally substituted C (O) C₁-C₈Alkyl, optionally substituted C (O) C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) C₁-C₈Haloalkyl, optionally substituted C (O) C₁-C₈Hydroxyalkyl, optionally substituted C (O) C₁-C₈Aminoalkyl, optionally substituted C (O) C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C (O) C₃-C₇A cycloalkyl group, a,Optionally substituted C (O) (3-to 7-membered heterocyclic group), optionally substituted C (O) C₂-C₈Alkenyl, optionally substituted C (O) C₂-C₈Alkynyl, optionally substituted C (O) OC₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) OC₁-C₈Haloalkyl, optionally substituted C (O) OC₁-C₈Hydroxyalkyl, optionally substituted C (O) OC₁-C₈Aminoalkyl, optionally substituted C (O) OC₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C (O) OC₃-C₇Cycloalkyl, optionally substituted C (O) O (3-to 7-membered heterocyclyl), optionally substituted C (O) OC₂-C₈Alkenyl, optionally substituted C (O) OC₂-C₈Alkynyl, optionally substituted C (O) NC ₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) NC₁-C₈Haloalkyl, optionally substituted C (O) NC₁-C₈Hydroxyalkyl, optionally substituted C (O) NC₁-C₈Aminoalkyl, optionally substituted C (O) NC₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C (O) NC₃-C₇Cycloalkyl, optionally substituted C (O) N (3-to 7-membered heterocyclyl), optionally substituted C (O) NC₂-C₈Alkenyl, optionally substituted C (O) NC₂-C₈Alkynyl, optionally substituted P (O) (OH)₂Optionally substituted P (O) (OC)₁-C₈Alkyl radical)₂And optionally substituted P (O) (OC)₁-C₈Aryl radical)₂(ii) a And

R⁴and R⁵Independently selected from hydrogen, COR⁶、CO₂R⁶、CONR⁶R⁷、SOR⁶、SO₂R⁶、SO₂NR⁶R⁷Optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 8-membered cycloalkyl, optionally substitutedA substituted 3-to 8-membered heterocyclic group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, wherein

R⁴And R⁵、R⁶And R⁷Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring;

Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: F. cl, CN, NO₂、OR⁸、NR⁸R⁹、COR⁸、CO₂R⁸、CONR⁸R⁹、SOR⁸、SO₂R⁸、SO₂NR⁹R¹⁰、NR⁹COR¹⁰、NR⁸C(O)NR⁹R¹⁰、NR⁹SOR¹⁰、NR⁹SO₂R¹⁰Optionally substituted C₁-C₆Alkyl, optionally substituted C₁-C₆Alkoxyalkyl, optionally substituted C₁-C₆Haloalkyl, optionally substituted C₁-C₆Hydroxyalkyl, optionally substituted C₁-C₆Alkylamino radical C₁-C₆Alkyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted C₂-C₆Alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted aryl, and optionally substituted C₄-C₅Heteroaryl group of which

R⁸、R⁹And R¹⁰Independently selected from the group consisting of empty, hydrogen, optionally substitutedC of (A)₁-C₆Alkyl, optionally substituted C₂-C₆Alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁸And R⁹、R⁹And R¹⁰Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring.

Wherein

v, W, X and Z are independently CR⁴Or N;

and

wherein

R¹、R²And R³Independently selected from hydrogen, halogen, optionally substituted C ₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted C₂-C₈Alkenyl, and optionally substituted C₂-C₈Alkynyl radical；

R⁴And R⁵Independently selected from hydrogen, COR⁶、CO₂R⁶、CONR⁶R⁷、SOR⁶、SO₂R⁶、SO₂NR⁶R⁷Optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted aryl-C₁-C₈An alkyl group, an optionally substituted 3-to 8-membered cycloalkyl group, an optionally substituted 3-to 8-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, wherein

R⁶And R⁷Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 8-membered cycloalkyl, optionally substituted 3-to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁶And R⁷Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring.

In some aspects, the degradation/disruption label may be, for example, pomalidomide (Fischer et al, 2014), thalidomide (Fischer et al, 2014), lenalidomide (Fischer et al, 2014), VH032(Galdeano et al, 2014; Maniaci et al, 2017), adamantane (Xie et al, 2014), 1- ((4,4,5,5, 5-pentafluoropentyl) sulfinyl) nonane (E.Wakeling, 1995), nutlin-3a (Vassilev et al, 2004), RG7112(Vu et al, 2013), RG 38, AMG 232(Sun et al, 2014), AA-115 (Aglarui et al, 2017), tadine (Hiroyi Suda et al, 1976), MV1 (Varmeev et al, LCL et al, 2007, Welarg et al, 2017), rapamycin (Outberg et al, 2010, 2016, and/2016).

In some aspects, the degradation/disruption tag can be, for example, one of the following structures:

in some aspects, the degradation/disruption tag may bind to ubiquitin ligase (e.g., E3 ligase such as cereblon E3 ligase, VHL E3 ligase, MDM2 ligase, TRIM21 ligase, TRIM24 ligase, KEAP1 ligase, and/or IAP ligase) and/or function as a hydrophobic group or tag group that causes misfolding of the PTK6 protein.

Linking group

In all of the above compounds, PTK6 ligand is conjugated to a degradation/disruption tag through a linking group. The linking group can include, for example, groups of varying lengths containing acyclic or cyclic saturated or unsaturated carbons, glycols, amides, amino groups, ethers, ureas, carbamates, aromatic, heteroaromatic, heterocyclic, and/or carbonyl groups.

In some aspects, the linking group can be a moiety as follows:

wherein

A. W and B are independently selected at each occurrence from null, or a divalent moiety selected from: r ' -R ', R ' COR ', R ' CO₂R”、R’C(O)N(R¹)R”、R’C(S)N(R¹)R”、R’OR”、R’OC(O)R”、R’OC(O)OR”、R’OCON(R¹)R”、R’SR”、R’SOR”、R’SO₂R”、R’SO₂N(R¹)R”、R’N(R¹)R”、R’NR¹COR”、R’NR¹C(O)OR”、R’NR¹CON(R²)R”、R’NR¹C(S)R”、R’NR¹S(O)R”、R’NR¹S(O)₂R ', and R' NR¹S(O)₂N(R²) R' is provided, wherein

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C ₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C ₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

r 'and R', R¹And R²R' and R¹R' and R²R' and R¹R' and R²Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring; and

m is 0 to 15.

Wherein

R¹、R²、R³And R⁴Independently at each occurrence, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₈Alkyl, aryl, heteroaryl, and heteroaryl,Optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino, and optionally substituted C₁-C₈Alkylamino radical C ₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 3-to 8-membered cycloalkyloxy, optionally substituted 3-to 10-membered carbocyclylamino, optionally substituted 4-to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹And R²、R³And R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C ₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁵and R⁶Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionallySubstituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

R 'and R', R⁵And R⁶R' and R⁵R' and R⁶R' and R⁵R' and R⁶Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15;

n is 0 to 15 at each occurrence; and

o is 0 to 15.

Wherein

R¹And R²Together with the atoms to which they are attached form a 3-membered ringTo a 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R ^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C ₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

r 'and R', R³And R⁴R' and R³R' and R⁴R' and R³R' and R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15 at each occurrence; and

n is 0 to 15.

Wherein

X is selected from O, NH, and NR⁷；

R¹、R²、R³、R⁴、R⁵And R⁶Independently at each occurrence, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C ₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 3-to 8-membered cycloalkyloxy group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C ₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁷、R⁸and R⁹Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substitutedC of (A)₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

r 'and R', R⁸And R⁹R' and R⁸R' and R ⁹R' and R⁸R' and R⁹Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15 at each occurrence;

n is 0 to 15 at each occurrence;

o is 0 to 15; and

p is 0 to 15.

In some aspects of formulas 7, 7A, 7B, and 7C, the linking group moiety comprises a ring selected from the group consisting of a 3-to 13-membered ring, a 3-to 13-membered fused ring, a 3-to 13-membered bridged ring, and a 3-to 13-membered spirocyclic ring.

In some aspects of formulas 7, 7A, 7B, and 7C, the linker moiety comprises a ring selected from the group consisting of formulas C1, C2, C3, C4, and C5:

in some aspects, the linking group can also be a moiety as follows:

wherein X is C ═ O or CH₂，

Y is C ═ O or CH₂And are and

n is 0 to 15;

wherein X is C ═ O or CH₂，

Y is C ═ O or CH₂，

m is 0 to 15, and m is,

n is 0 to 6, and

o is 0 to 15; or

Wherein

X is C ═ O or CH₂，

Y is C ═ O or CH₂，

m is 0 to 15, and

n is 0 to 15.

In some aspects of formula C, R is a 3-to 13-membered ring, a 3-to 13-membered fused ring, a 3-to 13-membered bridged ring, and/or a 3-to 13-membered spirocyclic ring, one or more of which may include one or more heteroatoms.

In some aspects of formula C, R has the structure:

in some aspects, as identified in table 1 below, the divalent compound is a compound selected from the group consisting of: YX39-86, YX39-89, YX39-90, YX39-91, YX39-92, YX39-93, YX39-94, YX39-96, YX39-97, YX39-98, YX39-99, YX39-100, YX39-101, YX39-102, YX39-103, YX39-104, YX39-105, YX39-106, YX39-107, YX39-127, YX39-128, YX39-129, YX 39-158, YX 39-172, YX 39-184, YX 39-7-2, YX39-8, YX39-9, YX39-10, YX 39-11, YX 39-72, YX 39-184, YX 39-157, YX 39-72, YX 39-157, YX 39-72, YX 39-39, YX 39-72, YX 39-157, YX 39-39, YX 39-72, YX39, YX 36, YX79-3, YX79-4, YX79-5, YX79-6, YX79-10, YX79-11, YX79-12, YX79-13, YX79-14, YX79-15, YX79-16, YX79-17, YX79-18, YX79-19, YX79-20, YX79-21, YX79-22, YX79-23, YX79-24, YX79-25, YX79-29, YX79-30, YX79-34, YX79-35, YX79-36, YX79-37, YX79-38, YX79-39, YX79-40, YX79-41, YX79-42, YX 79-72, YX79, YX79-67, YX79-68, YX79-69, YX79-70, YX79-86, YX79-87, YX79-88, YX79-89, YX79-90, YX79-91, YX79-92, YX79-93, YX79-94, YX79-95, YX79-967, YX79-97, YX79-131, YX79-132, YX79-133, YX79-134, YX79-135, YX79-136, YX79-137, YX79-138, YX79-139, YX79-140, YX79-141, YX79-142, YX79-143, YX79-144, YX79-145, YX79-149, YX79-145, YX79-157, YX79-157, YX 79-79, YX-36, YX79-158, YX79-159, YX79-160, YX79-161, YX79-162, YX79-164, YX79-165, JH077-29, JH077-30, JH077-31, JH077-32, JH077-33, JH077-34, JH077-35, JH077-36, JH077-37, JH077-38, JH077-39, JH077-40, JH077-41, JH077-47, JH077-48, JH077-49, JH077-51, JH077-52, JH077-53, JH077-54, JH 7-55, JH077-56, JH077-57, JH077-74, JH077-73, JH077-55, JH077-56, JH077-73, JH077-54, JH077-55, JH077-73, JH-077-73, JH077-73, JH077-76, JH077-77, JH077-78, JH077-79, JH077-80, JH077-81, JH077-82, JH077-83, JH077-84, JH077-85, JH077-86, JH077-87, JH077-88, JH077-89, JH077-90, JH077-91, JH077-92, JH077-93, EXAMPLE 190-.

In some aspects, the present disclosure provides methods of treating PTK 6-mediated cancer, the methods comprising administering to a subject in need thereof one or more divalent compounds comprising a PTK6 ligand conjugated via a linking group to a degradation/disruption tag. The PTK 6-mediated cancer may be a cancer caused by (aberrant) PTK6 activation. PTK 6-mediated cancers may have increased expression of PTK6 relative to wild-type tissue of the same species and tissue type. Non-limiting examples of PTK 6-mediated diseases include breast cancer, ovarian cancer, prostate cancer, colon cancer, pancreatic cancer, bladder cancer, liver cancer, and cervical cancer.

PTK 6-mediated cancer may be recurrent cancer. PTK 6-mediated cancers may be refractory to one or more prior treatments with different therapies.

In any of the above methods, the divalent compound may be YX39-86, YX39-89, YX39-90, YX39-91, YX39-92, YX39-93, YX39-94, YX39-96, YX39-97, YX39-98, YX39-99, YX39-100, YX39-101, YX39-102, YX39-103, YX39-104, YX39-105, YX39-106, YX39-107, YX39-127, YX39-128, YX39-129, YX 39-158, YX 39-172, YX 39-39, YX 39-2, YX39-8, YX39-9, YX39-10, YX 39-72, YX 39-157, YX 39-39, YX 39-157, YX 39-39, YX, YX69-182, YX69-183, YX69-184, YX79-3, YX79-4, YX79-5, YX79-6, YX79-10, YX79-11, YX79-12, YX79-13, YX79-14, YX79-15, YX79-16, YX79-17, YX79-18, YX79-19, YX79-20, YX79-21, YX79-22, YX79-23, YX79-24, YX79-25, YX79-29, YX79-30, YX79-34, YX79-35, YX79-36, YX79-37, YX79-38, YX79-39, YX79-40, YX 79-72, YX 79-79, YX 79-72, YX 79-72, Y, YX79-64, YX79-65, YX79-66, YX79-67, YX79-68, YX79-69, YX79-70, YX79-86, YX79-87, YX79-88, YX79-89, YX79-90, YX79-91, YX79-92, YX79-93, YX79-94, YX79-95, YX79-967, YX79-97, YX79-131, YX79-132, YX79-133, YX79-134, YX79-135, YX79-136, YX79-137, YX79-138, YX79-139, YX79-140, YX79-141, YX79-149, YX79-142, YX79-147, YX 79-79, YX-36, YX79-155, YX79-156, YX79-157, YX79-158, YX79-159, YX79-160, YX79-161, YX79-162, YX79-164, YX79-165, JH077-29, JH077-30, JH077-31, JH077-32, JH077-33, JH077-34, JH077-35, JH077-36, JH077-37, JH077-38, JH077-39, JH077-40, JH077-41, JH077-47, JH077-48, JH077-49, JH077-51, JH 7-52, JH077-53, JH077-54, JH077-56, JH077-47, JH077-48, JH077-49, JH077-51, JH077-52, JH077-53, JH077-54, JH 0765-077-0765, JH-077-72, JH-077, JH-0765, JH-077-0765, JH-077-0765, JH077-73, JH077-74, JH077-75, JH077-76, JH077-77, JH077-78, JH077-79, JH077-80, JH077-81, JH077-82, JH077-83, JH077-84, JH077-85, JH077-86, JH077-87, JH077-88, JH077-89, JH077-90, JH077-91, JH077-92, JH077-93, example 190-.

In some aspects of the methods disclosed herein, the divalent compound can be administered, for example, orally, parenterally, intradermally, subcutaneously, topically, and/or rectally.

Any of the above methods may further comprise treating the subject with one or more additional therapeutic regimens for treating cancer. The one or more additional treatment regimens for treating cancer may be, for example, one or more of surgery, chemotherapy, radiation therapy, hormonal therapy, or immunotherapy.

The present disclosure additionally provides methods for identifying a bivalent compound that mediates degradation/disruption of PTK6, the method comprising providing a heterobifunctional (heterobifunctional) test compound comprising a PTK6 ligand conjugated to a degradation/disruption tag via a linking group, contacting the heterobifunctional test compound with a cell containing ubiquitin ligase and PTK6 (e.g., a cancer cell such as a PTK6 mediated cancer cell).

As used herein, the terms "about" and "approximately" are defined as being within plus or minus 10% of a given value or state, preferably within plus or minus 5% of the value or state. The terms "divalent" and "bi-functional" are used interchangeably herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; in addition, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims.

Drawings

Com, Kaplan-Meier curves showing prognostic significance of high PTK6 transcriptional expression. Higher expression of PTK6 correlates with poor survival in patients with ovarian cancer (stage 2/stage 3).

2-5. Effect of exemplary Compounds on reducing PTK6 protein levels in breast cancer cells. Triple negative MDA-MB231 cells were treated with 500nM, 2. mu.M or 2.5. mu.M of test compound for 24 hours and lysed. Proteins were separated by SDS/PAGE and immunoblotted with an antibody to PTK6 (Santa Cruz, Cell Signaling) or GAPDH loading control (loading control).

Figure 6a. ptk6 degrader, but not kinase activity inhibitor, inhibited viability in 3D cultures. MDA-MB231 triple negative breast cancer cells were seeded into 3D matrigel cultures (4X 10)³Individual cells/well) and treated with 1 μ M of the indicated PTK6 degradant, negative control compound or PTK6 kinase activity inhibitor for 5 days, with re-addition (re-feeding) of compound to the culture after 3 days. Viability was assessed using 3D Cell Titer glo (Promega). Figure 6b. expression of PTK6 in cells treated with PTK6 degradant, negative control compound or PTK6 kinase activity inhibitor after 24 hours treatment with 1 μ M compound in monolayer cultures. Cells were lysed and proteins were isolated and probed (probe) with anti-PTK 6 antibody (Cell Signaling).

Figure 7a. ptk6 degrader treatment inhibited the growth of ER + breast cancer cells. ER + breast cancer cells (MCF-7) were treated with the indicated concentrations of the first candidate degradants (top cancer degraders), negative control compounds or inhibitors of PTK6 kinase activity for 24 hours, lysed and the proteins separated by SDS-PAGE. Expression of PTK6 was examined by Western analysis. Figure 7b MCF-7 cells were seeded into 3D matrigel cultures and treated with the indicated PTK6 degradant or PTK6 kinase inhibitor for 4 days. 3-D Cell Titer glo (Promega) was used to quantify viability.

Figure 8 treatment with PTK6 degrading agent instead of kinase activity inhibitor inhibited the viability of chemotherapy-resistant ovarian cancer cells (CP 70). Cells were seeded into 3D matrigel cultures and treated with compound (2 μ M) for 6 days. Viability was assessed using the 3D Cell Titre glo assay (Promega).

Figure 9.PTK6 degrading agents inhibited PTK6 expression in a proteasome-dependent manner. MDA-MB231 cells (left) or OV2008 cells (right) were pretreated with DMSO or MG-132(10 μ M) for two hours, followed by additional treatment with DMSO or PTK6 degradant at the indicated concentration for 4 hours.

Figure 10 PTK6 kinase activity inhibitor pretreatment prevented PTK6 degradant-dependent inhibition of PTK6 expression. MDA-MB231 cells in monolayer cultures were pre-treated with DMSO or an inhibitor of PTK6 kinase activity (5. mu.M) and then re-treated with PTK6 degradant (YX39-105) for 24 hours. Cells were lysed and expression of PTK6 was assessed by Western analysis.

FIG. 11 PTK6 degrading agents inhibit PTK6 expression in ER + breast cancer cells (MCF/EDR) resistant to endocrine therapy. MCF7EDR cells in monolayer cultures were treated with PTK6 degradant at the indicated concentration for 24 hours. Cells were lysed and expression of PTK6 was assessed.

Figure 12a. ptk6 degrader, but not kinase activity inhibitor, inhibited viability in 3D cultures. After 24 hours treatment with 1 μ M compound in monolayer cultures, expression of PTK6 in cells treated with PTK6 degradant, negative control compound, or PTK6 kinase activity inhibitor was assessed. Cells were lysed and proteins were isolated and probed with anti-PTK 6 antibody (Cell Signaling). FIG. 12b inoculation of MDA-MB231 triple negative breast cancer cells to3D matrigel culture (4X 10)³Individual cells/well) and treated with 1 μ M of the indicated PTK6 degradant, negative control compound or PTK6 kinase activity inhibitor for 6 days, with compound re-added to the culture after 3 days. Viability was assessed using 3D Cell Titer glo (Promega).

FIG. 13 PTK6 degradant inhibits PTK6 expression. In monolayer cultures, MDA-MB231 cells were treated with compound (500nM or 1. mu.M) for 24 hours. Cells were lysed and lysates probed with anti-PTK 6 antibody.

Detailed Description

The present disclosure is based in part on the following findings: novel heterobifunctional small molecules that degrade PTK6 and/or PTK6 mutants are useful in the treatment of PTK 6-mediated diseases, in particular breast, ovarian, prostate, colon, pancreatic, bladder, liver and cervical cancer.

Successful strategies for selective degradation/disruption of target proteins induced by bifunctional small molecules include recruitment of E3 ubiquitin ligase and mimicking protein misfolding with hydrophobic tags (Buckley and cress, 2014). Bifunctional molecules have three parts: an E3-conjugate (binder) moiety that binds to E3 ubiquitin ligase; a target protein-conjugate moiety that binds to a target protein of interest; and a linker moiety linking the E3-conjugate and the target protein-conjugate moiety (Buckley and cress, 2014). The induced proximity results in selective ubiquitination of the target, which is then degraded at the proteasome. Several types of high affinity small molecule E3 ligase ligands have been identified/developed. They include (1) immunomodulatory drugs (IMiD) such as thalidomide and pomalidomide, bound to cereblon (CRBN or CRL4CRBN), a component of the cullin-RING ubiquitin ligase (CRL) complex (Bondeson et al, 2015; Chamberlain et al, 2014; Fischer et al, 2014; Ito et al, 2010; Winter et al, 2015); (2) hydroxyproline-containing ligand VHL-1 bound to von Hippel-Lindau protein (VHL or CRL2VHL), a component of another CRL complex (Bondeson et al, 2015; Buckley et al, 2012 a; Buckley et al, 2012 b; Galdeano et al, 2014; Zengerle et al, 2015); (3) compound 7(Davies et al, 2016) that selectively binds to component KEAP1 of the CRL3 complex; (4) AMG232 that selectively binds to the heterodimeric RING 3 ligase MDM 2(Sun et al, 2014); and (5) LCL161 which selectively binds the homodimer RING 3 ligase IAP (Ohoka et al, 2017; Okuhira et al, 2011; Shibata et al, 2017). This technique has been applied to the degradation of several protein targets (Bondeson et al 2015; Buckley et al 2015; Lai et al 2016; Lu et al 2015; Winter et al 2015; Zengerle et al 2015), but has not been applied to the degradation of PTK6 or PTK6 muteins. Furthermore, hydrophobic labeling methods (hydrophic tagging approach) using bulky and hydrophobic adamantyl groups have been developed to mimic protein misfolding, resulting in degradation of target proteins by proteasomes (Buckley and cress, 2014). This approach has been applied to the selective degradation of the pseudokinase Her3 (Xie et al, 2014), but has not been applied to the degradation of PTK6 or PTK6 muteins.

As discussed in the examples below, the present disclosure provides specific examples of novel PTK6 degradants/disrupters, and reviews the role of exemplary degradants/disrupters in inhibiting/disrupting PTK6 function, reducing PTK6 protein levels, and inhibiting cancer cell proliferation. The results indicate that these novel small molecules would be beneficial in the treatment of human diseases, particularly breast, ovarian, prostate, colon, pancreatic, bladder, liver and cervical cancer.

A number of selective small molecule PTK6 kinase inhibitors have been reported, such as compound 21d (Zeng et al, 2011), compound 4f (Mahmoud et al, 2014), compound 1(Yamamoto, 2016), XMU-MP-2(Jiang et al, 2017), and compound 3s (Cardenas et al, 2018).

The small molecules currently available targeting PTK6 focus on inhibiting the kinase activity of PTK 6. In the present disclosure, different approaches are taken: compounds were developed that target not only the kinase activity of PTK6 but also its protein levels directly and selectively. Strategies for inducing protein degradation include recruitment of E3 ubiquitin ligase, mimicking protein misfolding with hydrophobic tags, and inhibition of chaperones (chaperones). For example, thalidomide-JQ 1 bivalent compounds have been used to hijack cereblon E3 ligase, induce highly selective BET protein degradation in vitro and in vivo and lead to a demonstrated delay in leukemia progression in mice (Winter et al, 2015). Similarly, BET proteolytic degradation was also induced via another E3 ligase VHL (zegerle et al, 2015). Partial degradation of Her3 was induced using adamantane modified compounds (Xie et al, 2014). Such methods based on the use of bivalent small molecule compounds allow for more flexible modulation of protein levels in vitro and in vivo compared to techniques such as gene knock-out or shRNA (short hairpin RNA) knock-down. Unlike gene knock-out or shRNA knockdown, the small molecule approach further provides the opportunity to study dose and time dependence in disease models by varying the concentration and frequency of administration of the relevant small molecule.

The present disclosure includes all stereoisomers, geometric isomers, tautomers and isotopes of the structures and named compounds depicted herein. The disclosure also includes compounds described herein, regardless of how they are prepared, e.g., synthetically, by a biological process (e.g., metabolic or enzymatic conversion), or a combination thereof.

The present disclosure includes pharmaceutically acceptable salts of the compounds of the structures and nomenclature depicted herein.

One or more of the constituent atoms of the compounds presented herein may be replaced or substituted with isotopes of atoms in natural or unnatural abundance. In some embodiments, the compound comprises at least one deuterium atom. In some embodiments, the compound comprises more than two deuterium atoms. In some embodiments, the compound contains 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 deuterium atoms. In some embodiments, all hydrogen atoms in a compound may be replaced or substituted with deuterium atoms. In some embodiments, the compound comprises at least one fluorine atom. In some embodiments, the compound comprises more than two fluorine atoms. In some embodiments, the compound comprises 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 fluorine atoms. In some embodiments, all hydrogen atoms in a compound may be replaced or substituted with fluorine atoms.

Degradation agent

In some aspects, the present disclosure provides a divalent compound (also referred to herein as a degradation agent) comprising a PTK6 ligand (or targeting moiety) conjugated to a degradation tag. The linkage of the PTK6 ligand to the degradation tag may be direct or indirect via a linking group.

As used herein, the terms "protein tyrosine kinase 6 ligand", "breast tumor kinase ligand", "PTK 6 ligand", "Brk ligand", or "PTK 6 targeting moiety" should be interpreted broadly and encompass a wide variety of molecules ranging from small to large proteins associated with PTK6 or bound to PTK 6. The PTK6 ligand or targeting moiety may be, for example, a small molecule compound (i.e., a molecule having a molecular weight of less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, a nucleic acid or oligonucleotide, a carbohydrate such as an oligosaccharide, or an antibody or fragment thereof.

The PTK6 ligand or targeting moiety may be a PTK6 kinase inhibitor capable of inhibiting the kinase activity of PTK6 (e.g., compound 21d (Zeng et al, 2011), compound 4f (Mahmoud et al, 2014), compound 1(Yamamoto, 2016), XMU-MP-2(Jiang et al, 2017), and compound 3s (Cardenas et al, 2018), and analogs thereof). As used herein, a "PTK 6 kinase inhibitor" refers to an agent that limits, delays, or otherwise causes inhibition of a physiological, chemical, or enzymatic action or function and causes at least a 5% reduction in binding. An inhibitor may also or alternatively refer to a drug, compound or agent that prevents or reduces expression, transcription or translation of a gene or protein. An inhibitor may reduce or prevent the function of a protein, for example, by binding to or activating/deactivating another protein or receptor.

Exemplary PTK6 ligands include, but are not limited to, the compounds listed below:

as used herein, the term "degradation/disruption tag" refers to a compound that is associated with or binds to ubiquitin ligase to recruit the corresponding ubiquitination machinery to PTK6, or to induce PTK6 protein misfolding and subsequent degradation or loss of function at the proteasome.

As used herein, a "linking group" is a bond, molecule, or group of molecules that binds two separate entities (entities) to each other. The linking group provides the optimum spacing of the two entities. The term "linking group" refers in some aspects to any agent or molecule that bridges the PTK6 ligand to the degradation/disruption tag. One of ordinary skill in the art recognizes that sites on the PTK6 ligand or degradation/disruption tag that are not necessary for the function of the degradation agents of the present disclosure are ideal sites for attachment of a linker, provided that the linker, once attached to the conjugates of the present disclosure, also does not interfere with the function of the PTK6 ligand (i.e., its ability to bind PTK 6), or the function of the degradation/disruption tag (i.e., its ability to recruit ubiquitin ligase).

The length of the linker group of the bivalent compound can be adjusted to minimize the molecular weight of the breaker/degrader and to avoid collision of PTK6 ligand or targeting moiety with ubiquitin ligase or to induce PTK6 misfolding simultaneously by hydrophobic tags.

In some aspects, the degradation/disruption tags of the present disclosure include, for example, pomalidomide (Fischer et al, 2014), thalidomide (Fischer et al, 2014), lenalidomide (Fischer et al, 2014), VH032(Galdeano et al, 2014; Maniaci et al, 2017), adamantane (Xie et al, 2014), 1- ((4,4,5,5, 5-pentafluoropentyl) sulfinyl) nonane (E.Wakeling, 1995), nutlin-3a (Vassilev et al, 2004), Nutlin-7112 (Vu et al, 2013), RG 38, AMG 232(Sun et al, 2007), AA-115(Agui et al, 2017), Betadine (Hiroyuki Suda et al, MV1 (Varlomelme et al, 2007), Lairl (Outberg et al, 201161, 2014 et al), Roxburg et al, 1972016, 2016), and analogs thereof. Degradation/disruption tags can be attached to various target moieties in the structure of PTK6 ligands or targeting moieties (e.g., compound 21d (Zeng et al, 2011), compound 4f (Mahmoud et al, 2014), compound 1(Yamamoto, 2016), XMU-MP-2(Jiang et al, 2017), and compound 3s (Cardenas et al, 2018), and analogs thereof) with different types and lengths of linkers, thereby generating potent divalent compounds. In particular, attaching pomalidomide or VHL-1 to any part of the molecule can recruit cereblon E3 ligase or VHL E3 ligase to PTK 6.

The bivalent compounds disclosed herein may selectively affect PTK 6-mediated disease cells (i.e., PTK6 degrader/disrupter is capable of killing PTK 6-mediated disease cells or inhibiting growth of PTK 6-mediated disease cells while also having a relatively low ability to lyse WT cells or inhibit growth of WT cells) as compared to WT (wild-type) cells, e.g., GI to one or more PTK 6-mediated disease cells₅₀GI vs for one or more WT cells, e.g., WT cells of the same species and tissue type as PTK 6-mediated disease cells₅₀Greater than 1.5 times lower, greater than 2 times lower, greater than 2.5 times lower, greater than 3 times lower, greater than 4 times lower, greater than 5 times lower, greater than 6 times lower, greater than 7 times lower, greater than 8 times lower, greater than 9 times lower, greater than 10 times lower, greater than 15 times lower, or greater than 20 times lower.

Additional divalent compounds (i.e., PTK6 degradants/disrupters) may be developed using the principles and methods disclosed herein. For example, other linkers, degradation/disruption tags, and PTK6 binding/inhibiting moieties (not limited to compound 21d (Zeng et al, 2011), compound 4f (Mahmoud et al, 2014), compound 1(Yamamoto, 2016), XMU-MP-2(Jiang et al, 2017), and compound 3s (Cardenas et al, 2018), and the like) can be synthesized and tested.

In some aspects, the PTK6 degrader/disrupter has the form "PI-linker-EL" as shown below:

wherein the PI ("target protein" (i.e., ligand of the protein to be degraded) comprises a PTK6 ligand (e.g., PTK6 kinase inhibitor) and the EL (e.g., ligand of E3 ligase) comprises a degradation/disruption tag (e.g., E3 ligase ligand). Exemplary PTK6 ligands (PI), exemplary degradation/disruption tags (EL) and exemplary linking groups (Linker) are shown below:

PTK6 ligand

PTK6 ligands include, but are not limited to:

wherein

R¹Selected from H, C_1-8Alkyl radical, C₁-C₈Hydroxyalkyl radical, C₁-C₈Alkoxyalkyl group, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, OR⁸、SR⁹、NR¹⁰R¹¹，

R²Is selected from C₆-C₁₀Aryl or C₅-C₁₀A heteroaryl group. R²Is unsubstituted or optionally substituted with one or more groups selected from: halogen, ═ O, ═ S, CN, NO₂、C_1-8Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C₁-C₈Alkylene radical OR¹²、C₁-C₈Alkylene SR¹³、C₁-C₈Alkylene radical NR¹⁴R¹⁵、C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, OR¹²、SR¹³、NR¹⁴R¹⁵，

R³Is selected from C ₆-C₁₀Aryl or C₅-C₁₀A heteroaryl group. R³Is unsubstituted or substituted by one or more groups selected from: c₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₁-C₈Alkoxyalkyl group, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, halogen, CN, NO₂、＝O、＝S、R¹⁶、OR¹⁶、SR¹⁷、SO₂R¹⁸、NR¹⁹R²⁰、C(O)R¹⁶、C(O)OR¹⁶、C(S)OR¹⁶、C(O)NR¹⁹R²⁰、C(S)NR¹⁹R²⁰、NR¹⁹C(O)R¹⁶、NR¹⁹C(O)OR¹⁶、NR¹⁹S(O)R¹⁶、NR¹⁹S(O)OR¹⁶、S(O)R¹⁶、S(O)OR¹⁶And S (O) ONR¹⁹R²⁰，

R⁶And R⁷、R¹⁰And R¹¹、R¹⁴And R¹⁵Together with the nitrogen atom to which they are attached may independently form a 3-to 10-membered heterocyclyl ring,

R¹⁹and R²⁰Independently selected from H, C₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Alkoxyalkyl group, C₁-C₈Hydroxy radical Alkyl radical, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl radical, C₅-C₁₀Heteroaryl, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₁-C₈Alkoxyalkyl group, C (O) C₃-C₁₀Cycloalkyl, C (O) C₃-C₁₀Heterocycloalkyl, C (O) C₆-C₁₀Aryl, C (O) C₅-C₁₀Heteroaryl, C (O) OC₁-C₈Alkyl, C (O) OC₁-C₈Haloalkyl, C (O) OC₁-C₈Hydroxyalkyl, C (O) OC₁-C₈Alkoxyalkyl group, C (O) OC₃-C₁₀Cycloalkyl, C (O) OC₃-C₁₀Heterocyclic group, C (O) OC₆-C₁₀Aryl, C (O) OC₅-C₁₀Heteroaryl, C (O) NC₁-C₈Alkyl, C (O) NC₁-C₈Haloalkyl, C (O) NC₁-C₈Hydroxyalkyl, C (O) NC₁-C₈Alkoxyalkyl group, C (O) NC₃-C₁₀Cycloalkyl, C (O) NC₃-C₁₀Heterocyclic group, C (O) NC₆-C₁₀Aryl, C (O) NC₅-C₁₀Heteroaryl, SO₂C₁-C₈Alkyl, SO₂C₁-C₈Halogenated alkyl, SO₂C₁-C₈Hydroxyalkyl, SO₂C₁-C₈Alkoxyalkyl group, SO₂C₃-C₁₀Cycloalkyl, SO₂C₃-C₁₀Heterocyclic radical, SO₂C₆-C₁₀Aryl, SO₂C₅-C₁₀Heteroaryl group, C₁-C₈Alkylene radical C₃-C₁₀Cycloalkyl radical, C₁-C₈Alkylene radical C₃-C₁₀Heterocycloalkyl radical, C₁-C₈Alkylene radical C₆-C₁₀Aryl radical, C₁-C₈Alkylene radical C₅-C₁₀Heteroaryl, or

R¹⁹And R²⁰May independently form, together with the nitrogen atom to which they are attached, a 3-to 10-membered heterocyclyl ring, and

x is selected from CH or N.

In some aspects of formula 1, R is selected from H, halogen, optionally substituted C_1-3Alkyl, and optionally substituted C_1-3An alkoxy group.

In some aspects of formula 1, R is selected from CH₃、CF₃、CH₂CH₃、CH₂CF₃And c-Pr.

In some aspects of formula 1, R is selected from CH₃And c-Pr.

In some aspects of formula 1, R is c-Pr.

In some aspects of formula 1, R¹Selected from H, halogen, optionally substituted C_1-3Alkyl, and optionally substituted C_1-3An alkoxy group.

In some aspects of formula 1, R¹Selected from H, F, CH₃And CF₃。

In some aspects of formula 1, R¹Is H.

In some aspects of formula 1, R²Is a 5-to 6-membered heteroaryl group, optionally substituted with C selected from halogen_1-3Alkyl and optionally substituted C_1-3One or more groups of alkoxy groups.

In some aspects of formula 1, R²Selected from phenyl,

In some aspects of formula 1, R²Is composed of

In some aspects of formula 1, R³Is selected from

In some aspects of the process of formula 1,R³is selected from

In some aspects of formula 1, R³Is composed of

In some aspects of formula 1, X is N.

PTK6 ligands may also be:

wherein

X, Y and Z are independently selected from null, CR⁵And N, wherein

R⁵Selected from hydrogen, halogen, or optionally substituted C_1-3An alkyl group;

a is selected from null or-R⁶-R⁷-, wherein

R⁶And R⁷Independently selected from null, NR ⁸、O、S、C(O)、C(O)NR⁸、NR⁸C(O)、NR⁸C(O)NR⁹、OC(O)NR⁹、NR⁸C(O)O、S(O)、S(O)NR⁸、NR⁸S(O)、NR⁸S(O)NR⁹、OS(O)NR⁹、NR⁸S(O)O、S(O)₂、S(O)₂NR⁸、NR⁸S(O)₂、NR⁸S(O)₂NR⁹、OS(O)₂NR⁹、NR⁸S(O)₂O, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸And R⁹Together with the atoms to which they are attached form a 4-to 20-membered heterocyclyl ring;

b and D are independently selected from CR¹⁰R¹¹、NR¹⁰O, SO, or SO₂Wherein

R¹⁰And R¹¹Independently selected from hydrogen, halogen, hydroxy, cyano, nitro, and optionally substituted C₁-C₃Alkyl, or

R¹⁰And R¹¹Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic ring or a 4-to 6-membered heterocyclic ring;

R¹and R²Independently selected from hydrogen and optionally substituted C₁-C₃Alkyl, or

R¹And R ²Together with the atoms to which they are attached form a 4-to 6-membered heterocyclyl ring;

m and n are independently selected from 0, 1, 2, 3 and 4.

R¹²And R¹³、R¹²And R¹⁴Together with the atoms to which they are attached form a 4-to 20-membered heterocyclyl ring;

in some aspects of formula 2, X, Y and Z are independently selected from CH, CF, and N.

In some aspects of formula 2, X is N; y and Z are independently selected from CH, CF and N.

In some aspects of formula 2, X is N; y and Z are CH.

In some aspects of formula 2, A is

In some aspects of formula 2, B and D are independently selected from CH₂、CHOH、CHCH₃、C(CH₃)₂、CHF、CF₂O, NH, and NCH₃。

In some aspects of formula 2, B is O.

In some aspects of formula 2, D is CH₂。

In some aspects of formula 2, R¹And R²Independently selected from H and optionally substituted C₁-C₃Alkyl, provided that R is¹And R²At least one of which is H.

In some aspects of formula 2, R¹And R²Independently selected from H and CH₃Provided that R is¹And R²At least one of which is H.

In some aspects of formula 2, R¹And R²Is H.

In some aspects of formula 2, R³And R⁴Independently at each occurrence, selected from H, F, OH, CN, NH₂、NO₂、CH₃、CF₃i-Pr, and c-Pr.

In some aspects of formula 2, R³And R⁴Independently at each occurrence, selected from H and F.

In some aspects of formula 2, m and n are independently selected from 0, 1 and 2.

In some aspects of formula 2, m and n are 1.

In some aspects of formula 2, Ar is 4-OCF₃A substituted phenyl group.

In some aspects, the PTK6 ligand may be a derivative of the following compounds:

in some aspects, the PTK6 ligand may be, for example:

PTK6 ligand may bind to PTK6 and/or PTK6 muteins.

Degradation/destruction label

Degradation/destruction labels (EL) include, but are not limited to:

wherein

V, W and X are independently selected from CR²And N;

y is selected from CO and CR³R⁴And N ═ N;

z is selected from among null, CO, CR⁵R⁶、NR⁵O, optionally substituted C₁-C₁₀Alkylene, optionally substituted C₁-C₁₀Alkenylene, optionally substituted C₁-C₁₀Alkynylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH ₂CH ═ CH, C ≡ C, NH, and O;

R⁵and R⁶Independently selected from the group consisting of empty, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₆An alkyl group, an optionally substituted 3-to 6-membered carbocyclyl group, and an optionally substituted 4-to 6-membered heterocyclyl group; or R⁵And R⁶Together with the atoms to which they are attached form a 3-to 6-membered carbocyclyl or a 4-to 6-membered heterocyclyl.

Wherein

V, W and X are independently CR²Or the number of N is greater than the number of N,

y is CO or CH₂，

Z is CH₂The content of the nitrogen is NH or O,

R¹is hydrogen, methyl or fluorine, and

R²is hydrogen, halogen or C₁-C₅An alkyl group;

wherein

U, V, W and X are independently selected from CR²And N;

y is selected from CR³R⁴、NR³And O; preferably, Y is selected from CH₂、NH、NCH₃And O;

z is selected from among null, CO, CR⁵R⁶、NR⁵O, optionally substituted C₁-C₁₀Alkylene, optionally substituted C ₁-C₁₀Alkenylene, optionally substituted C₁-C₁₀Alkynylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH₂CH ═ CH, C ≡ C, NH, and O;

R⁵and R⁶Independently selected from the group consisting of empty, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₆An alkyl group, an optionally substituted 3-to 6-membered carbocyclyl group, and an optionally substituted 4-to 6-membered heterocyclyl group; or R ⁵And R⁶Together with the atoms to which they are attached form a 3-to 6-membered carbocyclyl or a 4-to 6-membered heterocyclyl.

Wherein

R¹And R²Independently of one another is hydrogen, C₁-C₈Alkyl radical, C₁-C₈Alkoxyalkyl group, C₁-C₈Haloalkyl, C₁-C₈Hydroxyalkyl radical, C₁-C₈Aminoalkyl radical, C₁-C₈Alkylaminoalkyl, C₃-C₇Cycloalkyl radical, C₃-C₇Heterocyclic group, C₂-C₈Alkenyl, or C₂-C₈An alkynyl group;

R³is H, C (O) C₁-C₈Alkyl, C (O) C₁-C₈Alkoxyalkyl group, C (O) C₁-C₈Haloalkyl, C (O) C₁-C₈Hydroxyalkyl, C (O) C₁-C₈Aminoalkyl radical, C (O) C₁-C₈Alkylaminoalkyl, C (O) C₃-C₇Cycloalkyl, C (O) C₃-C₇Heterocyclic group, C (O) C₂-C₈Alkenyl, C (O) C₂-C₈Alkynyl, C (O) OC₁-C₈Alkoxyalkyl group, C (O) OC₁-C₈Haloalkyl, C (O) OC₁-C₈Hydroxyalkyl, C (O) OC₁-C₈Aminoalkyl, C (O) OC₁-C₈Alkylaminoalkyl, C (O) OC₃-C₇Cycloalkyl, C (O) OC₃-C₇Heterocyclic group, C (O) OC₂-C₈Alkenyl, C (O) OC₂-C₈Alkynyl, C (O) NC₁-C₈Alkoxyalkyl group, C (O) NC₁-C₈Haloalkyl, C (O) NC₁-C₈Hydroxyalkyl, C (O) NC₁-C₈Aminoalkyl, C (O) NC₁-C₈Alkylaminoalkyl, C (O) NC₃-C₇Cycloalkyl, C (O) NC₃-C₇Heterocyclic group, C (O) NC₂-C₈Alkenyl, C (O) NC₂-C₈Alkynyl, P (O) (OH)₂、P(O)(OC₁-C₈Alkyl radical)₂Or P (O) (OC)₁-C₈Aryl radical)₂。

Wherein

R¹And R²Independently selected from hydrogen, halogen, OH, NH₂CN, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C ₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Aminoalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted C₂-C₈Alkenyl, and optionally substituted C₂-C₈An alkynyl group; (preferably, R)¹Selected from isopropyl or tert-butyl; and R is²Selected from hydrogen or methyl);

R³is hydrogen, optionally substituted C (O) C₁-C₈Alkyl, optionally substituted C (O) C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) C₁-C₈Haloalkyl, optionally substituted C (O) C₁-C₈Hydroxyalkyl, optionally substituted C (O) C₁-C₈Aminoalkyl, optionally substituted C (O) C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C (O) C₃-C₇Cycloalkyl, optionally substituted C (O) (3-to 7-membered heterocyclyl), optionally substituted C (O) C₂-C₈Alkenyl, optionally substituted C (O) C₂-C₈Alkynyl, optionally substituted C (O) OC₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) OC₁-C₈Haloalkyl, optionally substituted C (O) OC₁-C₈Hydroxyalkyl, optionally substituted C (O) OC₁-C₈Aminoalkyl, optionally substituted C (O) OC₁-C₈Alkylamino radical C₁-C₈Alkyl radicalOptionally substituted C (O) OC₃-C₇Cycloalkyl, optionally substituted C (O) O (3-to 7-membered heterocyclyl), optionally substituted C (O) OC₂-C₈Alkenyl, optionally substituted C (O) OC₂-C₈Alkynyl, optionally substituted C (O) NC ₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C (O) NC₁-C₈Haloalkyl, optionally substituted C (O) NC₁-C₈Hydroxyalkyl, optionally substituted C (O) NC₁-C₈Aminoalkyl, optionally substituted C (O) NC₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C (O) NC₃-C₇Cycloalkyl, optionally substituted C (O) N (3-to 7-membered heterocyclyl), optionally substituted C (O) NC₂-C₈Alkenyl, optionally substituted C (O) NC₂-C₈Alkynyl, optionally substituted P (O) (OH)₂Optionally substituted P (O) (OC)₁-C₈Alkyl radical)₂And optionally substituted P (O) (OC)₁-C₈Aryl radical)₂(ii) a And

R⁶And R⁷Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 8-membered cycloalkyl, optionally substituted 3-to 8-membered heteroCyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁴And R⁵、R⁶And R⁷Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring;

R⁸And R⁹、R⁹And R¹⁰Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring.

Wherein

v, W, X and Z are independently CR⁴Or N.

And

wherein

R¹、R²And R³Independently selected from hydrogen, halogen, optionally substituted C ₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₃-C₇Cycloalkyl, optionally substituted 3-to 7-membered heterocyclyl, optionally substituted C₂-C₈Alkenyl, and optionally substituted C₂-C₈An alkynyl group;

R⁴and R⁵Independently selected from hydrogen, COR⁶、CO₂R⁶、CONR⁶R⁷、SOR⁶、SO₂R⁶、SO₂NR⁶R⁷Optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted aryl-C₁-C₈An alkyl group, an optionally substituted 3-to 8-membered cycloalkyl group, an optionally substituted 3-to 8-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, wherein

R⁶And R⁷Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted 3-to 8-membered cycloalkyl, optionally substituted 3-to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁶And R⁷Together with the atoms to which they are attached form a 4-to 8-membered cycloalkyl or heterocyclyl ring.

In some aspects, the degradation/disruption label may be, for example, pomalidomide (Fischer et al, 2014), thalidomide (Fischer et al, 2014), lenalidomide (Fischer et al, 2014), VH032(Galdeano et al, 2014; Maniaci et al, 2017), adamantane (Xie et al, 2014), 1- ((4,4,5,5, 5-pentafluoropentyl) sulfinyl) nonane (E.Wakeling, 1995), nutlin-3a (Vassilev et al, 2004), RG7112(Vu et al, 2013), RG 38, AMG 232(Sun et al, 2014), AA-115 (Aglarui et al, 2017), tadine (Hiroyi Suda et al, 1976), 1 (Varmeev et al, LCL et al, 2007, Welarg et al, 2017), rapamycin (Outberg et al, 2010, 2016, and analogs thereof.

In some aspects, the degradation/disruption tag can be, for example, one of the following structures:

in some aspects, the degradation/disruption tag may bind to ubiquitin ligase (e.g., E3 ligase such as cereblon E3 ligase, VHL E3 ligase, MDM2 ligase, TRIM21 ligase, TRIM24 ligase, KEAP 1E 3 ligase, and/or IAP ligase) and/or function as a hydrophobic group or tag that causes PTK6 protein misfolding.

Linking group

In some aspects, the linking group can be a moiety as follows:

wherein

A. W and B are independently selected at each occurrence from null, or a divalent moiety selected from: r ' -R ', R ' COR ', R ' CO₂R”、R’C(O)N(R¹)R”、R’C(S)N(R¹)R”、R’OR”、R’OC(O)R”、R’OC(O)OR”、R’OCON(R¹)R”、R’SR”、R’SOR”、R’SO₂R”、R’SO₂N(R¹)R”、R’N(R¹)R”、R’NR¹COR”、R’NR¹C(O)OR”、R’NR¹CON(R²)R”、R’NR¹C(S)R”、R’NR¹S(O)R”、R’NR¹S(O)₂R ', and R' NR¹S(O)₂N(R²) R' is provided, wherein

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C ₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C ₃-C₁₃SpirocycloalkanesRadical, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

r 'and R', R¹And R²R' and R¹R' and R²R' and R¹R' and R²Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring; and

m is 0 to 15.

Wherein

R¹、R²、R³And R⁴Independently at each occurrence, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino, and optionally substituted C₁-C₈Alkylamino radical C ₁-C₈Alkyl, optionally substituted 3-to 10-membered carbocyclylOptionally substituted 3-to 8-membered cycloalkyloxy, optionally substituted 3-to 10-membered carbocyclylamino, optionally substituted 4-to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹And R²、R³And R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C ₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁵and R⁶Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

R 'and R', R⁵And R⁶R' and R⁵R' and R⁶R' and R⁵R' and R⁶Together with the atom to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-membered ringTo a 20 membered heterocyclyl ring;

m is 0 to 15;

n is 0 to 15 at each occurrence; and

o is 0 to 15.

Wherein

R¹And R²Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R ^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxyalkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C ₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

r 'and R', R³And R⁴R' and R³R' and R⁴R' and R³R' and R⁴Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15 at each occurrence; and

n is 0 to 15.

Wherein

X is selected from O, NH, and NR⁷；

R¹、R²、R³、R⁴、R⁵And R⁶Independently at each occurrence, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxy, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C ₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 3-to 8-membered cycloalkyloxy group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

R 'and R' are independently selected from the group consisting of empty, optionally substituted R^r-(C₁-C₈Alkyl), or a moiety comprising: optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Alkylene, optionally substituted C₂-C₈Alkenylene, optionally substituted C₂-C₈Alkynylene, optionally substituted C₁-C₈Hydroxy radicalAlkylene, optionally substituted C₁-C₈Alkoxy radical C₁-C₈Alkylene, optionally substituted C₁-C₈Alkylamino radical C₁-C₈Alkylene, optionally substituted C₁-C₈Haloalkylene, optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C ₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^rselected from optionally substituted 3-to 10-membered carbocyclyl, optionally substituted 4-to 10-membered heterocyclyl, optionally substituted C₃-C₁₃Fused cycloalkyl, optionally substituted C₃-C₁₃Condensed heterocyclic group, optionally substituted C₃-C₁₃Bridged cycloalkyl, optionally substituted C₃-C₁₃Bridged heterocyclic radical, optionally substituted C₃-C₁₃Spirocycloalkyl, optionally substituted C₃-C₁₃Spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁷、R⁸and R⁹Independently selected from hydrogen, optionally substituted C₁-C₈Alkyl, optionally substituted C₂-C₈Alkenyl, optionally substituted C₂-C₈Alkynyl, optionally substituted C₁-C₈Alkoxyalkyl, optionally substituted C₁-C₈Haloalkyl, optionally substituted C₁-C₈Hydroxyalkyl, optionally substituted C₁-C₈Alkylamino radical C₁-C₈An alkyl group, an optionally substituted 3-to 10-membered carbocyclyl group, an optionally substituted 4-to 10-membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;

r 'and R', R⁸And R⁹R' and R⁸R' and R ⁹R' and R⁸R' and R⁹Together with the atoms to which they are attached form a 3-to 20-membered cycloalkyl ring or a 4-to 20-membered heterocyclyl ring;

m is 0 to 15 at each occurrence;

n is 0 to 15 at each occurrence;

o is 0 to 15; and

p is 0 to 15.

In some aspects of formulas 7, 7A, 7B, and 7C, the linker moiety comprises a ring selected from the group consisting of formulas C1, C2, C3, C4, and C5:

in some aspects, the linking group can also be a moiety as follows:

wherein X is C ═ O or CH₂，

Y is C ═ O or CH₂And are and

n is 0 to 15;

wherein X is C ═ O or CH₂，

Y is C ═ O or CH₂，

m is 0 to 15, and m is,

n is 0 to 6, and

o is 0 to 15; or

Wherein

X is C ═ O or CH₂，

Y is C ═ O or CH₂，

m is 0 to 15, and

n is 0 to 15.

In some aspects of formula C, R has the structure:

synthesis and testing of divalent Compounds

The binding affinity of the newly synthesized bivalent compound (i.e., PTK6 degrader/disrupter) can be assessed using standard biophysical assays known in the art (e.g., Isothermal Titration Calorimetry (ITC), Surface Plasmon Resonance (SPR)). The ability of the bivalent compound to induce PTK6 degradation and inhibit cancer cell proliferation can then be assessed using a cellular assay. In addition to assessing bivalent compound-induced changes in protein expression of PTK6 or PTK6 muteins, enzyme activity can be assessed. Assays suitable for use in any or all of these steps are known in the art and include, for example, western blotting, quantitative Mass Spectrometry (MS) analysis, flow cytometry, enzyme inhibition, ITC, SPR, cell growth inhibition, and xenograft and PDX models. Suitable cell lines for any or all of these steps are known in the art and include the following cancer cell lines: 1) breast cancer cell lines (MDA-MB231, MCF7, UACC893, HCC1954, T47D, BT474, ZR 751); 2) ovarian cancer cell lines (DOV-13, HeyC2, OV2008, OvCAR 5); 3) pancreatic cancer cell lines (PANC-1, BxP3, Capan1, Hs766T, MIAPaCa 2); 4) prostate cancer cell lines (PC-3, DU 145). Suitable mouse models for any or all of these steps are known in the art and include patient-derived xenograft models of triple negative breast cancer.

By way of non-limiting example, detailed synthetic schemes are described in the examples for a specific exemplary PTK6 degrader/disrupter.

Pharmaceutically acceptable isotopic variations of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (substituting the appropriate isotopic variations of the appropriate reagents for those reagents). In particular, isotopic variations are compounds in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature. Useful isotopes are known in the art and include isotopes of, for example, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine. Thus, exemplary isotopes include, for example²H、³H、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³⁵S、¹⁸F. And³⁶Cl。

isotopic variations (e.g. containing²Isotopic variants of H) may provide therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations (particularly those containing radioactive isotopes) can be used in drug or substrate tissue distribution studies. Radioisotope tritium ( ³H) And carbon-14 (¹⁴C) They are particularly suitable for this purpose in view of the ease of their introduction and the ready means of detection.

Is intended to be disclosed hereinPharmaceutically acceptable solvates of the disclosed compounds. Solvents for crystallizing the compounds disclosed herein (e.g., D) can be substituted, for example, by isotopic variations₂O instead of H₂O、d₆-acetone instead of acetone, or d₆DMSO instead of DMSO) to generate a solvate.

Pharmaceutically acceptable fluorinated variants of the compounds disclosed herein are contemplated and may be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (substituting appropriate fluorinated variants of appropriate reagents for these reagents). In particular, fluorinated variants are compounds in which at least one hydrogen atom is replaced by a fluorine atom. Fluorinated variants may provide therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

Pharmaceutically acceptable prodrugs of the compounds disclosed herein are contemplated and may be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (e.g., converting a hydroxyl or carboxylic acid group to an ester group). As used herein, "prodrug" refers to a compound that can be converted into a therapeutic agent via some chemical or physiological process (e.g., enzymatic process and metabolic hydrolysis). Thus, the term "prodrug" also refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs can be inactive (i.e., esters) when administered to a subject, but are converted in vivo to the active compound, for example, by hydrolysis to the free carboxylic acid or free hydroxyl group. Prodrug compounds generally provide the advantages of solubility, histocompatibility, or delayed release in an organism. The term "prodrug" is also intended to include any covalently bonded carriers that release the active compound in vivo upon administration of such prodrug to a subject. Prodrugs of an active compound may be prepared by modifying functional groups present in the active compound in such a way that the modification is cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols or acetamide, formamide and benzamide derivatives of amine functional groups in the active compound, and the like.

Characterization of exemplary PTK6 degradants/breakers

Specific exemplary PTK6 degradants/disruptors were characterized in triple negative MDA-231 breast cancer cells (examples 83-85, FIGS. 2-5). The bifunctional compounds YX39-101, YX39-102, YX39-103, YX39-104, YX39-105, YX39-106, and YX39-107 were found to be particularly effective at reducing PTK6 protein levels in MDA-231 cells at 500nM (FIG. 3). In addition, YX69-159, YX79-10, YX79-11, YX79-12, YX79-15, YX79-36, YX79-37, YX79-40, YX79-41, YX79-42, YX79-59, and YX79-65 were also found to potently inhibit PTK6 expression in MDA-MB231 cells at 500nM (FIGS. 4, 5).

Treating cells in a 3D matrigel culture assay generally provides a better understanding of the activity of compounds in vivo (mouse) biological models than standard (2D) monolayer culture systems. Treatment of triple negative breast cancer cells or ER + breast cancer cells with PTK6 degradants that reduce PTK6 protein levels inhibited the viability and invasive branching (fig. 6, 7) of triple negative MDA-MB231 breast cancer cells in 3D cultures. The effect of PTK6 degradant treatment on Cell viability was quantified using 3D Cell Titer Glo (Promega); treatment with PTK6 degrading agent significantly impaired viability in a concentration-dependent manner, comparable to the effect observed with PTK6 shRNA vector (fig. 6, 7). At comparable concentrations, the PTK6 kinase inhibitor (P21D) had only a moderate effect on the viability of cells in 3D cell culture (fig. 6, 7), thus demonstrating that PTK6 regulates the kinase-independent function of the growth of some PTK6+ tumors that would be better targeted by PTK6 degradants. Similarly, treatment with the preferred PTK6 degrading agent instead of the PTK6 kinase activity inhibitor inhibited the viability of 3D cultures of CP70 cells, an ovarian cancer cell line resistant to platinum-based chemotherapy (fig. 8).

Mechanistically, the inhibition of PTK6 expression observed with the degradant treatment depends on proteasome activity. Pretreatment of cells with the proteasome inhibitor MG-132 prevented down-regulation of PTK6 expression (fig. 9). Furthermore, pretreatment with inhibitors of PTK6 kinase activity bound to the same binding site as PTK6 degradants restored (rescue) PTK6 protein levels in cells treated with the degradants (fig. 10).

PTK6 degrading agents inhibit PTK6 expression in cell lines resistant to current standard of care therapies (care therapeutics). The degradant downregulated expression in ER + breast cancer cells that were resistant to estrogen deprivation (estrogen depletion) (fig. 11), highlighting the potential efficacy of PTK6 degradants to target the disease resistant to treatment.

Definition of terms

"alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation and consisting only of carbon and hydrogen atoms. The alkyl group can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbon atoms. In certain embodiments, the alkyl group contains 1 to 15 carbon atoms (e.g., C)₁-C₁₅Alkyl groups). In certain embodiments, the alkyl group contains 1 to 13 carbon atoms (e.g., C) ₁-C₁₃Alkyl groups). In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C)₁-C₈Alkyl groups). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C)₅-C₁₅Alkyl groups). In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C)₅-C₈Alkyl groups). Alkyl groups are attached to the rest of the molecule by single bonds, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), pentyl, 3-methylhexyl, 2-methylhexyl, and the like.

"alkenyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond. The alkenyl group can contain 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbon atoms. In certain embodiments, alkenyl groups contain 2 to 12 carbon atoms (e.g., C)₂-C₁₂Alkenyl). In certain embodiments, alkenyl groups contain 2 to 8 carbon atoms (e.g., C)₂-C₈Alkenyl). In certain embodiments, alkenyl groups contain 2 to 6 carbon atoms (e.g., C)₂-C₆Alkenyl). In other embodiments, alkenyl groups contain 2 to 4 carbon atoms (e.g., C) ₂-C₄Alkenyl). Alkenyl groups are attached to the remainder of the molecule by single bonds, for example, vinyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and pent-1, 4-dienyl, and the like.

As used herein, the term "allyl" means-CH₂CH＝CH₂A group.

As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms containing at least one triple bond. The alkynyl group can contain 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbon atoms. In certain embodiments, alkynyl contains 2 to 12 carbon atoms (e.g., C)₂-C₁₂Alkynyl). In certain embodiments, alkynyl groups contain 2 to 8 carbon atoms (e.g., C)₂-C₈Alkynyl). In other embodiments, alkynyl has 2 to 6 carbon atoms (e.g., C)₂-C₆Alkynyl). In other embodiments, alkynyl groups have 2 to 4 carbon atoms (e.g., C)₂-C₄Alkynyl). The alkynyl group is connected to the rest of the molecule by a single bond. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.

As used herein, the term "alkoxy" means an alkyl group, as defined herein, attached to the remainder of the molecule via an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy, and the like.

As used herein, the term "aryl" refers to a compound obtained by substituting a ring carbon atom with a carbonyl groupGroups derived from aromatic monocyclic or polycyclic hydrocarbon ring systems with the removal of hydrogen atoms. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon atoms. The aryl group may comprise from 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e. it contains a cyclic delocalized (4n +2) pi-electron system according to Huckel theory. In certain embodiments, aryl contains 6 to 14 carbon atoms (C)₆-C₁₄Aryl). In certain embodiments, aryl contains 6 to 10 carbon atoms (C)₆-C₁₀Aryl). Examples of such groups include, but are not limited to, phenyl, fluorenyl, and naphthyl. As used herein, the terms "Ph" and "phenyl" mean-C₆H₅A group.

The term "heteroaryl" refers to a group derived from a 3-to 18-membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring of the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n +2) pi-electron system, according to the theory of huckel. Heteroaryl groups include fused or bridged ring systems. In certain embodiments, heteroaryl refers to a group derived from a 3-to 10-membered aromatic ring group (3-to 10-membered heteroaryl). In certain embodiments, heteroaryl refers to a group derived from a 5-to 7-membered aromatic ring (5-to 7-membered heteroaryl). Heteroaryl groups include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl group is attached to the rest of the molecule through any atom of the ring. Examples of such groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridyl (furylpyridinyl), and the like. In certain embodiments, the heteroaryl group is attached to the remainder of the molecule via a ring carbon atom. In certain embodiments, the heteroaryl group is attached to the remainder of the molecule via a nitrogen atom (N-linked) or a carbon atom (C-linked). For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, the groups derived from imidazole may be imidazol-1-yl (N-linked) or imidazol-3-yl (C-linked).

As used herein, the term "heterocyclyl" means a non-aromatic monocyclic, bicyclic, tricyclic, or tetracyclic group having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms in its ring system and containing from 3 to 12 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, with the proviso that the ring of the group does not contain two adjacent O atoms or two adjacent S atoms. Heterocyclyl groups may include fused, bridged or spiro ring systems. In certain embodiments, heterocyclyl groups contain 3 to 10 ring atoms (3-to 10-membered heterocyclyl groups). In certain embodiments, heterocyclyl groups contain 3 to 8 ring atoms (3-to 8-membered heterocyclyl groups). In certain embodiments, heterocyclyl groups contain 4 to 8 ring atoms (4-to 8-membered heterocyclyl groups). In certain embodiments, heterocyclyl groups contain 3 to 6 ring atoms (3-to 6-membered heterocyclyl groups). The heterocyclyl group may contain an oxo substituent at any available atom that will result in a stable compound. For example, such groups may contain oxo atoms on available carbon or nitrogen atoms. Such groups may contain more than one oxo substituent, if chemically feasible. Furthermore, it is to be understood that when such heterocyclyl groups contain a sulfur atom, the sulfur atom may be oxidized by one or two oxygen atoms to give the sulfoxide or sulfone. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6-membered cycloheteroalkyl group is piperidinyl. An example of a 9-membered cycloheteroalkyl group is indolinyl. 10 Yuan An example of a cycloheteroalkyl group is 4H-quinolizinyl (4H-quinolizinyl). Other examples of such heterocyclyl groups include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioalkyl (thioacyl), piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl (oxepanyl), thietanyl (thiepanyl), oxazepinyl (oxazepinyl), oxazepinyl (thia-nyl), thiazepinyl (thia-nyl), thiaOxazepinyl, diazaRadical (diazepinyl), thiazalA group (thiazepinyl), 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl (1,3-dioxolanyl), pyrazolinyl, dithianyl, dithiocyclopentyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0 ] group]Hexyl, 3-azabicyclo [4.1.0]Heptyl, 3H-indolyl, quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo-2, 8, diazaspiro [4.5 ]]Decan-8-yl. Heteroaryl groups may be attached to the rest of the molecule via a carbon atom (C-linked) or a nitrogen atom (N-linked). For example, a group derived from piperazine may be piperazin-1-yl (N-linked) or piperazin-2-yl (C-linked).

The term "cycloalkyl" means a saturated monocyclic, bicyclic, tricyclic, or tetracyclic group having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms in its ring system. Cycloalkyl groups may be fused, bridged or spiro. In certain embodiments, cycloalkyl contains 3 to 8 carbon ring atoms (C)₃-C₈Cycloalkyl groups). In certain embodiments, cycloalkyl groups contain 3 to 6 carbon ring atoms(C₃-C₆Cycloalkyl groups). Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl, and the like.

The term "cycloalkylene" is a bidentate radical obtained by removing a hydrogen atom from a cycloalkyl ring as defined above. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like.

The term "spiro" as used herein has its conventional meaning, i.e., any ring system containing more than two rings, wherein two of the rings have a common ring carbon. As defined herein, each ring in a spiro ring system independently contains from 3 to 20 ring atoms. Preferably, they have from 3 to 10 ring atoms. Non-limiting examples of spiro ring systems include spiro [3.3] heptane, spiro [3.4] octane, and spiro [4.5] decane.

The term "cyano" refers to a-C.ident.N group.

An "aldehyde" group refers to a-C (O) H group.

As defined herein, "alkoxy" groups all refer to-O-alkyl.

As defined herein, "alkoxycarbonyl" refers to-C (O) -alkoxy.

As defined herein, an "alkylaminoalkyl" group refers to an-alkyl-NR-alkyl group.

As defined herein, an "alkylsulfonyl" group refers to-SO₂An alkyl group.

An "amino" group refers to optionally substituted-NH₂。

As defined herein, an "aminoalkyl" group refers to an-alkyl-amino group.

As defined herein, "aminocarbonyl" refers to-C (O) -amino.

An "arylalkyl" group refers to an-alkylaryl group, wherein alkyl and aryl are as defined herein.

As defined herein, an "aryloxy" group refers to both an-O-aryl and an-O-heteroaryl group.

As defined herein, "aryloxycarbonyl" refers to-C (O) -aryloxy.

As defined herein, an "arylsulfonyl" group refers to-SO₂And (4) an aryl group.

As defined herein, a "carbonyl" group refers to a-C (O) -group.

"Carboxylic acid" groups refer to-C (O) OH groups.

As defined herein, "cycloalkoxy" refers to an-O-cycloalkyl group.

"halo" or "halogen" groups refer to fluorine, chlorine, bromine or iodine.

A "haloalkyl" group refers to an alkyl group substituted with one or more halogen atoms.

A "hydroxy" group refers to an-OH group.

The "nitro" group means-NO₂A group.

An "oxo" (oxo) "group refers to an ═ O substituent.

A "trihalomethyl" group refers to a methyl group substituted with three halogen atoms.

The term "substituted" means that the specified group or moiety bears one or more substituents independently selected from C₁-C₄Alkyl, aryl, heteroaryl, aryl-C₁-C₄Alkyl-, heteroaryl-C₁-C₄Alkyl-, C₁-C₄Haloalkyl, -OC₁-C₄Alkyl, -OC₁-C₄Alkylphenyl, -C₁-C₄alkyl-OH, -OC₁-C₄Haloalkyl, halogen, -OH, -NH₂、-C₁-C₄alkyl-NH₂、-N(C₁-C₄Alkyl) (C₁-C₄Alkyl), -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl) (C₁-C₄Alkylphenyl), -NH (C)₁-C₄Alkylphenyl), cyano, nitro, oxo, -CO₂H、-C(O)OC₁-C₄Alkyl, -CON (C)₁-C₄Alkyl) (C₁-C₄Alkyl), -CONH (C)₁-C₄Alkyl), -CONH₂、-NHC(O)(C₁-C₄Alkyl), -NHC (O) (phenyl), -N (C)₁-C₄Alkyl radical C (O) (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl group C (O) (phenyl), -C (O) C₁-C₄Alkyl, -C (O) C₁-C₄Alkylphenyl, -C (O) C₁-C₄Haloalkyl, -OC (O) C₁-C₄Alkyl, -SO₂(C₁-C₄Alkyl), -SO₂(phenyl), -SO₂(C₁-C₄Haloalkyl), -SO ₂NH₂、-SO₂NH(C₁-C₄Alkyl), -SO₂NH (phenyl), -NHSO₂(C₁-C₄Alkyl), -NHSO₂(phenyl), and-NHSO₂(C₁-C₄Haloalkyl).

The term "empty" means that no atoms or moieties are present and that there are bonds between adjacent atoms in the structure.

The term "optionally substituted" means that the specified group can be unsubstituted or substituted with one or more substituents as defined herein. It will be understood that in the compounds of the present invention, when a group is referred to as being "unsubstituted" or "substituted" with groups that are less than the group that would fill the valences of all the atoms in the compound, the remaining valences on such groups are filled with hydrogen. For example, if C₆Aryl (also referred to herein as "phenyl") is substituted with one additional substituent, and one of ordinary skill in the art would understand such a group to be at C₆The aryl ring leaves 4 open positions on the carbon atom (6 initial positions, minus one position attached to the remainder of the compounds of the invention and additional substituents, the remaining 4 positions being open). In such cases, the remaining 4 carbon atoms are each bonded to a hydrogen atom to fill their valences. Similarly, if C is present in the compounds of the invention ₆Aryl is said to be "disubstituted" and those of ordinary skill in the art will understand that this means C₆An aryl group has 3 remaining, unsubstituted carbon atoms. Each of the three unsubstituted carbon atoms is bonded to a hydrogen atom to fill their valences.

As used herein, the same symbols in different formulae may have different definitions, e.g., the definition of R1 in formula 1 is defined for formula 1 and the definition of R1 in formula 6 is defined for formula 6.

As used herein, when m (or n or o or p) is defined by a range, for example, "m is 0 to 15" or "m is 0-3" means that m is an integer from 0 to 15 (i.e., m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) or m is an integer from 0 to 3 (i.e., m is 0, 1, 2, or 3) or is any integer within the defined range.

"pharmaceutically acceptable salts" include both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any of the divalent compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, and phosphorous acids. Also included are salts with the following organic acids: for example, aliphatic mono-and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids (alkanedioic acids), aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are Salts of amino acids, such as arginine, gluconate, and galacturonate (see, e.g., "Pharmaceutical Salts" of Berge S.M. et al, Journal of Pharmaceutical Science, 66:1-19(1997), which is incorporated herein by reference in its entirety). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

"pharmaceutically acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-meglumine, glucosamine, meglumine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al, supra.

As used herein, the same symbols in different formulae may have different definitions, e.g., R in formula 1¹Is defined as in formula 6¹Are defined differently.

As used herein, when m (or n or o or p) is defined as, for example, "m is 0 to 15" or "m ═ 0-5" means that m is an integer of 0 to 15 (or 0 to 5).

Pharmaceutical composition

In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments comprising one or more divalent compounds as disclosed herein. Also included are the pharmaceutical compositions themselves.

In some aspects, the compositions disclosed herein may include other compounds, drugs, or agents for the treatment of cancer. For example, in some cases, a pharmaceutical composition disclosed herein can be combined with one or more (e.g., one, two, three, four, five, or less than ten) compounds. Such additional compounds may include, for example, conventional chemotherapeutic agents known in the art. When co-administered, the PTK6 degradants/disrupters disclosed herein may act in conjunction with conventional chemotherapeutic agents to produce a mechanistically additive or synergistic therapeutic effect.

In some aspects, the pH of the compositions disclosed herein may be adjusted with pharmaceutically acceptable acids, bases, or buffers to improve the stability of the PTK6 degrader/disrupter or its delivery form.

The pharmaceutical composition typically includes a pharmaceutically acceptable carrier, adjuvant or vehicle (vehicle). As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally considered physiologically tolerable and do not generally produce an allergy or similar adverse reactions such as gastric upset and dizziness when administered to a human. A pharmaceutically acceptable carrier, adjuvant, or vehicle is a composition that can be administered to a patient with a compound of the invention and that does not destroy the pharmacological activity and is non-toxic when administered at a dose sufficient to deliver a therapeutic amount of the compound. Exemplary conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles include saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, and isotonic and absorption delaying agents and the like, which are compatible with pharmaceutical administration.

In particular, pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, Self Emulsifying Drug Delivery Systems (SEDDS) such as d- α -tocopheryl polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as tweens or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycols and lanolin. Cyclodextrins, such as alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin, can also be advantageously used to enhance the delivery of the compounds of the formulae described herein.

As used herein, PTK6 degraders/disrupters disclosed herein are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. By "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, solvate, or prodrug, e.g., carbamate, ester, phosphate, ester salt, or other derivative of a compound or agent disclosed herein, which, when administered to a recipient, is capable of providing (directly or indirectly) a compound described herein, or an active metabolite or residue thereof. Particularly advantageous derivatives and prodrugs are those that increase the bioavailability of the compounds disclosed herein when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent substance. Preferred prodrugs include derivatives wherein a group that enhances water solubility or active transport through the intestinal membrane is appended to the structures of the formulae described herein. Those skilled in the art will recognize such derivatives without undue experimentation. Nevertheless, reference is made to Burger's Medicinal Chemistry and Drug Discovery, 5 th edition, volume 1: the teachings of Principles and Practice, which are incorporated herein by reference to the extent such derivatives are taught.

The PTK6 degraders/disrupters disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms thereof, as well as pharmaceutically acceptable salts, solvent complexes, morphological forms or deuterated derivatives thereof.

In particular, pharmaceutically acceptable salts of PTK6 degradants/disruptors disclosed herein include, for example, those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate, triflate, and undecanoate. Salts derived from suitable bases include, for example, alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts, and N- (alkyl) 4+ salts. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the PTK6 degraders/breakers disclosed herein. Water-or oil-soluble or dispersible products can be obtained by such quaternization.

In some aspects, the pharmaceutical compositions disclosed herein may comprise an effective amount of one or more PTK6 degradants/disrupters. As used herein, the terms "effective amount" and "therapeutically effective" refer to the amount or concentration of one or more compounds or pharmaceutical compositions described herein that is effective, upon administration thereof, to elicit the desired effect or physiological result (e.g., treating or preventing cell growth, cell proliferation, or cancer), used over a period of time, including acute or chronic administration, as well as periodic or continuous administration. In some aspects, the pharmaceutical composition can further comprise one or more additional compounds, drugs, or agents useful for treating cancer (e.g., conventional chemotherapeutic agents) in an amount effective to elicit a desired effect or physiological result (e.g., treating or preventing cell growth, cell proliferation, or cancer).

In some aspects, the pharmaceutical compositions disclosed herein can be formulated for sale in the united states, import into the united states, or export from the united states.

Administration of pharmaceutical compositions

The pharmaceutical compositions disclosed herein can be formulated and adapted for administration to a subject via any route, for example, any route approved by the Food and Drug Administration (FDA). Exemplary methods are described in the FDA Data Standard Manual (DSM) (available at http:// www.fda.gov/Drugs/development approach/FormsSubmission Requirements/electronics submissions/DataStandarddsManualmonographs). In particular, the pharmaceutical composition may be formulated for administration via oral delivery, parenteral delivery, or transdermal delivery. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

For example, the pharmaceutical compositions disclosed herein can be administered, e.g., topically, rectally, nasally (e.g., by inhalation spray or nebulizer), bucally, vaginally, subdermally (e.g., by injection or via an implantable reservoir), or ocularly.

For example, the pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase and combined with emulsifying or suspending agents. Certain sweetening, flavoring, or coloring agents may be added, if desired.

For example, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

For example, the pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other solubilizing or dispersing agents known in the art.

For example, the pharmaceutical composition of the present invention may be administered by injection (e.g., as a solution or powder). Such compositions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents (such as, for example, tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be used are mannitol, water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, for example olive oil or castor oil, especially in the polyoxyethylated versions of which are natural pharmaceutically-acceptable oils. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and/or suspensions. Other commonly used surfactants such as tweens, Spans, and the like, or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

In some aspects, an effective dose of a pharmaceutical composition of the invention may include, but is not limited to, for example, about 0.00001, 0.0001, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 5000, 10000, or 10000mg/kg of the composition per day, or per day of the particular composition required or per day.

When the pharmaceutical compositions disclosed herein comprise a combination of a compound of the formulae described herein (e.g., PTK6 degrader/disrupter) and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents for treating cancer or any other condition or disease, including conditions or diseases known to be associated with or caused by cancer), both the compound and the additional compound should be present at dosage levels of between about 1% and 100%, and more preferably between about 5% and 95% of the dosage normally administered in a monotherapy regimen. The additional agent may be administered separately from the compound of the invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition.

In some aspects, the pharmaceutical compositions disclosed herein may be included in a container, package, or dispenser with instructions for administration.

Method of treatment

The methods disclosed herein contemplate administration of an effective amount of a compound or composition to achieve a desired or claimed effect. Typically, a compound or composition of the invention will be administered from about 1 to about 6 times per day, or alternatively or additionally, as a continuous infusion. Such administration can be used as a long-term therapy or an acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Typical formulations will contain from about 5% to about 95% active compound (w/w). Alternatively, such formulations may contain from about 20% to about 80% of the active compound.

In some aspects, the present disclosure provides methods of using compositions comprising PTK6 degradants/disrupters, including the pharmaceutical compositions disclosed herein (hereinafter denoted as 'X') in the following methods:

substance X for use as a medicament in the treatment of one or more diseases or conditions disclosed herein (e.g. cancer, referred to as 'Y' in the examples below). Use of substance X for the manufacture of a medicament for the treatment of Y; and substance X for the treatment of Y.

In some aspects, the disclosed methods comprise administering to a subject (e.g., a mammalian subject, e.g., a human subject) in need or determined to be in need of such treatment a therapeutically effective amount of one or more compounds or compositions described herein. In some aspects, the disclosed methods comprise selecting a subject and administering to the subject an effective amount of one or more compounds or compositions described herein, and optionally repeating the administration as needed to prevent or treat the cancer.

In some aspects, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample to indicate that the subject is eligible for the selection. In some aspects, the subject may be confirmed or identified, e.g., by a healthcare professional, as having or being affected by a condition or disease. In some aspects, suitable subjects include, for example, subjects that have or have had a condition or disease but have resolved the disease or an aspect thereof, exhibit reduced disease symptoms (e.g., relative to other subjects having the same condition or disease (e.g., a majority of subjects)), or survive for a long time in the presence of a condition or disease (e.g., relative to other subjects having the same condition or disease (e.g., a majority of subjects)), e.g., in an asymptomatic state (e.g., relative to other subjects having the same condition or disease (e.g., a majority of subjects)). In some aspects, a positive immune response to a condition or disease can be shown from patient records, family history, or detection of an indication of a positive immune response. In some aspects, multiple parties may be included in the subject selection. For example, a first party may obtain a sample from a candidate subject and a second party may test the sample. In some aspects, the subject may be selected or referred by a practitioner (e.g., a general practitioner). In some aspects, subject selection can include obtaining a sample from a selected subject and storing the sample or using it in the methods disclosed herein. The sample may comprise, for example, a cell or a population of cells.

In some aspects, a method of treatment can comprise single administration, multiple administrations, and repeated administrations of one or more compounds disclosed herein as needed to prevent or treat a disease or condition from which the subject suffers (e.g., a PTK 6-mediated disease). In some aspects, the method of treatment can include assessing the subject's disease level before, during, or after treatment. In some aspects, treatment can be continued until a decrease in the subject's disease level is detected.

As used herein, the term "subject" refers to any animal. In some cases, the subject is a mammal. In some cases, the term "subject" as used herein refers to a human (e.g., male, female, or child).

As used herein, the terms "administration," or "administration" refer to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of its form. For example, the methods disclosed herein comprise administering an effective amount of a compound or composition to achieve the desired or claimed effect.

As used herein, the terms "treat," "treating," or "treatment" refer to partially or completely alleviating, inhibiting, ameliorating, or alleviating a disease or condition from which a subject suffers. This means any manner in which one or more symptoms of a disease or disorder (e.g., cancer) are ameliorated or otherwise beneficially altered. As used herein, amelioration of a symptom of a particular disorder (e.g., cancer) refers to any alleviation, whether permanent or temporary, persistent or transient, that can be attributed to or associated with treatment with the compositions and methods of the present invention. In some embodiments, the treatment can promote or result in, for example, a reduction in the number of tumor cells (e.g., in the subject) relative to the number of tumor cells prior to the treatment, a reduction in the viability (e.g., average/mean) viability) of the tumor cells (e.g., in the subject) relative to the viability of the tumor cells prior to the treatment, a reduction in the growth rate of the tumor cells, a reduction in the rate of local or distal tumor metastasis, or a reduction in one or more symptoms associated with one or more tumors in the subject relative to the symptoms of the subject prior to the treatment.

As used herein, the term "treating cancer" means causing a partial or complete reduction in the growth rate of a tumor, and/or the size of a tumor, and/or the rate of local or distant tumor metastasis, and/or the overall tumor burden in a subject, and/or any reduction in tumor survival in the presence of a degradant/disruptant described herein (e.g., PTK6 degradant/disruptant).

As used herein, the terms "preventing", and "prevention" shall mean a reduction in the occurrence of a disease or a reduction in the risk of acquiring a disease or symptoms associated therewith in a subject. Prevention can be complete, e.g., complete absence of disease or diseased cells in the subject. Prevention may also be partial, such that the presence of disease or diseased cells in a subject is less than, occurs later than, or progresses more slowly than disease or diseased cells that would occur in the absence of the present invention. Exemplary PTK 6-mediated diseases that may be treated with PTK6 degradants/disruptors include, for example, breast, ovarian, prostate, colon, pancreatic, bladder, liver, and cervical cancer.

As used herein, the term "preventing a disease" (e.g., preventing cancer) in a subject means arresting the development of one or more symptoms of a disease in the subject, e.g., before the one or more symptoms of the disease appear or are perceived, e.g., by the patient or a doctor of the patient. Preferably, the disease (e.g., cancer) does not develop at all, i.e., symptoms of the disease are not detectable. However, it may also lead to a delay or delay in the development of one or more symptoms of the disease. Alternatively or additionally, it may result in a reduction in the severity of one or more subsequently developed symptoms.

The specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptom, the patient's disposition to the disease, condition or symptom, and the judgment of the treating physician.

An effective amount may be administered in one or more administrations, applications or doses. The therapeutically effective amount (i.e., effective dose) of the therapeutic compound depends on the therapeutic compound selected. Furthermore, treatment of a subject with a therapeutically effective amount of a compound or composition described herein can include a single treatment or a series of treatments. For example, an effective amount may be administered at least once. The composition may be administered from one or more times per day to one or more times per week, including once every other day. One skilled in the art will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health or age of the subject, and other diseases present.

After administration, the subject can be evaluated to detect, assess or determine their disease level. In some cases, treatment can be continued until a change (e.g., a decrease) in the subject's disease level is detected. In ameliorating a condition in a patient (e.g., a change (e.g., a decrease) in the level of a disease in a subject), a maintenance dose of a compound or composition disclosed herein can be administered, if desired. Subsequently, the dose or frequency of administration, or both, can be reduced, e.g., as a function of symptoms, to a level that maintains an improved condition. However, patients may require long-term intermittent treatment when any disease symptoms recur.

The disclosure is also described and illustrated by the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the invention or any exemplified terms. Likewise, the invention is not limited to any particular preferred embodiment or aspect described herein. Indeed, many modifications and variations will be apparent to those of skill in the art upon reading this specification, and such variations may be made without departing from the spirit or scope of the invention. Accordingly, the invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.

Examples

Synthesis process of intermediate of PTK6 PROTAC

Scheme 1 Synthesis of intermediate 1

Intermediate 1: tert-butyl 2- (4- (4-amino-3-fluorobenzoyl) piperazin-1-yl) acetate. To a mixture of 4-amino-3-fluorobenzoic acid (613mg, 3.9mmol) and tert-butyl 2- (piperazin-1-yl) acetate hydrochloride (908mg, 3.3mmol) in THF (20mL) was added DIEA (2.3mL, 13.2mmol) and EDCI (762mg, 4.0 mmol). The obtained solution is mixed inStirred at room temperature ("rt"). After stirring for 12 hours ("h"), the reaction was quenched with water. After concentration under reduced pressure, the resulting residue was purified by reverse phase chromatography to give the title compound as a brown oil (740mg, yield 56%).¹H NMR(600MHz,CDCl₃)δ7.13(dd,J＝11.4,1.5Hz,1H),7.07(d,J＝8.1Hz,1H),6.77(t,J＝8.5Hz,1H),3.95(s,2H),3.68(br,4H),2.62(br,4H),1.48(s,9H)。

Scheme 2 Synthesis of intermediate 4

Intermediate 4: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetic acid. To a solution of intermediate 1(298mg, 0.88mmol) and intermediate 2(Zeng et al, 2011) (170mg, 0.39mmol) in DMF (6mL) was added NaH (39mg, 0.98 mmol). The reaction solution was stirred at room temperature for 3h and then quenched with water. After concentration under reduced pressure, the resulting residue was purified by reverse phase chromatography to give intermediate 3(160mg, yield 59%) as a brown oil. Intermediate 3(160mg, 0.23mmol) was dissolved in DCM/TFA (2:1, 3 mL). The resulting solution was stirred at room temperature for 1h, then concentrated under reduced pressure to give the title compound (170mg, 0.23mmol) as a brown oil. ¹H NMR(600MHz,CD₃OD)δ8.45(q,J＝7.8Hz,1H),8.18(s,2H),8.06(s,1H),8.01(s,1H),7.43(dd,J＝11.1,1.5Hz,1H),7.38(dd,J＝8.5,1.3Hz,1H),4.21(s,2H),3.98(br,4H),3.55(br,4H),2.19–2.08(m,1H),1.06–0.91(m,4H)。

Scheme 3 Synthesis of intermediate 5

Intermediate 5: 4- (4-amino-3-fluorobenzoyl) piperazine-1-carboxylic acid tert-butyl ester. To a mixture of 4-amino-3-fluorobenzoic acid (182mg, 1.1mmol) and tert-butyl piperazine-1-carboxylate (228mg, 1.2mmol) in DCM (5mL) was added DIEA (0.26mL, 1.5mmol) andEDCI (236mg, 1.2 mmol). The resulting solution was stirred at room temperature for 12h and then quenched with water. After concentration under reduced pressure, the obtained residue was purified by reverse phase chromatography to give the title compound (306mg, yield 81%) as a white solid.¹H NMR(600MHz,CDCl₃)δ7.13(d,J＝11.3Hz,1H),7.06(d,J＝8.0Hz,1H),6.78(t,J＝8.4Hz,1H),3.99(s,2H),3.60(br,4H),3.47(br,4H),1.49(s,9H)。

Scheme 4 Synthesis of intermediate 7

Intermediate 7: (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorophenyl) (piperazin-1-yl) methanone. Intermediate 7 was synthesized as a brown oil according to the procedure used to prepare intermediate 4.¹H NMR(600MHz,CD₃OD)δ8.47(t,J＝8.1Hz,1H),8.17(s,2H),8.03(s,1H),8.01(s,1H),7.43(dd,J＝11.2,1.6Hz,1H),7.38(dd,J＝8.4,1.5Hz,1H),3.92(s,4H),3.45–3.26(m,4H),2.19–2.07(m,1H),1.09–0.92(m,4H)。

Scheme 5 Synthesis of intermediate 8

Intermediate 8: (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) carbamic acid tert-butyl ester. To a solution of intermediate 7(10mg, 0.018mmol) and tert-butyl (2-oxoethyl) carbamate (4.3mg, 0.027mmol) in DCM (1mL) was added sodium cyanoborohydride (5.9mg, 0.1 mmol). After stirring at room temperature for 12h, the solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound as a brown oil (5.5mg, 52%). ¹H NMR(600MHz,CD₃OD)δ8.76(t,J＝8.2Hz,1H),8.15(s,2H),7.98(s,1H),7.84(s,1H),7.47(dd,J＝11.2,1.7Hz,1H),7.41(dd,J＝9.3,7.9Hz,1H),3.86–3.39(m,12H),2.18–2.08(m,1H),1.49(s,9H),1.11–1.02(m,2H),1.02–0.91(m,2H)。

Scheme 6 Synthesis of intermediate 9

Intermediate 9: 7- (4-amino-3-fluorobenzoyl) -2, 7-diazaspiro [3.5 ]]Nonane-2-carboxylic acid tert-butyl ester. Intermediate 9 was synthesized as a white solid according to the procedure used to prepare intermediate 5.¹H NMR(500MHz,CD₃OD)δ7.09(dd,J＝11.7,1.7Hz,1H),7.03(dd,J＝8.2,1.6Hz,1H),6.85(t,J＝8.5Hz,1H),3.72(br,4H),3.58(br,4H),1.81(br,4H),1.46(s,9H)。

Scheme 7 Synthesis of intermediate 11

Intermediate 11: (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorophenyl) (2, 7-diazaspiro [3.5]Nonan-7-yl) methanone. Intermediate 11 was synthesized according to the procedure used to prepare intermediate 4.¹H NMR(600MHz,CD₃OD)δ8.47(t,J＝8.0Hz,1H),8.18(s,2H),8.03(s,1H),8.01(s,1H),7.36(d,J＝11.1Hz,1H),7.31(d,J＝8.3Hz,1H),3.96(br,4H),3.80–3.44(m,4H),2.20–2.09(m,1H),1.95(br,4H),1.06–0.94(m,4H)。

Scheme 8 Synthesis of intermediate 14

Intermediate 14: (S) -3-amino-3- (4- (4-methylthiazol-5-yl) phenyl) propionic acid benzyl ester. Intermediate 14 was synthesized in 2 steps (82% yield) according to known procedures (Han et al, 2019) from commercially available intermediate 12.

Scheme 9 Synthesis of intermediate 17

Intermediate 17: (S) -3- ((2S,4R) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamido) -3- (4- (4-methylthiazol-5-yl) phenyl) propionic acid. Intermediate 17 was synthesized according to known procedures (Han et al, 2019).¹H NMR(600MHz,CD₃OD)δ9.31(s,1H),7.52(d,J＝8.2Hz,1H),7.49–7.44(m,2H),5.42–5.27(m,1H),4.77–4.69(m,1H),4.62–4.37(m,2H),3.97–3.81(m,1H),3.78–3.72(m,1H),3.05–2.97(m,1H),2.94–2.83(m,1H),2.51(s,3H),2.30–2.14(m,1H),2.13–1.90(m,1H),1.41–1.22(m,3H),1.11(s,3H),1.05(s,6H)。

Intermediate 18 (S) -3- ((2S,4R) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamido) -3- (4- (4-methylthiazol-5-yl) phenyl) propionic acid. Intermediate 18 was synthesized according to the procedure used to prepare intermediate 17. δ 9.22-9.08 (m,1H), 7.62-7.39 (m,4H), 6.29-6.13 (m,1H), 5.47-5.31 (m,1H), 4.63-4.34 (m,2H), 3.93-3.84 (m,1H),3.76(dd, J ═ 29.5,10.4Hz,1H), 3.69-3.57 (m,1H), 3.08-2.83 (m,2H),2.53(s,3H), 2.47-2.36 (m,1H), 2.30-2.23 (m,3H), 2.23-2.13 (m,1H), 2.03-1.94 (m,1H), 1.11-1.02 (m,3H), 0.93-0.86 (m, 3H).

Scheme 10 Synthesis of intermediate 19

Intermediate 19: 4- (4-iodo-1H-imidazol-1-yl) butanoic acid tert-butyl ester. To a solution of 4-iodo-1H-imidazole (1.5g, 7.73mmol) in DMF (10mL) at 0 deg.C was added NaH (0.93g, 23.19 mmol). After stirring at 0 ℃ for 0.5h, tert-butyl 4-bromobutyrate (3.45g, 15.46mmol) was added. The mixture was warmed to room temperature and stirred for 16h, then water (100mL) was poured into the reaction mixture at 0 ℃ and extracted with EtOAc (3X 100mL). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated. The resulting residue was purified by reverse phase column to give the title compound as a yellow oil (1.3g, yield 50%).¹H NMR(600MHz,CD₃OD)δ8.12(d,J＝1.4Hz,1H),7.46(d,J＝1.4Hz,1H),4.14(t,J＝7.1Hz,2H),2.26(t,J＝7.2Hz,2H),2.06(p,J＝7.1Hz,2H),1.44(s,9H)。

Scheme 11 Synthesis of intermediate 22

Intermediate 22: 4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butanoic acid. To intermediate 20(1.0g, 2.06mmol) in DMF (5mL) and H₂To a solution of O (1mL) were added intermediate 19(0.76g, 2.27mmol), K₂CO₃(1.14g, 8.24mmol) and Pd (dppf) Cl₂(151mg, 0.21 mmol). The reaction mixture was purged with nitrogen for 5min and then irradiated at 100 ℃ for 1h with the aid of microwaves. The solvent was evaporated and purified by reverse phase column to afford intermediate 21(0.7g, 52%) as a yellow solid. ¹H NMR(800MHz,CD₃OD) δ 9.03(s,1H),8.66(dd, J ═ 6.5,2.6Hz,1H),8.57(dd, J ═ 8.5,2.6Hz,1H),8.07(d, J ═ 3.2Hz,1H),7.37(d, J ═ 8.0Hz,2H), 7.29-7.19 (m,2H), 5.70-5.61 (m,1H),4.32(t, J ═ 7.3Hz,2H), 4.14-4.00 (m,1H), 3.95-3.85 (m,3H), 3.83-3.77 (m,2H), 3.63-3.58 (m,1H),2.39(t, J ═ 7.1Hz,2H),2.21(p, J ═ 7.1, 1H), 1.76(m,1H), 9.44 (s, 1H). To a solution of intermediate 21(0.7g, 1.08mmol) in DCM (2mL) was added TFA (2 mL). After stirring at room temperature for 2h, the solvent was evaporated to give the title compound as a yellow solid (0.7g, 92% yield) which was used in the next step without further purification.

Intermediate 23: 5- (1- (4-aminobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. Intermediate 23 was synthesized following the procedure used to prepare intermediate 22.

Process for the synthesis of linking groups

Scheme 12 Synthesis of linker 1

Intermediate 10: (2S,4R) -1- ((S) -2- (8-Bromomocatanoyl) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. To a mixture of 8-bromooctanoic acid (24mg, 0.11mmol) and VHL-1(48mg, 0.11mmol) in THF (1mL) was added DIEA (0.05mL, 0.29mmol) and EDCI (23.5mg, 0.12 mmol). After stirring at room temperature for 12h, the reaction was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the title compound as a brown oil (32mg, 50% yield). ¹H NMR(600MHz,CD3OD)δ9.01(s,1H),7.49(d,J＝6.8Hz,2H),7.45(d,J＝8.1Hz,2H),4.66(s,1H),4.63–4.48(m,3H),4.38(dd,J＝15.3,6.8Hz,1H),3.93(d,J＝11.1Hz,1H),3.83(dd,J＝10.9,3.9Hz,1H),3.60–3.54(m,2H),2.51(s,3H),2.38–2.16(m,3H),2.17–2.04(m,1H),1.80–1.73(m,2H),1.64(dt,J＝13.5,7.1Hz,2H),1.51–1.43(m,2H),1.42–1.33(m,4H),1.06(s,9H)。

Linking group 1: 4- (8- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctyl) piperazine-1-carboxylic acid tert-butyl ester. To a solution of intermediate 10(28mg, 0.043mmol) and tert-butyl piperazine-1-carboxylate (17mg, 0.092mmol) in DMF (1mL) was added K₂CO₃(14mg, 0.1 mmol). After heating at 60 ℃ for 4h, the reaction mixture was cooled to room temperature. The insoluble material was filtered off. And the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the title compound as a brown oil (30mg, yield 44%).¹H NMR(600MHz,CD₃OD)δ9.20(s,1H),7.51(d,J＝8.1Hz,2H),7.46(d,J＝8.1Hz,2H),4.66(s,1H),4.61–4.49(m,3H),4.40(d,J＝15.6Hz,1H),4.23(d,J＝13.1Hz,2H),3.93(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.8Hz,1H),3.60–3.51(m,2H),3.28–3.10(m,4H),3.02(t,J＝11.1Hz,2H),2.53(s,3H),2.37–2.21(m,3H),2.14–2.06(m,1H),1.82–1.71(m,2H),1.68–1.57(m,2H),1.49(s,9H),1.45–1.33(m,6H),1.06(s,9H)。

Linker 2, linker 3, linker 4, and linker 5 were synthesized according to the procedure used to prepare linker 1.

Linking group 2: 4- (9- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -9-oxononyl) piperazine-1-carboxylic acid tert-butyl ester. White solid, yield 67%.¹H NMR(600MHz,CD₃OD)δ9.15(s,1H),7.51(d,J＝7.9Hz,2H),7.46(d,J＝8.0Hz,2H),4.66(s,1H),4.63–4.49(m,3H),4.40(d,J＝15.5Hz,1H),4.23(d,J＝12.9Hz,2H),3.93(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.6Hz,1H),3.63–3.51(m,2H),3.29–3.08(m,4H),3.02(t,J＝10.5Hz,2H),2.53(s,3H),2.37–2.21(m,3H),2.17–2.04(m,1H),1.82–1.72(m,2H),1.70–1.56(m,2H),1.49(s,9H),1.46–1.31(m,8H),1.05(s,9H)。

Linking group 3: 4- (10- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -10-oxodecyl) piperazine-1-carboxylic acid tert-butyl ester. White solid, yield 60%. ¹H NMR(600MHz,CD₃OD)δ9.14(s,1H),7.51(d,J＝8.1Hz,2H),7.45(d,J＝7.6Hz,2H),4.66(s,1H),4.63–4.50(m,3H),4.39(d,J＝15.5Hz,1H),4.23(d,J＝13.1Hz,2H),3.93(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.9Hz,1H),3.68–3.48(m,2H),3.28–3.10(m,4H),3.02(t,J＝10.6Hz,2H),2.53(s,3H),2.41–2.18(m,3H),2.17–2.04(m,1H),1.82–1.70(m,2H),1.70–1.58(m,2H),1.49(s,9H),1.44–1.28(m,10H),1.06(s,9H)。

Linking group 4: 4- (11- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -11-oxoundecyl) piperazine-1-carboxylic acid tert-butyl ester. White solid, yield 62%.¹H NMR(600MHz,CD₃OD)δ9.17(s,1H),7.51(d,J＝7.5Hz,2H),7.46(d,J＝7.8Hz,2H),4.66(s,1H),4.63–4.49(m,3H),4.39(d,J＝15.4Hz,1H),4.23(d,J＝12.6Hz,2H),3.93(d,J＝10.8Hz,1H),3.87–3.78(m,1H),3.72–3.45(m,2H),3.28–3.11(m,4H),3.06–2.97(m,2H),2.53(s,3H),2.36–2.19(m,3H),2.15–2.04(m,1H),1.85–1.71(m,2H),1.72–1.56(m,2H),1.49(s,9H),1.45–1.26(m,12H),1.04(s,9H)。

Linking group 5: 4- (12- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -12-oxododecyl) piperazine-1-carboxylic acid tert-butyl ester. White solid, yield 56%.¹H NMR(600MHz,CD₃OD)δ9.16(s,1H),7.51(t,J＝6.6Hz,2H),7.46(d,J＝8.1Hz,2H),4.66(s,1H),4.62–4.49(m,3H),4.38(d,J＝9.7Hz,1H),4.23(d,J＝13.2Hz,2H),3.93(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.7Hz,1H),3.71–3.46(m,2H),3.28–3.08(m,4H),3.09–2.90(m,2H),2.53(s,3H),2.39–2.18(m,3H),2.15–2.02(m,1H),1.76(s,2H),1.71–1.55(m,2H),1.49(s,9H),1.44–1.27(m,14H),1.04(s,9H)。

Scheme 13 Synthesis of linker 6

Intermediate 26: (3R,5S) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -5- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-3-yl acetate. To a solution of Boc protected VHL-1(600mg, 1.1mmol) in DCM (6mL) was added Ac₂O (0.2mL, 2.1mmol) and TEA (0.32mL, 2.3 mmol). The solution was stirred at room temperature for 3 days, then quenched with water and extracted with DCM (3 × 5 mL). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated. The resulting residue was purified by reverse phase column to give intermediate 25(340mg, yield 54%) as a white oil. Intermediate 25 was dissolved in DCM and TFA (7:2, 9mL) in an ice-water bath. The resulting solution was stirred at 0 ℃ for 30min, then concentrated to give the title compound as an oil (556mg, 99% yield).

Linking group 6: (3R,5S) -1- ((S) -2- (7-aminoheptanoylamino) -3, 3-dimethylbutyryl) -5- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-3-yl acetate. To a solution of intermediate 26(29mg, 0.05mmol) in DMSO (0.5mL) was added Boc protected amino acid (12mg, 0.05mmol), TBTU (17mg, 0.05mmol) and DIEA (0.1mL, 0.57 mmol). The solution was stirred at room temperature for 1 h. After quenching with MeOH, the reaction was diluted with DCM (2mL) and TFA (0.5 mL). The resulting solution was stirred at 0 ℃ for 30min and then concentrated. The resulting residue was purified by preparative HPLC to give the title compound (17mg, 49% yield).¹H NMR(600MHz,CD₃OD)δ9.21(s,1H),7.53–7.45(m,4H),5.44–5.36(m,1H),4.62–4.50(m,3H),4.40(d,J＝15.5Hz,1H),4.19(d,J＝11.8Hz,1H),3.94(dd,J＝11.7,4.0Hz,1H),2.93(t,J＝7.6Hz,2H),2.53(s,3H),2.42(dd,J＝13.9,7.6Hz,1H),2.38–2.23(m,3H),2.07(s,3H),1.73–1.60(m,4H),1.50–1.36(m,4H),1.06(s,10H)。

Linking group 7: (3R,5S) -1- ((S) -2- (7-aminoheptanoylamino) -3, 3-dimethylbutyryl) -5- ((4- (4-methylthiazol-5-yl) benzyl)) Carbamoyl) pyrrolidin-3-yl isobutyrate. Linker 7 was synthesized according to the procedure used to prepare linker 6 in 57% yield.¹H NMR(600MHz,CD₃OD)δ9.31(s,1H),7.50(dd,J＝26.4,8.1Hz,4H),5.42–5.35(m,1H),4.61–4.54(m,3H),4.41(d,J＝15.6Hz,1H),4.16(d,J＝11.8Hz,1H),3.95(dd,J＝11.7,3.9Hz,1H),2.93(t,J＝7.6Hz,2H),2.58–2.53(m,4H),2.44–2.38(m,1H),2.37–2.23(m,3H),1.73–1.60(m,4H),1.47–1.34(m,4H),1.16(d,J＝7.0Hz,6H),1.06(s,9H)。

Scheme 14 Synthesis of linker 8

Linking group 8: (2S,4R) -1- ((S) -2- (4- (4-aminopiperidin-1-yl) -4-oxobutanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. Linker 8 was synthesized according to the procedure used to prepare linker 6 in 86% yield. ¹H NMR(500MHz,CD₃OD)δ9.14(s,1H),7.51(d,J＝8.3Hz,2H),7.49–7.42(m,2H),4.65–4.50(m,4H),4.39(d,J＝15.5Hz,1H),3.98–3.86(m,2H),3.81(dd,J＝11.0,3.9Hz,1H),3.47–3.37(m,2H),3.11(td,J＝12.9,3.0Hz,2H),2.64(dd,J＝14.9,7.5Hz,1H),2.58–2.45(m,6H),2.29–2.20(m,1H),2.10(ddd,J＝13.2,9.0,4.4Hz,3H),1.78–1.65(m,2H),1.05(s,9H)。

Linking group 9: (2S,4R) -1- ((S) -2- (4- (4-aminopiperidin-1-yl) -4-oxobutanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. Linker 9 was synthesized according to the procedure used to prepare linker 6 in 73% yield. δ 9.28(s,1H),7.51(dd, J ═ 10.2,5.7Hz,2H),7.46(d, J ═ 8.2Hz,2H), 4.68-4.49 (m,5H),4.41(dd, J ═ 15.6,2.1Hz,1H),4.10(d, J ═ 13.8Hz,1H),3.91(d, J ═ 11.0Hz,1H),3.81(dd, J ═ 11.0,3.8Hz,1H),3.39(t, J ═ 11.5Hz,1H),3.18(t, J ═ 13.3Hz,1H), 2.79-2.60 (m,4H), 2.60-2.49 (m,4H),2.26(dd, J ═ 13.13, 1H), 2.17.7, 1H), 1H (dd, 1H), 1H), 2.9.7.9.7.5 Hz, 1H.

Scheme 15 Synthesis of linker group 10

Intermediate 28: (2S,4R) -1- ((S) -2- (5-azidopentanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. Intermediate 28 was synthesized according to the procedure used to prepare linker 6 in 79% yield.¹H NMR(500MHz,CD₃OD)δ8.88(s,1H),7.50–7.38(m,4H),4.66(s,1H),4.62(t,J＝8.3Hz,1H),4.59–4.50(m,2H),4.38(d,J＝15.5Hz,1H),3.93(d,J＝11.1Hz,1H),3.82(dd,J＝10.9,3.9Hz,1H),3.31(t,J＝6.7Hz,2H),2.49(s,3H),2.41–2.20(m,4H),2.14–2.07(m,1H),1.77–1.56(m,4H),1.06(s,9H)。

Linking group 10: (2S,4R) -1- ((S) -2- (5- (1- (aminomethyl) -1H-1,2,3l 4-triazol-3-yl) pentanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. Intermediate 28(35mg, 0.06mmol) was dissolved in t-BuOH and water (5:1, 0.5mL), then allylamine (3.4mg, 0.06mmol), CuSO, were added ₄(20mg, 0.08mmol) and Vc (1mg, 0.004 mmol). The mixture was stirred at room temperature. After 24h, the solvent was concentrated and the resulting residue was purified by preparative HPLC to give the title compound (15mg, 33% yield).¹H NMR(500MHz,CD₃OD)δ9.13(s,1H),8.06(s,1H),7.48(dd,J＝24.2,8.2Hz,4H),4.64(s,1H),4.60–4.51(m,3H),4.47(t,J＝6.9Hz,2H),4.40(d,J＝15.5Hz,1H),4.26(s,2H),3.92(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.9Hz,1H),2.52(s,3H),2.40–2.30(m,2H),2.28–2.21(m,1H),2.16–2.07(m,1H),1.98–1.90(m,2H),1.66–1.56(m,2H),1.05(s,9H)。

Scheme 16 Synthesis of linker 11

Linking group 11: linker 11 was synthesized according to the procedure used to prepare linker 6 in 95% yield.¹H NMR(500MHz,CD₃OD)δ9.28(s,1H),7.51(d,J＝8.1Hz,2H),7.44(d,J＝8.1Hz,2H),4.70–4.50(m,4H),4.39(d,J＝15.6Hz,1H),3.92(d,J＝10.1Hz,1H),3.82(dd,J＝10.9,3.6Hz,1H),3.74–3.53(m,5H),3.14(t,J＝12.2Hz,4H),2.79–2.65(m,1H),2.52(s,3H),2.40(d,J＝12.7Hz,2H),2.31–2.22(m,1H),2.20–1.93(m,8H),1.06(s,9H)。

Scheme 17 Synthesis of linker group 12

Linking group 12: n- (2-aminoethyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. Linker 12 was synthesized according to the procedure used to prepare linker 6 in 80% yield.¹H NMR(500MHz,CD₃OD)δ9.28(s,1H),7.51(d,J＝8.1Hz,2H),7.44(d,J＝8.1Hz,2H),4.70–4.50(m,4H),4.39(d,J＝15.6Hz,1H),3.92(d,J＝10.1Hz,1H),3.82(dd,J＝10.9,3.6Hz,1H),3.74–3.53(m,5H),3.14(t,J＝12.2Hz,4H),2.79–2.65(m,1H),2.52(s,3H),2.40(d,J＝12.7Hz,2H),2.31–2.22(m,1H),2.20–1.93(m,8H),1.06(s,9H)。

The linker groups 13-23 were synthesized according to the procedure used to prepare linker group 12.

Linking group 13: n- (3-aminopropyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 82%.¹H NMR(500MHz,CD₃OD)δ8.60(t,J＝8.2Hz,1H),8.14(s,2H),7.95(s,1H),7.90(s,1H),7.43(dd,J＝11.2,1.6Hz,1H),7.39(d,J＝8.5Hz,1H),4.12–3.85(m,6H),3.49(br,4H),3.40(t,J＝6.7Hz,2H),3.01(t,J＝7.4Hz,2H),2.21–2.04(m,1H),1.97–1.84(m,2H),1.07–0.92(m,4H)。

Linking group 14: n- (4-aminobutyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 86%.¹H NMR(500MHz,CD₃OD)δ8.73(t,J＝8.1Hz,1H),8.14(s,2H),7.90(s,1H),7.77(s,1H),7.42(d,J＝11.3Hz,1H),7.38(d,J＝8.4Hz,1H),3.96(br,6H),3.41(br,4H),2.97(t,J＝7.3Hz,2H),2.14–2.03(m,1H),1.79–1.58(m,4H),1.07–1.00(m,2H),1.00–0.89(m,2H)。

Linking group 15: n- (5-Aminopentyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 80%.¹H NMR(500MHz,CD₃OD)δ8.66(t,J＝8.2Hz,1H),8.14(s,2H),7.94(s,1H),7.85(s,1H),7.44(dd,J＝11.3,1.8Hz,1H),7.39(d,J＝8.4Hz,1H),4.21–3.77(m,6H),3.48(br,4H),3.30(t,J＝7.1Hz,2H),2.95(t,J＝7.6Hz,2H),2.15–2.04(m,1H),1.79–1.66(m,2H),1.66–1.55(m,2H),1.51–1.41(m,2H),1.09–0.92(m,4H)。

Linking group 16: n- (6-aminohexyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 79%.¹H NMR(500MHz,CD₃OD)δ8.73(t,J＝8.2Hz,1H),8.12(s,2H),7.90(s,1H),7.76(s,1H),7.46–7.40(m,1H),7.38(d,J＝8.5Hz,1H),4.13–3.86(m,6H),3.43(br,4H),3.29(t,J＝7.1Hz,2H),2.94(t,J＝7.5Hz,2H),2.14–2.04(m,1H),1.74–1.64(m,2H),1.64–1.54(m,2H),1.49–1.39(m,4H),1.07–1.00(m,2H),1.00–0.92(m,2H)。

Linking group 17: n- (7-aminoheptyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 83%.¹H NMR(500MHz,CD₃OD)δ8.74(t,J＝8.2Hz,1H),8.12(s,2H),7.91(s,1H),7.76(s,1H),7.43(dd,J＝11.3,1.7Hz,1H),7.38(d,J＝8.5Hz,1H),4.05–3.86(m,6H),3.43(br,4H),3.28(t,J＝7.2Hz,2H),3.00–2.86(m,2H),2.21–2.00(m,1H),1.73–1.63(m,2H),1.63–1.53(m,2H),1.47–1.33(m,6H),1.07–0.99(m,2H),0.99–0.91(m,2H)。

Linking group 18: n- (7-aminoheptyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 83%.¹H NMR(500MHz,CD₃OD)δ8.74(t,J＝8.2Hz,1H),8.12(s,2H),7.91(s,1H),7.76(s,1H),7.43(dd,J＝11.3,1.7Hz,1H),7.38(d,J＝8.5Hz,1H),4.05–3.86(m,6H),3.43(br,4H),3.28(t,J＝7.2Hz,2H),3.00–2.86(m,2H),2.21–2.00(m,1H),1.73–1.63(m,2H),1.63–1.53(m,2H),1.47–1.33(m,6H),1.07–0.99(m,2H),0.99–0.91(m,2H)。

Linking group 19: n- (2- (2-aminoethoxy) ethyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 82%.¹H NMR(500MHz,CD₃OD)δ8.65(t,J＝8.2Hz,1H),8.16(s,2H),7.98(s,1H),7.92(s,1H),7.46(dd,J＝11.3,1.6Hz,1H),7.41(d,J＝8.5Hz,1H),4.13–3.89(m,6H),3.76–3.68(m,2H),3.63(t,J＝5.4Hz,2H),3.56–3.44(m,6H),3.18–3.12(m,2H),2.18–2.09(m,1H),1.09–1.02(m,2H),1.01–0.96(m,2H)。

Linking group 20: n- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 85%.¹H NMR(500MHz,CD₃OD)δ8.75(t,J＝8.2Hz,1H),8.12(s,2H),7.91(s,1H),7.76(s,1H),7.43(dd,J＝11.3,1.7Hz,1H),7.39(d,J＝8.5Hz,1H),4.04–3.86(m,6H),3.77–3.71(m,2H),3.69(s,4H),3.62(t,J＝5.6Hz,2H),3.49(t,J＝5.5Hz,2H),3.40(br,4H),3.20–3.11(m,2H),2.16–2.04(m,1H),1.06–1.01(m,2H),1.00–0.91(m,2H)。

Linking group 21: n- (2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 84%.¹H NMR(500MHz,CD₃OD)δ8.66(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.93(s,1H),7.46(d,J＝12.7Hz,1H),7.42(d,J＝8.4Hz,1H),4.09–3.95(m,6H),3.78–3.64(m,12H),3.64–3.58(m,2H),3.52–3.45(m,4H),3.19–3.12(m,2H),2.15(t,J＝6.3Hz,1H),1.13–0.93(m,4H)。

Linking group 22: n- (14-amino-3, 6,9, 12-tetraoxatetradecyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl radical) Amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 81%.¹H NMR(500MHz,CD₃OD)δ8.66(t,J＝8.2Hz,1H),8.15(s,2H),7.97(s,1H),7.89(s,1H),7.45(dd,J＝11.3,1.7Hz,1H),7.41(d,J＝8.4Hz,1H),4.14–3.88(m,6H),3.78–3.72(m,2H),3.72–3.64(m,12H),3.61(t,J＝5.4Hz,2H),3.53–3.42(m,6H),3.20–3.12(m,2H),2.17–2.08(m,1H),1.08–1.01(m,2H),1.01–0.93(m,2H)。

Linking group 23: n- (17-amino-3, 6,9,12, 15-pentaoxaheptadecyl) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamide. The yield was 78%.¹H NMR(500MHz,CD3OD)δ8.66(t,J＝8.2Hz,1H),8.15(s,2H),7.97(s,1H),7.89(s,1H),7.45(dd,J＝11.2,1.7Hz,1H),7.41(d,J＝8.5Hz,1H),4.12–3.94(m,6H),3.77–3.73(m,2H),3.73–3.65(m,16H),3.62–3.60(m,2H),3.52–3.44(m,6H),3.18–3.10(m,2H),2.19–2.07(m,1H),1.08–0.92(m,4H)。

Linking group 24: 10- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -10-oxodecanoic acid. The linker 24 was synthesized in the reported manner (Galdeano et al, 2014; Maniaci et al, 2017).

Linking group 25: 7- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -7-oxoheptanoic acid. The linker 25 was synthesized in the reported manner (Galdeano et al, 2014; Maniaci et al, 2017).

Linking group 26: 8- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctanoic acid. The linker 24 was synthesized in the reported manner (Galdeano et al, 2014; Maniaci et al, 2017).

Linking group 27: (2S,4R) -1- ((S) -2- (2- (2-aminoethoxy) acetylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The linker 26 was synthesized in the reported manner (Galdeano et al, 2014; Maniaci et al, 2017).

Linking group 28: 12- (((S) -1- ((2S,4R) -4-acetoxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -12-oxododecanoic acid. The linker 28 is synthesized in the same procedure as the linker 6.

Scheme 18 Synthesis of linker 29

Linking group 29: 2- (3- (2- ((R) -1- ((S) -2- (((benzyloxy) carbonyl) (methyl) amino) propionylamino) -2-cyclohexylacetyl) pyrrolidin-2-yl) thiazole-4-carbonyl) phenoxy) acetic acid. The title compound can be synthesized according to the following procedure: to a solution of intermediate 30(1 eq) in DMF was added K₂CO₃(1.5 equiv.) then tert-butyl 2-bromoacetate (1.5 equiv.) is added. After stirring at room temperature for 12h, the mixture was filtered. The filtrate was collected and concentrated. The resulting residue was purified by HPLC. The purified compound was dissolved in DCM and TFA (1: 1). After stirring at room temperature for 1h, the solvent was removed to give the title compound.

Scheme 19 Synthesis of linker 30

Linking group 30: 4- (4- (((S) -2- ((3R,5R,6S) -3- (2- (tert-butoxy) -2-oxoethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-1-yl) -3, 3-dimethylbutyl) sulfonyl) piperazin-1-yl) -4-oxobutanoic acid. The title compound can be synthesized according to the following procedure: to a solution of intermediate 31(1 eq) in DMSO was added succinic acid (5 eq), followed by TBTU (1.1 eq) and DIEA (1.5 eq). After stirring at room temperature for 1h, the mixture was concentrated. The resulting residue was purified by HPLC to give the title compound.

Scheme 20 Synthesis of linker group 31

Linking group 31: (3- (N- (6- (3-butoxyphenoxy) -1, 3-dimethyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) sulfamoyl) benzoyl) glycine. The title compound can be synthesized according to the following procedure: to a solution of intermediate 32(1 eq) in DMSO was added glycine (1.1 eq), followed by TBTU (1.1 eq) and DIEA (1.5 eq). After stirring at room temperature for 1h, the mixture was concentrated. The resulting residue was purified by HPLC to give the title compound.

Scheme 21 Synthesis of linker 32

Linking group 32: tert-butyl ((S) -1- (((S) -2- ((R) -2- (4- (3- (2-aminoethoxy) benzoyl) thiazol-2-yl) pyrrolidin-1-yl) -1-cyclohexyl-2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate. The title compound can be synthesized according to the following procedure: to a mixture of intermediate 33(1.2 equiv.) and intermediate 34(1 equiv.) in DMF was added K ₂CO₃(1.5 equiv.). After heating at 60 ℃ for 12h, the mixture was filtered. The filtrate was collected and concentrated. The resulting residue was purified by HPLC. The purified compound was dissolved in MeOH, then Pd/C (0.1 equiv) was added. At H₂After stirring at room temperature for 2h under an atmosphere, the mixture was filtered. The filtrate was collected and concentrated to give the title compound.

Scheme 22 Synthesis of linker 33

Linking group 33: tert-butyl 2- ((3R,5R,6S) -1- ((4- (3-aminopropionyl) piperazin-1-yl) sulfonyl) -3, 3-dimethylbutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetate. The title compound can be synthesized according to the following procedure: to a mixture of intermediate 35(1 eq) and intermediate 36(1.1 eq) in DMSO was added TBTU (1.1 eq) and DIEA (1.5 eq). After stirring at room temperature for 1h, the solution was concentrated. The resulting residue was diluted with HCl in dioxane (4N). The resulting mixture was stirred at room temperature for 2h, then concentrated. The resulting residue was purified by HPLC to give the title compound.

Scheme 23 Synthesis of linker 34

Linking group 34: n- (2-aminoethyl) -3- (N- (6- (3-butoxyphenoxy) -1, 3-dimethyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) sulfamoyl) benzamide. The linker 34 will be synthesized according to the procedure used to synthesize the linker 33.

Linking group 35: (2S,4R) -N- (2- (2-aminoethoxy) -4- (4-methylthiazol-5-yl) benzyl) -1- ((1-fluorocyclopropane-1-carbonyl) -L-valyl) -4-hydroxypyrrolidine-2-carboxamide. The linking group 35 will be synthesized using known methods (Farnaby et al, 2019).

Procedure for the syntheses of the examples

Scheme 24 Synthesis of example 1

Example 1: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) acetamide. To a solution of intermediate 4(7mg, 0.011mmol) and linking group 6(5mg, 0.012mmol) in DMF (0.5mL) was added DIEA (17. mu.L, 0.1mmol) and TBTU (6mg, 0.02 mmol). After stirring at room temperature for 12h, the mixture was purified by HPLC to give the title compound as a brown oil (6mg, 50% yield).¹H NMR(600MHz,CD₃OD)δ8.82(t,J＝8.2Hz,1H),8.13(s,2H),7.93(s,1H),7.75(s,1H),7.64–7.55(m,1H),7.40(dd,J＝26.8,9.8Hz,2H),7.17(d,J＝8.6Hz,1H),7.09(d,J＝7.0Hz,1H),5.04(dd,J＝12.8,5.3Hz,1H),4.14–3.71(m,6H),3.66–3.46(m,4H),3.27–3.12(m,2H),2.84(dd,J＝25.0,11.5Hz,1H),2.81–2.63(m,2H),2.18–2.01(m,2H),1.11–1.02(m,2H),1.01–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₀H₄₀FN₁₂O₆ ⁺Of [ M + H]⁺Calculated values: 803.3172, respectively; the following are found: 803.3190.

example compounds 2-22, 37-45, 63, 64, 102-134 and 130-134 were synthesized according to the procedure used to prepare example compound 1.

Example 2: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) acetamide. The yield was 55%.¹H NMR(600MHz,CD₃OD)δ8.77(t,J＝8.1Hz,1H),8.11(s,2H),7.92(s,1H),7.80(s,1H),7.56(t,J＝7.7Hz,1H),7.40(dd,J＝27.8,9.8Hz,2H),7.06(t,J＝8.7Hz,2H),5.08(dd,J＝12.7,5.2Hz,1H),3.96(br,6H),3.53–3.36(m,6H),2.91–2.53(m,3H),2.22–2.00(m,2H),2.00–1.82(m,2H),1.12–1.01(m,2H),1.00–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₄₁H₄₂FN₁₂O₆ ⁺Of [ M + H]⁺Calculated values: 817.3329, respectively; the following are found: 817.3310.

example 3: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyl) acetamide. The yield was 48%.¹H NMR(600MHz,CD₃OD)δ8.80(t,J＝8.2Hz,1H),8.14(s,2H),7.94(s,1H),7.78(s,1H),7.57(dd,J＝13.9,6.5Hz,1H),7.44(d,J＝11.1Hz,1H),7.40(d,J＝8.5Hz,1H),7.11–7.02(m,2H),5.07(dd,J＝12.8,5.4Hz,1H),3.95(br,6H),3.45–3.34(m,6H),2.92–2.82(m,2H),2.80–2.66(m,2H),2.17–2.05(m,3H),1.78–1.61(m,4H),1.08–1.02(m,2H),0.99–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₂H₄₄FN₁₂O₆ ⁺Of [ M + H]⁺Calculated values: 831.3485, respectively; the following are found: 831.3502.

example 4: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentyl) acetamide. The yield was 60%.¹H NMR(600MHz,CD₃OD)δ8.82(t,J＝8.2Hz,1H),8.13(s,2H),7.93(s,1H),7.74(s,1H),7.59–7.53(m,1H),7.44(d,J＝12.5Hz,1H),7.40(d,J＝8.5Hz,1H),7.10–7.03(m,2H),5.09(dd,J＝12.6,5.5Hz,2H),3.80(br,6H),3.43–3.35(m,4H),2.94–2.81(m,2H),2.81–2.65(m,3H),2.18–2.04(m,2H),1.79–1.67(m,2H),1.68–1.56(m,2H),1.56–1.43(m,2H),1.05(dd,J＝7.4,3.0Hz,2H),0.97–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₃H₄₆FN₁₂O₆ ⁺Of [ M + H]⁺Calculated values: 845.3642, respectively; the following are found: 845.3620.

example 5: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexyl) acetamide. The yield was 50%.¹H NMR(600MHz,CD₃ODδ8.76(t,J＝8.1Hz,1H),8.08(s,2H),7.89(s,1H),7.80(s,1H),7.56–7.51(m,1H),7.44–7.33(m,2H),7.08–6.96(m,2H),5.04(dd,J＝12.5,4.9Hz,2H),4.09–3.77(m,6H),3.41(br,4H),3.30–3.22(m,2H),2.93–2.70(m,5H),2.16–2.05(m,2H),1.76–1.67(m,2H),1.63–1.54(m,2H),1.53–1.38(m,4H),1.08–1.00(m,2H),1.00–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₄H₄₈FN₁₂O₆ ⁺Of [ M + H ]⁺Calculated values: 859.3798, respectively; the following are found: 859.3810.

example 6: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptyl) acetamide. The yield was 49%.¹H NMR(600MHz,CD₃OD)δ8.81(t,J＝8.2Hz,1H),8.09(s,2H),7.88(s,1H),7.72(s,1H),7.56–7.50(m,1H),7.44–7.34(m,2H),7.08–6.96(m,2H),5.10–4.96(m,1H),4.13–3.68(m,6H),3.41(br,4H),3.30–3.22(m,2H),2.92–2.81(m,2H),2.81–2.67(m,3H),2.17–2.04(m,2H),1.75–1.64(m,2H),1.61–1.50(m,2H),1.50–1.34(m,6H),1.07–0.99(m,2H),0.99–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₅H₅₀FN₁₂O₆ ⁺Of [ M + H]⁺Calculated values: 873.3955, respectively; the following are found: 873.3543.

example 7: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octyl) acetamide. The yield was 51%.¹H NMR(600MHz,CD₃OD)δ8.79(t,J＝8.2Hz,1H),8.14(s,2H),7.93(s,1H),7.78(s,1H),7.55–7.48(m,1H),7.48–7.33(m,2H),7.09–6.97(m,2H),5.13–5.01(m,1H),4.07–3.77(m,6H),3.42(br,4H),3.30–3.18(m,2H),2.94–2.82(m,2H),2.82–2.64(m,3H),2.17–2.03(m,2H),1.74–1.61(m,2H),1.62–1.50(m,2H),1.50–1.27(m,8H),1.09–1.00(m,2H),0.97–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₆H₅₂FN₁₂O₆ ⁺Of [ M + H]⁺Calculated values: 887.4111, respectively; the following are found: 887.4119.

example 8: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) acetamide. The yield was 65%.¹H NMR(600MHz,CD₃OD)δ8.80(t,J＝8.3Hz,1H),8.10(s,2H),7.90(s,1H),7.74(s,1H),7.55(d,J＝7.4Hz,1H),7.37(dd,J＝23.0,9.9Hz,2H),7.11–7.00(m,2H),5.09(dd,J＝12.8,5.5Hz,1H),4.03–3.80(m,6H),3.80–3.70(m,2H),3.70–3.58(m,2H),3.58–3.41(m,6H),2.93–2.83(m,1H),2.82–2.68(m,3H),2.56–2.35(m,1H),2.19–2.13(m,1H),2.11–2.05(m,1H),1.10–1.00(m,2H),0.97–0.89(m,2H)。HRMS(ESI-TOF)m/z：C₄₂H₄₄FN₁₂O₇ ⁺Of [ M + H]⁺Calculated values: 847.3434, respectively; the following are found: 847.3455.

example 9: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) acetamide. The yield was 62%. ¹H NMR(600MHz,CD₃OD)δ8.80(t,J＝8.1Hz,1H),7.97(s,2H),7.73(s,1H),7.61(s,1H),7.50(dd,J＝8.4,7.2Hz,1H),7.29(t,J＝10.1Hz,2H),7.06–7.02(m,1H),6.98(d,J＝8.5Hz,1H),4.98(dd,J＝12.4,5.4Hz,1H),3.86–3.70(m,6H),3.67(d,J＝4.6Hz,4H),3.61(t,J＝5.2Hz,2H),3.52–3.39(m,6H),3.07–2.86(m,4H),2.87–2.68(m,3H),2.19–2.09(m,1H),2.05–1.97(m,1H),1.07–1.00(m,2H),0.99–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₄H₄₈FN₁₂O₈ ⁺Of [ M + H]⁺Calculated values: 891.3697, respectively; the following are found: 891.3682.

example 10: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (2- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) acetamide. The yield was 59%.¹H NMR(600MHz,CD₃OD)δ8.82(t,J＝8.2Hz,1H),7.98(s,2H),7.75(s,1H),7.60(s,1H),7.56–7.47(m,1H),7.31(t,J＝9.5Hz,2H),7.09–6.90(m,2H),5.02–4.96(m,1H),3.86–3.70(m,6H),3.67–3.61(m,8H),3.50–3.30(m,8H),3.09–2.89(m,4H),2.87–2.68(m,3H),2.16–2.05(m,1H),2.04–1.97(m,1H),1.07–0.98(m,2H),0.96–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₆H₅₂FN₁₂O₉ ⁺Of [ M + H]⁺Calculated values: 835.3959, respectively; the following are found: 935.3966.

example 11: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -N- (17- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3,6,9,12, 15-pentaoxaheptadecyl) acetamide. The yield was 51%.¹H NMR(600MHz,CD₃OD)δ8.80(t,J＝8.2Hz,1H),8.03(s,2H),7.82(s,1H),7.69(s,1H),7.54–7.46(m,1H),7.41–7.30(m,2H),7.06–6.97(m,2H),5.02(dd,J＝12.6,5.4Hz,1H),4.04–3.79(m,6H),3.72(dd,J＝14.2,9.0Hz,2H),3.71–3.60(m,14H),3.58(t,J＝5.2Hz,2H),3.46(ddd,J＝15.6,12.3,7.9Hz,4H),3.33(br,2H),2.88–2.67(m,3H),2.19–2.08(m,1H),2.08–1.98(m,1H),1.09–1.00(m,2H),1.00–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₈H₅₆FN₁₂O₁₀ ⁺Of [ M + H]⁺Calculated values: 979.4221, respectively; the following are found: 979.4241.

example 12: 2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino group-3-fluorobenzoyl) piperazin-1-yl) -N- (17- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3,6,9,12, 15-pentaoxaheptadecyl) acetamide. The yield was 56%.¹H NMR(600MHz,CD₃ODδ8.81(t,J＝8.2Hz,1H),8.01(s,2H),7.80(s,1H),7.66(s,1H),7.53–7.47(m,1H),7.40–7.28(m,2H),7.02(dd,J＝22.3,7.8Hz,2H),5.06–4.95(m,1H),3.92(br,4H),3.83–3.53(m,22H),3.52–3.36(m,4H),3.26(br,4H),2.89–2.66(m,3H),2.18–2.06(m,1H),2.08–1.96(m,1H),1.09–0.98(m,2H),0.99–0.88(m,2H)。HRMS(ESI-TOF)m/z：C₅₀H₆₀FN₁₂O₁₁ ⁺Of [ M + H]⁺Calculated values: 1023.4483, respectively; the following are found: 1023.4509.

example 13: (2S,4R) -1- ((S) -2- (5- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) pentanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 60%.¹H NMR(600MHz,CD₃OD)δ8.94(s,1H),8.74(t,J＝8.0Hz,1H),8.15(s,2H),7.97(s,1H),7.85(s,1H),7.52–7.35(m,6H),4.65(s,1H),4.61–4.32(m,4H),4.12–3.87(m,7H),3.82(dd,J＝10.9,3.7Hz,1H),3.48(br,4H),3.31–3.21(m,2H),2.48(s,3H),2.40–2.18(m,3H),2.16–2.03(m,2H),1.74–1.49(m,4H),1.08–1.00(m,11H),1.01–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₅₂H₆₃FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1016.4724, respectively; the following are found: 1016.4701.

example 14: (2S,4R) -1- ((S) -2- (6- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) hexanoylamino) -3,3-Dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 70%.¹H NMR(600MHz,CD₃OD)δ8.96(s,1H),8.73(t,J＝8.1Hz,1H),8.15(s,2H),7.98(s,1H),7.86(s,1H),7.54–7.34(m,6H),4.65(s,1H),4.64–4.43(m,3H),4.42–4.35(m,1H),4.15–3.86(m,7H),3.83(dd,J＝10.9,3.4Hz,1H),3.47(br,4H),3.29(t,J＝6.9Hz,2H),2.49(s,3H),2.37–2.19(m,3H),2.19–2.00(m,2H),1.75–1.48(m,4H),1.46–1.32(m,2H),1.10–1.00(m,11H),1.00–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₅₃H₆₅FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1030.4880, respectively; the following are found: 1030.4855.

example 15: (2S,4R) -1- ((S) -2- (7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) heptanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 55%.¹H NMR(600MHz,CD₃OD)δ9.00(s,1H),8.70(t,J＝8.2Hz,1H),8.14(s,2H),8.01(s,1H),7.89(s,1H),7.51–7.39(m,6H),4.66(s,1H),4.63–4.48(m,3H),4.39(d,J＝15.6Hz,1H),4.06–3.86(m,7H),3.83(dd,J＝10.9,3.8Hz,1H),3.47(br,4H),3.30–3.23(m,2H),2.49(s,3H),2.36–2.18(m,3H),2.12(dddd,J＝17.4,13.2,8.6,4.6Hz,2H),1.72–1.49(m,4H),1.43–1.32(m,4H),1.10–1.01(m,11H),1.00–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₄H₆₇FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1044.5037, respectively; the following are found: 1044.5020.

example 16: (2S,4R) -1- ((S) -2- (8- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl ) Acetamido) octanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 65%.¹H NMR(600MHz,CD₃OD)δ8.97(s,1H),8.73(t,J＝8.2Hz,1H),8.15(s,2H),7.98(s,1H),7.87(s,1H),7.50–7.37(m,6H),4.66(s,1H),4.62–4.49(m,3H),4.39(d,J＝15.4Hz,1H),3.97(br,6H),3.92(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.9Hz,1H),3.47(br,4H),3.28(t,J＝7.0Hz,2H),2.49(s,3H),2.35–2.18(m,3H),2.18–2.03(m,2H),1.68–1.51(m,4H),1.37(br,6H),1.10–1.00(m,11H),0.99–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1058.5192, respectively; the following are found: 1058.5211.

example 17: (2S,4R) -1- ((S) -2- (9- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) nonanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 54%.¹H NMR(600MHz,CD₃OD)δ8.91(s,1H),8.80(t,J＝8.2Hz,1H),8.14(s,2H),7.94(s,1H),7.77(s,1H),7.53–7.32(m,6H),4.66(s,1H),4.63–4.46(m,3H),4.38(d,J＝15.5Hz,1H),4.11–3.87(m,7H),3.83(dd,J＝11.0,3.4Hz,1H),3.43(br,4H),3.27(t,J＝6.8Hz,1H),2.49(s,3H),2.37–2.16(m,3H),2.17–1.95(m,2H),1.68–1.50(m,4H),1.45–1.26(m,8H),1.09–1.00(m,11H),0.99–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₅₆H₇₁FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1072.5350, respectively; the following are found: 1072.5380.

example 18: (2S,4R) -1- ((S) -2- (10- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino group-3-fluorobenzoyl) piperazin-1-yl) acetylamino) decanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 56%.¹H NMR(600MHz,CD₃OD)δ8.87(s,1H),8.83(t,J＝8.2Hz,1H),8.09(s,2H),7.88(d,J＝16.1Hz,1H),7.71(s,1H),7.50–7.34(m,6H),4.65(s,1H),4.62–4.42(m,3H),4.37(d,J＝15.5Hz,1H),4.02–3.78(m,8H),3.34–3.32(m,4H),3.27(t,J＝7.1Hz,2H),2.50(s,3H),2.35–2.19(m,3H),2.14–2.00(m,2H),1.70–1.38(m,4H),1.40–1.23(m,10H),1.08–0.99(m,11H),0.99–0.88(m,2H)。HRMS(ESI-TOF)m/z：C₅₇H₇₃FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1086.5506, respectively; the following are found: 1086.5530.

example 19: (2S,4R) -1- ((S) -2- (11- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) undecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 59%. ¹H NMR(600MHz,CD₃OD)δ8.89(s,1H),8.78(t,J＝8.2Hz,1H),8.09(s,2H),7.90(s,1H),7.76(s,1H),7.49–7.34(m,6H),4.66(s,1H),4.61–4.46(m,3H),4.36(dd,J＝15.2,8.7Hz,1H),4.12–3.86(m,7H),3.82(dd,J＝10.9,3.8Hz,1H),3.42(br,4H),3.28–3.20(m,2H),2.50(s,3H),2.40–2.18(m,3H),2.17–2.03(m,2H),1.68–1.49(m,4H),1.41–1.21(m,12H),1.12–1.00(m,11H),1.00–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₅₈H₇₅FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1100.5663, respectively; the following are found: 1100.5639.

example 20: (2S,4R) -1- ((S) -2- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a]pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) ethoxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 67%.¹H NMR(600MHz,CD₃OD)δ8.93(s,1H),8.67(t,J＝8.1Hz,1H),8.16(s,2H),7.98(s,1H),7.90(s,1H),7.52–7.30(m,6H),4.76(s,1H),4.61–4.42(m,3H),4.31(d,J＝15.3Hz,1H),4.18–3.88(m,9H),3.87–3.67(m,2H),3.67–3.56(m,2H),3.57–3.40(m,5H),2.45(s,3H),2.34–2.21(m,1H),2.19–2.02(m,2H),1.11–1.01(m,11H),1.00–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₁H₆₁FN₁₃O₇S⁺Of [ M + H]⁺Calculated values: 1018.4516, respectively; the following are found: 1018.4501.

example 21: (2S,4R) -1- ((S) -2- (tert-butyl) -14- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 13-dioxo-6, 9-dioxa-3, 12-diazadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 65%.¹H NMR(600MHz,CD₃OD)δ8.94(s,1H),8.70(t,J＝8.1Hz,1H),8.16(s,2H),7.97(s,1H),7.88(s,1H),7.51–7.34(m,6H),4.82(s,1H),4.59–4.47(m,3H),4.46–4.38(m,1H),4.19–3.81(m,10H),3.79–3.53(m,8H),3.47(br,4H),2.49(s,3H),2.39–2.27(m,1H),2.18–2.07(m,2H),1.14–1.01(m,11H),1.01–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₅₃H₆₅FN₁₃O₈S⁺Of [ M + H]⁺Calculated values: 1062.4778, respectively; the following are found: 1062.4790.

example 22: (2S,4R) -1- ((S) -2- (tert-butyl) -17- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-heptadiazanyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 70%. ¹H NMR(600MHz,CD₃OD)δ8.93(s,1H),8.77(t,J＝8.1Hz,1H),8.15(s,2H),7.95(s,1H),7.83(s,1H),7.54–7.30(m,6H),4.64(s,1H),4.63–4.48(m,3H),4.38(d,J＝15.5Hz,1H),4.15–3.88(m,7H),3.82(d,J＝7.2Hz,1H),3.80–3.71(m,2H),3.71–3.56(m,10H),3.48(br,4H),2.65–2.55(m,1H),2.53(m,4H),2.32–2.23(m,1H),2.18–2.00(m,2H),1.13–1.02(m,11H),1.00–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₉S⁺Of [ M + H]⁺Calculated values: 1106.5040, respectively; the following are found: 1106.5018.

example 37: (2S,4R) -1- ((S) -2- (7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) heptanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide. The yield was 65%.¹H NMR(600MHz,CD₃OD)δ9.10(s,1H),8.64(t,J＝8.2Hz,1H),8.18(s,2H),8.03(s,1H),7.99(s,1H),7.52–7.27(m,6H),5.02(q,J＝7.0Hz,1H),4.65(s,1H),4.59(dd,J＝14.1,5.7Hz,1H),4.45(s,1H),4.05–4.01(m,6H),3.90(d,J＝11.0Hz,1H),3.77(dd,J＝11.0,3.9Hz,1H),3.57–3.38(m,4H),3.28(t,J＝7.0Hz,2H),2.51(s,3H),2.40–2.25(m,2H),2.25–2.13(m,2H),2.01–1.92(m,1H),1.69–1.55(m,4H),1.52(d,J＝7.0Hz,3H),1.44–1.33(m,4H),1.12–1.03(m,11H),1.03–0.97(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1058.5193, respectively; the following are found: 1058.5165.

example 38: (2S,4R)) -1- ((S) -2- (9- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) nonanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide. The yield was 67%.¹H NMR(600MHz,CD₃OD)δ9.01(s,1H),8.72(t,J＝8.2Hz,1H),8.16(s,2H),8.00(s,1H),7.90(s,1H),7.53–7.34(m,6H),5.02(q,J＝6.8Hz,1H),4.65(s,1H),4.62–4.54(m,1H),4.47–4.42(m,1H),4.20–3.82(m,7H),3.77(dd,J＝11.1,3.9Hz,1H),3.58–3.38(m,4H),3.28(t,J＝7.0Hz,2H),2.51(s,3H),2.37–2.19(m,3H),2.18–2.11(m,1H),2.01–1.93(m,1H),1.61(dd,J＝18.7,6.8Hz,4H),1.52(d,J＝7.0Hz,3H),1.39–1.34(m,8H),1.10–1.01(m,11H),1.01–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₅₇H₇₃FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1086.5506, respectively; the following are found: 1086.5545.

example 39: (2S,4R) -1- ((S) -2- (tert-butyl) -17- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-heptadiazanyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide. The yield was 50%. ¹H NMR(600MHz,CD₃OD)δ9.14(s,1H),8.62(t,J＝8.2Hz,1H),8.19(s,2H),8.05(s,1H),8.03(s,1H),7.52–7.40(m,6H),5.02(q,J＝6.9Hz,1H),4.71(s,1H),4.62–4.56(m,1H),4.47(s,1H),4.14–4.08(m,2H),4.04(s,2H),3.88(d,J＝11.2Hz,1H),3.80–3.74(m,4H),3.73–3.65(m,8H),3.61(t,J＝5.2Hz,2H),3.58–3.40(m,7H),2.51(s,3H),2.29–2.22(m,1H),2.20–2.13(m,1H),2.01–1.93(m,1H),1.53(d,J＝7.0Hz,3H),1.09–1.05(m,11H),1.03–0.97(m,2H)。HRMS(ESI-TOF)m/z：C₅₆H₇₁FN₁₃O₉S⁺Of [ M + H]⁺Calculated values: 1120.5179, respectively; the following are found: 1120.5148.

example 40: (2R,4S) -1- ((S) -2- (7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) heptanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 62%.¹H NMR(500MHz,CD₃OD)δ8.95(s,1H),8.72(t,J＝8.2Hz,1H),8.15(s,2H),7.97(s,1H),7.86(s,1H),7.50–7.37(m,6H),4.59(t,J＝7.4Hz,1H),4.55–4.45(m,3H),4.40(d,J＝15.6Hz,1H),4.10–3.85(m,7H),3.74(d,J＝10.7Hz,1H),3.55–3.42(m,4H),3.26–3.17(m,2H),2.51(s,3H),2.35–2.20(m,2H),2.20–2.04(m,3H),1.59–1.42(m,4H),1.34–1.23(m,4H),1.15–1.02(m,11H),1.01–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₄H₆₇FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1044.5037, respectively; the following are found: 1044.5058.

example 41: (2R,4S) -1- ((S) -2- (9- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) nonanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 67%.¹H NMR(500MHz,CD₃OD)δ8.96(s,1H),8.72(t,J＝8.2Hz,1H),8.15(s,2H),7.97(s,1H),7.86(s,1H),7.50–7.36(m,6H),4.64–4.56(m,1H),4.56–4.44(m,3H),4.38(d,J＝15.6Hz,1H),4.14–3.85(m,7H),3.78–3.72(m,1H),3.57–3.41(m,4H),3.27–3.20(m,2H),2.51(s,3H),2.36–2.00(m,5H),1.57–1.19(m,12H),1.15–1.03(m,11H),1.02–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₆H₇₁FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1072.5350, respectively; the following are found: 1072.5359.

example 42: (2R,4S) -1- ((S) -2- (tert-butyl) -17- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-diazaheptanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 54%.¹H NMR(500MHz,CD₃OD)δ9.01(s,1H),8.63(t,J＝8.2Hz,1H),8.17(s,2H),8.01(s,1H),7.96(s,1H),7.51–7.32(m,6H),4.68–4.63(m,1H),4.60–4.47(m,3H),4.37(d,J＝15.6Hz,1H),4.09–3.84(m,8H),3.80(d,J＝10.9Hz,1H),3.71–3.54(m,11H),3.54–3.40(m,6H),2.50(s,3H),2.34–2.25(m,1H),2.19–2.10(m,2H),1.13–1.03(m,11H),1.03–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₉S⁺Of [ M + H]⁺Calculated values: 1106.5040, respectively; the following are found: 1106.5017.

Example 43: (2S,4R) -1- ((S) -2- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 57%.¹H NMR(500MHz,CD₃OD)δ9.06(s,1H),8.65(t,J＝8.2Hz,1H),8.16(s,2H),8.01(s,1H),7.96(s,1H),7.55–7.37(m,6H),4.67(s,1H),4.61–4.47(m,3H),4.38(d,J＝15.5Hz,1H),4.14–3.92(m,8H),3.92–3.79(m,2H),3.50(br,4H),2.50(s,3H),2.30–2.20(m,1H),2.20–2.04(m,2H),1.06(s,9H),1.05–1.02(m,2H),1.02–0.96(m,2H)。HRMS(ESI-TOF)m/z：C₄₉H₅₇FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 974.4254, respectively; the following are found: 974.4266.

example 44: (2S,4R) -1- ((S) -2- (3- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) propionylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 53%.¹H NMR(500MHz,CD₃OD)δ8.97(s,1H),8.66(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.92(s,1H),7.53–7.33(m,6H),4.64(s,1H),4.62–4.47(m,3H),4.42(d,J＝15.5Hz,1H),3.97(dd,J＝12.8,8.7Hz,6H),3.83(dd,J＝10.9,3.7Hz,1H),3.63–3.55(m,1H),3.52–3.42(m,4H),2.72–2.57(m,2H),2.54–2.44(m,5H),2.32–2.22(m,1H),2.21–2.08(m,2H),1.12–1.02(m,11H),1.02–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₅₀H₅₉FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 988.4411, respectively; the following are found: 988.4432.

example 45: (2S,4R) -1- ((S) -2- (4- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) butyrylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 51%.¹H NMR(500MHz,CD₃OD)δ8.95(s,1H),8.75–8.64(m,1H),8.15(s,2H),7.97(s,1H),7.87(s,1H),7.52–7.33(m,6H),4.64(s,1H),4.62–4.48(m,3H),4.40(d,J＝15.4Hz,1H),4.12–3.89(m,7H),3.83(dd,J＝10.9,3.8Hz,1H),3.64–3.36(m,4H),2.48(s,3H),2.42–2.30(m,2H),2.30–2.21(m,1H),2.19–2.06(m,2H),1.97–1.77(m,2H),1.14–1.02(m,11H),1.02–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₁H₆₁FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1002.4567, respectively; the following are found: 1002.4578.

example 63: (2R,4S) -1- ((S) -2- (7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) heptanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide. The yield was 59%.¹H NMR(500MHz,CD₃OD)δ8.98(s,1H),8.70(t,J＝8.2Hz,1H),8.15(s,2H),7.98(s,1H),7.89(s,1H),7.55–7.37(m,6H),5.03(q,J＝6.7Hz,1H),4.61–4.51(m,2H),4.51–4.44(m,1H),4.08–3.87(m,6H),3.71(d,J＝10.9Hz,1H),3.55–3.42(m,4H),3.30–3.16(m,3H),2.52(s,3H),2.35–2.27(m,1H),2.27–2.18(m,2H),2.18–2.09(m,2H),1.65–1.50(m,4H),1.48(d,J＝7.0Hz,3H),1.39–1.27(m,4H),1.15–1.02(m,11H),1.02–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1058.5193, respectively; the following are found: 1058.5165.

example 64: (2R,4S) -1- ((S) -2- (9- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) nonanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide. The yield was 61%.¹H NMR(500MHz,CD₃OD)δ8.96(s,1H),8.73(t,J＝8.2Hz,1H),8.15(s,2H),7.97(s,1H),7.86(s,1H),7.56–7.32(m,6H),5.03(q,J＝6.8Hz,1H),4.60–4.55(m,1H),4.53(s,1H),4.50–4.45(m,1H),4.10–3.85(m,6H),3.76–3.67(m,1H),3.56–3.40(m,4H),3.30–3.21(m,3H),2.51(s,3H),2.35–2.26(m,1H),2.26–2.17(m,2H),2.17–2.08(m,2H),1.65–1.50(m,4H),1.47(d,J＝7.0Hz,3H),1.37–1.28(m,8H),1.11–1.03(m,11H),1.00–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₇H₇₃FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1086.5506, respectively; the following are found: 1086.5545.

example 102: (2S,4R) -1- ((S) -2- (4- (4- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) piperidin-1-yl) -4-oxobutanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 70%.¹H NMR(500MHz,CD₃OD)δ8.97(s,1H),8.71(t,J＝8.2Hz,1H),8.14(s,2H),7.96(s,1H),7.85(s,1H),7.54–7.29(m,6H),4.64–4.48(m,4H),4.44–4.35(m,2H),4.10–3.93(m,6H),3.90(d,J＝10.6Hz,1H),3.81(dd,J＝11.0,3.8Hz,1H),3.57–3.42(m,4H),3.28–3.20(m,1H),2.87(t,J＝12.2Hz,1H),2.79–2.52(m,4H),2.50(s,3H),2.29–2.19(m,1H),2.17–2.06(m,2H),2.04–1.89(m,2H),1.58–1.34(m,2H),1.11–1.01(m,11H),1.01–0.94(m,2H)。

HRMS(ESI-TOF)m/z：C₅₆H₆₈FN₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1099.5095, respectively; the following are found: 1099.5107.

example 103: 1' - (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetyl) -N- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) - [1,4' -bipiperidine]-4-carboxamide. The yield was 66%.¹H NMR(600MHz,CD₃OD)δ9.00(s,1H),8.69(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.90(s,1H),7.52–7.39(m,6H),4.73(d,J＝12.8Hz,1H),4.65(d,J＝8.8Hz,1H),4.61–4.50(m,3H),4.46(d,J＝16.2Hz,1H),4.41–4.32(m,2H),4.14–3.94(m,2H),3.90–3.88(m,1H),3.83(dd,J＝10.9,3.7Hz,1H),3.69–3.61(m,2H),3.59–3.41(m,4H),3.22(t,J＝12.4Hz,1H),3.11–3.06(m,1H),2.79(t,J＝12.4Hz,1H),2.74–2.65(m,1H),2.50(s,3H),2.31–2.18(m,3H),2.18–2.06(m,4H),2.06–1.93(m,2H),1.91–1.78(m,1H),1.76–1.62(m,1H),1.11–1.01(m,11H),1.01–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₆H₆₈FN₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1099.5095, respectively; the following are found: 1099.5088.

example 104: n is a radical of¹- (1- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetyl) piperidin-4-yl) -N⁴- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) succinamide. The yield was 60%.¹H NMR(600MHz,CD₃OD)δ9.00(s,1H),8.70(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.89(s,1H),7.52–7.39(m,6H),4.63(s,1H),4.60–4.49(m,3H),4.44–4.30(m,5H),4.27–3.76(m,7H),3.76–3.63(m,2H),3.65–3.36(m,4H),3.23(t,J＝12.9Hz,1H),2.98(t,J＝12.1Hz,1H),2.66–2.59(m,1H),2.57–2.52(m,1H),2.52–2.47(m,6H),2.29–2.20(m,1H),2.17–2.06(m,2H),2.03–1.89(m,2H),1.57–1.28(m,4H),1.09–1.01(m,11H),1.01–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₆H₇₂FN₁₄O₆S⁺Of [ M + H]⁺Calculated values: 1111.5499, respectively; the following are found: 1111.5483.

example 105: (2S,4R) -1- ((R) -2- (5- (4- ((2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) methyl) -1H-1,2, 3-triazol-1-yl) pentanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-me-thylAn amide. The yield was 71%.¹H NMR(600MHz,CD₃OD)δ8.97(s,1H),8.69(t,J＝8.2Hz,1H),8.16(s,2H),7.98(s,1H),7.95(s,1H),7.88(s,1H),7.51–7.35(m,6H),4.63(s,1H),4.60–4.56(m,1H),4.56–4.49(m,4H),4.44–4.36(m,3H),4.10–3.85(m,7H),3.82(dd,J＝10.9,3.8Hz,1H),3.57–3.40(m,4H),2.49(s,3H),2.37–2.28(m,2H),2.28–2.22(m,1H),2.17–2.06(m,2H),1.96–1.87(m,2H),1.66–1.55(m,2H),1.07–1.00(m,11H),1.00–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₆FN₁₆O₆S⁺Of [ M + H]⁺Calculated values: 1097.5050, respectively; the following are found: 1097.5059.

Example 106: (3R,5S) -1- ((R) -2- (7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) heptanoylamino) -3, 3-dimethylbutyryl) -5- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-3-ylacetate. The yield was 64%.¹H NMR(600MHz,CD₃OD)δ8.95(s,1H),8.72(t,J＝8.2Hz,1H),8.15(s,2H),7.96(s,1H),7.85(s,1H),7.53–7.30(m,6H),5.40–5.34(m,1H),4.60–4.49(m,3H),4.39(d,J＝15.4Hz,1H),4.19(d,J＝11.8Hz,1H),4.14–3.77(m,7H),3.55–3.39(m,4H),3.28(t,J＝7.0Hz,2H),2.49(s,3H),2.44–2.37(m,1H),2.37–2.22(m,3H),2.16–2.10(m,1H),2.06(s,3H),1.69–1.60(m,2H),1.60–1.51(m,2H),1.44–1.33(m,4H),1.10–1.00(m,11H),0.99–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₇S⁺Of [ M + H]⁺Calculated values: 1086.5142, respectively; the following are found: 1086.5154.

example 107: (3R,5S) -1- ((R) -2- (7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazine-1-yl) acetylamino) heptanoylamino) -3, 3-dimethylbutyryl) -5- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-3-yl isobutyrate. The yield was 68%.¹H NMR(600MHz,CD₃OD)δ8.99(s,1H),8.68(t,J＝8.2Hz,1H),8.16(s,2H),7.98(s,1H),7.89(s,1H),7.50–7.36(m,6H),5.41–5.35(m,1H),4.63–4.51(m,3H),4.39(d,J＝15.5Hz,1H),4.16(d,J＝11.8Hz,1H),4.11–3.81(m,7H),3.42(d,J＝61.1Hz,4H),3.27(t,J＝7.0Hz,2H),2.59–2.52(m,1H),2.49(s,3H),2.43–2.36(m,1H),2.36–2.20(m,3H),2.17–2.08(m,1H),1.68–1.50(m,4H),1.44–1.30(m,4H),1.15(d,J＝7.0Hz,6H),1.08–1.02(m,11H),1.01–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₇H₇₃FN₁₃O₇S⁺Of [ M + H]⁺Calculated values: 1114.5455, respectively; the following are found: 1114.5437.

example 130: (2S,4R) -1- ((S) -2- (3- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) ethoxy) propionylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 60%.¹H NMR(600MHz,CD₃OD)δ8.92(s,1H),8.70(t,J＝8.1Hz,1H),8.15(s,2H),7.96(d,J＝1.3Hz,1H),7.86(s,1H),7.49–7.36(m,6H),4.68(s,1H),4.61–4.50(m,2H),4.50–4.41(m,2H),4.13–3.81(m,8H),3.75(t,J＝5.7Hz,2H),3.66–3.54(m,2H),3.54–3.41(m,6H),2.60–2.51(m,2H),2.46(s,3H),2.33–2.24(m,1H),2.18–2.06(m,2H),1.11–1.01(m,11H),1.01–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₂H₆₃FN₁₃O₇S⁺Of [ M + H]⁺Calculated values: 1032.4673, respectively; the following are found: 1032.4677.

Example 131: (2S,4R) -1- ((S) -14- (Tert-butyl)1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) -yl) -1]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2, 12-dioxo-6, 9-dioxa-3, 13-diazepipentadecan-15-yl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 62%.¹H NMR(600MHz,CD₃OD)δ8.94(s,1H),8.71(t,J＝8.2Hz,1H),8.16(s,2H),7.97(s,1H),7.87(s,1H),7.49–7.37(m,6H),4.68(s,1H),4.60–4.55(m,1H),4.55–4.48(m,2H),4.41(d,J＝15.4Hz,1H),4.10–3.81(m,8H),3.79–3.73(m,2H),3.66–3.62(m,4H),3.59(t,J＝5.3Hz,2H),3.52–3.43(m,6H),2.64–2.56(m,1H),2.56–2.49(m,1H),2.47(s,3H),2.30–2.22(m,1H),2.17–2.03(m,2H),1.08–1.03(m,11H),1.00–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₅₄H₆₇FN₁₃O₈S⁺Of [ M + H]⁺Calculated values: 1076.4935, respectively; the following are found: 1076.4931.

example 132: (2S,4R) -1- ((S) -17- (tert-butyl) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2, 15-dioxo-6, 9, 12-trioxa-3, 16-diazacyclooctadecan-18-yl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 61%.¹H NMR(600MHz,CD₃OD)δ8.96(s,1H),8.70(t,J＝8.2Hz,1H),8.16(s,2H),7.98(s,1H),7.88(s,1H),7.51–7.37(m,6H),4.67(s,1H),4.58(t,J＝8.4Hz,1H),4.55–4.50(m,2H),4.39(d,J＝15.5Hz,1H),4.10–3.85(m,7H),3.82(dd,J＝11.0,3.8Hz,1H),3.80–3.72(m,2H),3.66–3.62(m,8H),3.59(t,J＝5.3Hz,2H),3.55–3.43(m,6H),2.65–2.56(m,1H),2.56–2.50(m,1H),2.48(s,3H),2.30–2.22(m,1H),2.17–2.06(m,2H),1.08–1.02(m,11H),0.97(dm,J＝8.0,2.4Hz,2H)。HRMS(ESI-TOF)m/z：C₅₆H₇₁FN₁₃O₉S⁺Of [ M + H]⁺Calculated values: 1120.5197, respectively; the following are found: 1120.5190.

example 133: (2S,4R) -1- ((S) -23- (tert-butyl) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2, 21-dioxo-6, 9,12,15, 18-pentaoxa-3, 22-diaza-tetracosan-24-acyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 60%. ¹H NMR(600MHz,CD₃OD)δ8.98(s,1H),8.70(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.89(s,1H),7.52–7.32(m,6H),4.67(s,1H),4.58(t,J＝8.4Hz,1H),4.56–4.50(m,2H),4.38(d,J＝15.5Hz,1H),4.09–3.84(m,7H),3.82(dd,J＝10.9,3.8Hz,1H),3.74(ddd,J＝13.1,8.9,4.7Hz,3H),3.65–3.63(m,16H),3.60(t,J＝5.3Hz,2H),3.52–3.46(m,6H),2.63–2.57(m,1H),2.53–2.47(m,4H),2.28–2.22(m,1H),2.19–2.06(m,2H),1.07–1.03(m,11H),1.00–0.96(m,2H)。HRMS(ESI-TOF)m/z：C₆₀H₇₉FN₁₃O₁₁S⁺Of [ M + H]⁺Calculated values: 1208.5721, respectively; the following are found: 1208.5744.

example 134: (2S,4R) -1- ((S) -2- (tert-butyl) -17- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 16-dioxo-6, 9, 12-trioxa-3, 15-diazaheptanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 51%.¹H NMR(600MHz,CD₃OD)δ9.02(s,1H),8.64(t,J＝8.2Hz,1H),8.17(s,2H),8.01(s,1H),7.96(s,1H),7.44(ddd,J＝16.4,12.1,7.9Hz,6H),4.72(s,1H),4.62–4.49(m,3H),4.40(d,J＝15.5Hz,1H),4.15–3.95(m,6H),3.91(d,J＝11.0Hz,1H),3.85–3.81(m,1H),3.77–3.73(m,2H),3.73–3.69(m,2H),3.69–3.66(m,2H),3.66–3.62(m,2H),3.58(t,J＝5.0Hz,2H),3.55–3.40(m,6H),2.50(s,3H),2.32–2.23(m,1H),2.12(ddd,J＝22.6,10.6,4.4Hz,2H),1.11–1.02(m,11H),1.01–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₉S⁺Of [ M + H]⁺Calculated values: 1106.5040, respectively; the following are found: 1106.5049.

scheme 25 Synthesis of example 23

Example 23: (2S,4R) -1- ((S) -2- (8- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) octanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. A solution of linking group 1(14mg,0.019mmol) in DCM/TFA (2:1, 1mL) was stirred at room temperature for 2 h. After concentration under reduced pressure, the resulting crude intermediate 11 was obtained without further purification. To a solution of intermediate 11 and intermediate 7(5.2mg, 0.014mmol) in DMF (1mL) was added DIEA (17. mu.L, 0.1mmol) and TBTU (7mg, 0.02 mmol). After stirring at room temperature for 12h, the mixture was purified by HPLC to give the title compound as a brown oil (6mg, 45% yield). ¹H NMR(600MHz,CD₃OD)δ8.97(s,1H),8.72(t,J＝8.1Hz,1H),8.16(s,2H),7.99(s,1H),7.88(s,1H),7.52–7.38(m,6H),4.67(s,1H),4.61–4.48(m,3H),4.39(d,J＝15.4Hz,1H),3.93(d,J＝10.9Hz,1H),3.83(d,J＝7.6Hz,1H),3.73–3.39(m,6H),3.26–3.11(m,4H),2.50(s,3H),2.38–2.20(m,3H),2.20–2.05(m,2H),1.83–1.73(m,2H),1.73–1.58(m,2H),1.50–1.34(m,6H),1.11–0.93(m,13H)。HRMS(ESI-TOF)m/z：C₅₃H₆₆FN₁₂O₅S⁺Of [ M + H]⁺Calculated values: 1001.4978, respectively; the following are found: 1001.4999.

example compounds 24-27 were synthesized according to the procedure used to prepare example compound 23.

Example 24: (2S,4R) -1- ((S) -2- (9- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazole)And [1,2-a ]]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) nonanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 58%.¹H NMR(600MHz,CD₃OD)δ8.98(s,1H),8.72(t,J＝8.2Hz,1H),8.15(s,2H),7.98(s,1H),7.88(s,1H),7.52–7.38(m,6H),4.67(s,1H),4.64–4.50(m,3H),4.39(d,J＝15.5Hz,1H),3.92(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.8Hz,1H),3.73–3.40(m,6H),3.27–3.13(m,4H),2.50(s,3H),2.37–2.20(m,3H),2.17–2.07(m,2H),1.83–1.73(m,2H),1.71–1.59(m,2H),1.50–1.35(m,8H),1.04(d,J＝13.8Hz,11H),1.00–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₅₄H₆₈FN₁₂O₅S⁺Of [ M + H]⁺Calculated values: 1015.5135, respectively; the following are found: 1015.5110.

example 25: (2S,4R) -1- ((S) -2- (10- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) decanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 67%.¹H NMR(600MHz,CD₃OD)δ8.95(s,1H),8.77(t,J＝8.2Hz,1H),8.16(s,2H),7.98(s,1H),7.83(s,1H),7.52–7.34(m,6H),4.66(s,1H),4.62–4.48(m,3H),4.38(d,J＝15.5Hz,1H),3.92(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.9Hz,1H),3.74–3.38(m,6H),3.25–3.12(m,4H),2.49(s,3H),2.37–2.18(m,3H),2.18–2.04(m,2H),1.85–1.72(m,2H),1.69–1.54(m,2H),1.48–1.30(m,10H),1.11–0.87(m,13H)。HRMS(ESI-TOF)m/z：C₅₅H₇₀FN₁₂O₅S⁺Of [ M + H]⁺Calculated values: 1029.5291, respectively; the following are found: 1029.5270.

example 26: (2S,4R) -1- ((S) -2- (11- (4- (4- ((6-cyclopropyl)-3- (1H-pyrazol-4-yl) imidazo [1,2-a]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) undecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 63%. ¹H NMR(600MHz,CD₃OD)δ8.95(s,1H),8.77(t,J＝8.2Hz,1H),8.15(s,2H),7.97(s,1H),7.83(s,1H),7.51–7.39(m,6H),4.69–4.64(m,1H),4.61–4.49(m,3H),4.38(dd,J＝15.3,4.8Hz,1H),3.92(d,J＝11.1Hz,1H),3.83(dd,J＝10.9,3.9Hz,1H),3.76–3.37(m,6H),3.28–3.06(m,4H),2.50(s,3H),2.38–2.20(m,3H),2.20–2.05(m,2H),1.87–1.72(m,2H),1.71–1.54(m,2H),1.48–1.28(m,12H),1.09–0.93(m,13H)。HRMS(ESI-TOF)m/z：C₅₆H₇₂FN₁₂O₅S⁺Of [ M + H]⁺Calculated values: 1043.5448, respectively; the following are found: 1043.5440.

example 27: (2S,4R) -1- ((S) -2- (12- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) dodecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 62%.¹H NMR(600MHz,CD₃OD)δ8.94(s,1H),8.77(t,J＝8.2Hz,1H),8.15(s,2H),7.96(s,1H),7.81(s,1H),7.50–7.38(m,6H),4.67(s,1H),4.63–4.50(m,3H),4.42–4.33(m,1H),3.92(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.9Hz,1H),3.75–3.39(m,6H),3.27–3.10(m,4H),2.49(s,3H),2.38–2.17(m,3H),2.17–2.05(m,2H),1.87–1.73(m,2H),1.69–1.54(m,2H),1.47–1.27(m,14H),1.13–0.89(m,13H)。HRMS(ESI-TOF)m/z：C₅₇H₇₄FN₁₂O₅S⁺Of [ M + H]⁺Calculated values: 1057.5604, respectively; the following are found: 1057.5630.

scheme 26 Synthesis of example 28

Example 28: (2S,4R) -1- ((S) -2- (10- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -10-oxodecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. To a solution of intermediate 7(12mg, 0.021mmol) and linking group 7(11mg, 0.018mmol) in DMF (0.5mL) was added DIEA (17. mu.L, 0.1mmol) and TBTU (6mg, 0.02 mmol). After stirring at room temperature for 12h, the mixture was purified by HPLC to give the title compound as a brown oil (11mg, 59%).¹H NMR(600MHz,CD₃OD)δ9.10(s,1H),8.57(t,J＝8.1Hz,1H),8.19(s,2H),8.08–8.01(m,2H),7.55–7.35(m,6H),4.66(s,1H),4.63–4.48(m,3H),4.38(dd,J＝15.2,6.4Hz,1H),3.93(d,J＝11.0Hz,1H),3.82(dd,J＝10.9,3.8Hz,1H),3.63(br,8H),2.50(s,3H),2.45(s,2H),2.36–2.20(m,3H),2.20–2.14(m,1H),2.10(ddd,J＝11.2,8.1,3.4Hz,1H),1.63(br,4H),1.35(br,J＝12.8Hz,8H),1.10–0.96(m,13H)。HRMS(ESI-TOF)m/z：C₅₅H₆₈FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1043.5084, respectively; the following are found: 1043.5103.

example compounds 29, 30, 32-36, 46-62, and 65-74 were synthesized according to the procedure used to prepare the compound of example 28.

Example 29: (2S,4R) -1- ((S) -2- (11- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -11-oxoundecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 60%.¹H NMR(600MHz,CD₃OD)δ9.12(s,1H),8.56(t,J＝8.1Hz,1H),8.20(s,2H),8.07(s,2H),7.55–7.33(m,6H),4.66(s,1H),4.63–4.48(m,3H),4.38(d,J＝15.3Hz,1H),3.93(d,J＝10.9Hz,1H),3.82(dd,J＝10.9,3.7Hz,1H),3.78–3.47(m,8H),2.53(s,3H),2.49–2.38(m,2H),2.35–2.21(m,3H),2.21–2.14(m,1H),2.14–2.06(m,1H),1.63(d,J＝6.2Hz,4H),1.35(br,10H),1.12–0.96(m,13H)。HRMS(ESI-TOF)m/z：C₅₆H₇₀FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1057.5241, respectively; the following are found: 1057.5269.

example 30: (2S,4R) -1- ((S) -2- (12- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -12-oxododecanoylamino) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 69%.¹H NMR(600MHz,CD₃OD)δ9.04(s,1H),8.60(t,J＝8.0Hz,1H),8.18(s,2H),8.02(s,1H),7.98(s,1H),7.54–7.32(m,6H),4.66(s,1H),4.63–4.49(m,3H),4.38(d,J＝15.5Hz,1H),3.92(d,J＝10.9Hz,1H),3.87–3.45(m,9H),2.50(s,3H),2.45(br,2H),2.38–2.20(m,3H),2.19–2.01(m,2H),1.62(br,4H),1.34(br,12H),1.12–0.89(m,13H)。HRMS(ESI-TOF)m/z：C₅₇H₇₂FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1071.5397, respectively; the following are found: 1071.5420.

example 32: (2S,4R) -1- ((S) -2- (13- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -13-oxotridecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 65%.¹H NMR(600MHz,CD₃OD)δ8.99(s,1H),8.65(t,J＝8.0Hz,1H),8.17(s,2H),8.00(s,1H),7.92(s,1H),7.52–7.35(m,6H),4.65(s,1H),4.61–4.49(m,3H),4.37(d,J＝15.5Hz,1H),3.92(d,J＝10.8Hz,1H),3.86–3.50(m,9H),2.50(s,3H),2.48–2.41(m,2H),2.37–2.19(m,3H),2.18–2.05(m,2H),1.70–1.53(m,4H),1.43–1.24(m,14H),1.12–1.01(m,11H),1.01–0.96(m,2H)。HRMS(ESI-TOF)m/z：C₅₈H₇₄FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1085.5554, respectively; the following are found: 1085.5529.

example 33: (2S,4R) -1- ((S) -2- (14- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -14-oxotetradecanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 61%.¹H NMR(600MHz,CD₃OD)δ9.01(s,1H),8.64(t,J＝7.9Hz,1H),8.17(s,2H),8.01(s,1H),7.95(s,1H),7.52–7.34(m,6H),4.65(s,1H),4.62–4.48(m,3H),4.37(d,J＝15.5Hz,1H),3.92(d,J＝10.9Hz,1H),3.86–3.52(m,9H),2.50(s,3H),2.48–2.41(m,2H),2.36–2.20(m,3H),2.18–2.06(m,2H),1.72–1.55(m,4H),1.45–1.24(m,16H),1.10–1.02(m,11H),1.02–0.96(m,2H)。HRMS(ESI-TOF)m/z：C₅₉H₇₆FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1099.5710, respectively; the following are found: 1099.5709.

example 34: (2S,4R) -1- ((S) -2- (12- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -12-oxododecanoylamino) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide. The yield was 63%.¹H NMR(600MHz,CD₃OD)δ9.04(s,1H),8.61(t,J＝6.5Hz,1H),8.18(s,2H),8.02(s,1H),7.97(s,1H),7.50–7.35(m,6H),5.02(q,J＝6.5Hz,1H),4.65(s,1H),4.59(t,J＝8.3Hz,1H),4.45(s,1H),3.90(d,J＝11.0Hz,1H),3.86–3.50(m,9H),2.51(s,3H),2.49–2.41(m,2H),2.37–2.18(m,3H),2.18–2.11(m,1H),2.00–1.92(m,1H),1.72–1.56(m,5H),1.52(d,J＝6.9Hz,3H),1.44–1.28(m,12H),1.11–1.02(m,11H),1.02–0.96(m,2H)。HRMS(ESI-TOF)m/z：C₅₈H₇₄FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1085.5554, respectively; the following are found: 1085.5550.

example 35: (2S,4S) -1- ((S) -2- (12- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -12-oxododecanoylamino) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 70%.¹H NMR(600MHz,CD₃OD)δ9.13(s,1H),8.55(t,J＝8.1Hz,1H),8.20(s,2H),8.06(s,1H),7.52–7.36(m,6H),4.61–4.49(m,3H),4.41(s,2H),4.07(dd,J＝10.5,5.1Hz,1H),3.88–3.50(m,9H),2.51(s,3H),2.48–2.39(m,3H),2.34–2.22(m,2H),2.20–2.13(m,1H),2.01–1.96(m,1H),1.70–1.52(m,4H),1.44–1.29(m,12H),1.10–0.97(m,13H)。HRMS(ESI-TOF)m/z：C₅₇H₇₂FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1071.5397, respectively; the following are found: 1071.5388.

example 36: (2R,4S) -1- ((S) -2- (12- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -12-oxododecanoylamino) -3, 3-dimethylbutanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide. The yield was 69%. ¹H NMR(500MHz,CD₃OD)δ8.91(s,1H),8.73(t,J＝8.2Hz,1H),8.13(s,2H),7.91(s,1H),7.77(s,1H),7.52(d,J＝8.2Hz,2H),7.45(d,J＝8.2Hz,2H),7.43–7.38(m,1H),7.35(d,J＝8.7Hz,1H),5.12–4.98(m,1H),4.61–4.54(m,1H),4.52–4.42(m,2H),3.97(dd,J＝10.7,4.9Hz,1H),3.84–3.51(m,9H),2.50(s,3H),2.48–2.39(m,2H),2.34–2.27(m,1H),2.27–2.17(m,2H),2.16–2.04(m,2H),1.70–1.51(m,4H),1.47(d,J＝7.0Hz,3H),1.31(d,J＝23.5Hz,14H),1.13–1.01(m,11H),0.95(dt,J＝6.8,3.9Hz,2H)。HRMS(ESI-TOF)m/z：C₅₈H₇₄FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1085.5554, respectively; the following are found: 1085.5561.

example 46: (2S,4R) -1- ((S) -2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4-oxobutanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 63%.¹H NMR(500MHz,CD₃OD)δ9.03(s,1H),8.59(t,J＝8.1Hz,1H),8.17(s,2H),8.03–7.95(m,2H),7.57–7.35(m,6H),4.62(s,1H),4.61–4.49(m,3H),4.39(d,J＝15.5Hz,1H),3.91(d,J＝10.9Hz,1H),3.82(dd,J＝10.9,3.7Hz,1H),3.68(s,8H),2.81–2.56(m,4H),2.50(s,3H),2.31–2.20(m,1H),2.20–2.06(m,2H),1.06(s,11H),1.02–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₄₉H₅₆FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 959.4145, respectively; the following are found: 959.4130.

example 47: (2S,4R) -1- ((S) -2- (5- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -5-oxopentanoylamino) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 69%.¹H NMR(500MHz,CD₃OD)δ8.97(s,1H),8.63(s,1H),8.16(s,2H),7.99(s,1H),7.93(s,1H),7.52–7.33(m,6H),4.64(s,1H),4.63–4.47(m,3H),4.37(d,J＝15.5Hz,1H),4.03–3.89(m,1H),3.82(d,J＝8.3Hz,2H),3.80–3.54(m,8H),2.55–2.42(m,5H),2.37(t,J＝7.0Hz,2H),2.30–2.18(m,1H),2.19–2.07(m,2H),2.00–1.89(m,2H),1.13–1.03(m,11H),1.03–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₀H₅₈FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 973.4302, respectively; the following are found: 973.4335.

example 48: (2S,4R) -1- ((S) -2- (6- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -6-oxohexanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 68%.¹H NMR(500MHz,CD₃OD)δ8.98(s,1H),8.64(t,J＝8.1Hz,1H),8.17(s,2H),8.00(s,1H),7.93(s,1H),7.53–7.34(m,6H),4.66(s,1H),4.62–4.49(m,3H),4.38(d,J＝15.5Hz,1H),3.93(d,J＝11.2Hz,1H),3.87–3.80(m,1H),3.78–3.54(m,8H),2.56–2.41(m,5H),2.41–2.29(m,2H),2.28–2.20(m,1H),2.19–2.07(m,2H),1.80–1.54(m,4H),1.12–1.02(m,11H),1.02–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₁H₆₀FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 987.4458, respectively; the following are found: 987.4440.

example 49: (2S,4R) -1- ((S) -2- (7- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -7-oxoheptanoylamino) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 61%.¹H NMR(500MHz,CD₃OD)δ9.98–9.35(m,1H),9.00(s,1H),8.61(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.94(s,1H),7.42(td,J＝26.5,8.6Hz,6H),4.66(s,1H),4.63–4.48(m,3H),4.37(d,J＝15.5Hz,1H),3.93(d,J＝11.0Hz,1H),3.82(dd,J＝10.9,3.7Hz,1H),3.79–3.50(m,8H),2.59–2.39(m,5H),2.39–2.19(m,3H),2.13(ddd,J＝13.4,8.2,3.7Hz,2H),1.66(d,J＝6.6Hz,4H),1.52–1.32(m,2H),1.12–1.02(m,11H),1.02–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₅₂H₆₂FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1001.4615, respectively; the following are found: 1001.4601.

example 50: (2S,4R) -1- ((S) -2- (8- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -8-oxooctanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 55%.¹H NMR(500MHz,CD₃OD)δ9.01(s,1H),8.61(t,J＝8.2Hz,1H),8.17(s,2H),7.99(s,1H),7.95(s,1H),7.55–7.33(m,6H),4.66(s,1H),4.56(dt,J＝23.6,8.2Hz,3H),4.38(d,J＝15.5Hz,1H),3.93(d,J＝11.0Hz,1H),3.82(dd,J＝10.9,3.7Hz,1H),3.78–3.53(m,8H),2.50(s,3H),2.49–2.41(m,2H),2.38–2.20(m,3H),2.20–2.06(m,2H),1.70–1.55(m,4H),1.40(d,J＝3.4Hz,4H),1.10–1.02(m,11H),1.02–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₅₃H₆₄FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1015.4771, respectively; the following are found: 1015.4788.

example 51: (2S,4R) -1- ((S) -2- (9- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -9-oxononanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 59%.¹H NMR(500MHz,CD₃OD)δ8.93(s,1H),8.69(t,J＝8.2Hz,1H),8.14(s,2H),7.94(s,1H),7.84(s,1H),7.53–7.33(m,6H),4.70–4.48(m,4H),4.38(d,J＝15.5Hz,1H),3.93(d,J＝11.0Hz,1H),3.82(dd,J＝10.9,3.8Hz,1H),3.79–3.51(m,8H),2.52–2.41(m,5H),2.36–2.27(m,2H),2.27–2.18(m,1H),2.15–2.08(m,2H),1.71–1.58(m,4H),1.47–1.30(m,6H),1.14–0.91(m,13H)。HRMS(ESI-TOF)m/z：C₅₄H₆₆FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1029.4928, respectively; the following are found: 1029.4943.

example 52: (2S,4R) -1- ((S) -2- (3- (3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropoxy) propionylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 66%. ¹H NMR(500MHz,CD₃OD)δ8.94(s,1H),8.62(t,J＝8.2Hz,1H),8.17(s,2H),7.98(s,1H),7.92(s,1H),7.48–7.31(m,6H),4.70(s,1H),4.65–4.42(m,3H),4.36(d,J＝15.3Hz,1H),3.91(d,J＝10.5Hz,1H),3.86–3.54(m,13H),2.83–2.66(m,2H),2.59–2.49(m,2H),2.46(s,3H),2.31–2.20(m,1H),2.12(ddd,J＝19.8,10.8,6.1Hz,2H),1.13–0.91(m,13H)。HRMS(ESI-TOF)m/z：C₅₁H₆₀FN₁₂O₇S⁺Of [ M + H]⁺Calculated values: 1003.4407, respectively; the following are found: 1003.4427.

example 53: (2S,4R) -1- ((S) -2- (3- (2- (3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) propionylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 64%.¹H NMR(500MHz,CD₃OD)δ9.01(s,1H),8.59(t,J＝8.2Hz,1H),8.17(s,2H),8.00(s,1H),7.98(s,1H),7.51–7.33(m,6H),4.68(s,1H),4.63–4.48(m,3H),4.37(d,J＝15.5Hz,1H),3.90(d,J＝10.9Hz,1H),3.84–3.56(m,17H),2.79–2.69(m,2H),2.62–2.42(m,5H),2.29–2.19(m,1H),2.20–2.05(m,2H),1.12–0.94(m,15H)。HRMS(ESI-TOF)m/z：C₅₃H₆₄FN₁₂O₈S⁺Of [ M + H]⁺Calculated values: 1047.4669, respectively; the following are found: 1047.4671.

example 54: (2S,4R) -1- ((S) -2- (tert-butyl) -16- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 16-dioxo-7, 10, 13-trioxa-3-azahexadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 56%.¹H NMR(500MHz,CD₃OD)δ9.04(s,1H),8.57(t,J＝5.9Hz,1H),8.18(s,2H),8.02(s,1H),8.00(s,1H),7.52–7.30(m,6H),4.67(s,1H),4.64–4.48(m,3H),4.37(d,J＝15.5Hz,1H),3.91(d,J＝11.0Hz,1H),3.88–3.46(m,21H),2.71(s,2H),2.65–2.44(m,5H),2.30–2.20(m,1H),2.20–2.04(m,2H),1.13–0.93(m,13H)。HRMS(ESI-TOF)m/z：C₅₅H₆₈FN₁₂O₉S⁺Of [ M + H]⁺Calculated values: 1091.4931, respectively; the following are found: 1091.4933.

example 55: (2S,4R) -1- ((S) -2- (tert-butyl) -19- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 19-dioxo-7, 10,13, 16-tetraoxa-3-azanonadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 63%. ¹H NMR(500MHz,CD₃OD)δ9.03(s,1H),8.59(t,J＝8.1Hz,1H),8.18(s,2H),8.02(s,1H),7.99(s,1H),7.59–7.34(m,6H),4.66(s,1H),4.63–4.49(m,3H),4.37(d,J＝15.5Hz,1H),3.90(d,J＝11.0Hz,1H),3.87–3.49(m,25H),2.70(d,J＝19.9Hz,2H),2.67–2.42(m,5H),2.23(dd,J＝13.0,7.6Hz,1H),2.20–2.04(m,2H),1.15–0.90(m,13H)。HRMS(ESI-TOF)m/z：C₅₇H₇₂FN₁₂O₁₀S⁺Of [ M + H]⁺Calculated values: 1135.5194, respectively; the following are found: 1135.5208.

example 56: (2S,4R) -1- ((S) -2- (tert-butyl) -22- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 22-dioxo-7, 10,13,16, 19-pentaoxa-3-azadocosanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 51%.¹H NMR(500MHz,CD₃OD)δ8.95(s,1H),8.66(t,J＝8.2Hz,1H),8.15(s,2H),7.96(s,1H),7.88(s,1H),7.52–7.34(m,6H),4.66(s,1H),4.63–4.49(m,3H),4.36(d,J＝15.5Hz,1H),3.90(d,J＝10.9Hz,1H),3.85–3.50(m,29H),2.72(s,2H),2.63–2.54(m,1H),2.53–2.43(m,4H),2.30–2.18(m,1H),2.11(m,2H),1.13–0.93(m,13H)。HRMS(ESI-TOF)m/z：C₅₉H₇₆FN₁₂O₁₁S⁺Of [ M + H]⁺Calculated values: 1179.5456, respectively; the following are found: 1179.5440.

example 57: 4- ((2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2-oxoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 70%.¹H NMR (500MHz, acetone) δ 8.81(t, J ═ 8.4Hz,1H),8.21(s,2H), 8.07-7.97 (m,1H),7.79(d, J ═ 8.8Hz,1H), 7.67-7.59 (m,1H), 7.50-7.40 (m,2H),7.11(d, J ═ 7.3Hz,2H),5.12(dd, J ═ 12.6,5.4Hz,1H),4.35(s,2H),3.80(s,8H), 3.06-2.93 (m,1H), 2.88-2.76 (m,2H), 2.28-2.20 (m,1H), 2.19-2.14 (m,2H), 1.13-1.05 (m,2H), 1.00-2H (m, 0.00-2H). HRMS (ESI-TOF) m/z: c₃₈H₃₅FN₁₁O₆S⁺Of [ M + H]⁺Calculated values: 760.2750, respectively; hair-like deviceNow: 760.2755.

example 58: 4- ((3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 72%.¹H NMR (500MHz, acetone) δ 8.67-8.57 (m,1H),8.09(s,1H), 7.94-7.86 (m,2H),7.70(d, J ═ 3.8Hz,1H),7.50(dd, J ═ 8.4,7.2Hz,1H), 7.34-7.25 (m,2H),7.07(d, J ═ 8.6Hz,1H),6.96(d, J ═ 7.0Hz,1H),4.97(dd, J ═ 12.7,5.5Hz,1H), 3.67-3.52 (m,10H), 2.90-2.79 (m,1H),2.75(s,2H), 2.72-2.61 (m,2H), 2.16-2.06 (m,1H), 2.01-2.88 (m,1H), 2.01-0.78 (m, 0H), 0.0.0.0.0 (m, 1H). HRMS (ESI-TOF) m/z: c₃₉H₃₇FN₁₁O₆S⁺Of [ M + H]⁺Calculated values: 774.2907, respectively; the following are found: 774.2901.

example 59: 4- ((4- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4-oxobutyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 60%.¹H NMR(500MHz,CD₃OD)δ8.73(t,J＝8.1Hz,1H),8.01(s,2H),7.80(s,1H),7.72(s,1H),7.59–7.50(m,1H),7.33(t,J＝4.9Hz,2H),7.12–7.00(m,2H),4.99(dd,J＝12.0,5.5Hz,1H),3.65(d,J＝30.6Hz,8H),3.42(t,J＝6.7Hz,2H),2.87–2.70(m,3H),2.60–2.51(m,2H),2.16–2.08(m,1H),2.08–1.97(m,3H),1.10–1.01(m,2H),1.01–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₄₀H₃₉FN₁₁O₆S⁺Of [ M + H]⁺Calculated values: 788.3063, respectively; the following are found: 788.3089.

example 60: 4- ((5- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -5-oxopentyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 69%. ¹H NMR(500MHz,CD₃OD)δ8.77(t,J＝8.3Hz,1H),7.96(s,2H),7.74(s,1H),7.64(s,1H),7.55–7.47(m,1H),7.31(t,J＝8.3Hz,2H),7.07(d,J＝7.1Hz,1H),6.98(d,J＝8.6Hz,1H),4.96(dd,J＝11.0,6.5Hz,1H),3.77–3.50(m,8H),3.39–3.34(m,2H),2.85–2.70(m,3H),2.53–2.42(m,2H),2.18–2.04(m,1H),2.05–1.92(m,1H),1.85–1.67(m,4H),1.10–1.03(m,2H),1.00–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₁H₄₁FN₁₁O₆S⁺Of [ M + H]⁺Calculated values: 802.3220, respectively; the following are found: 802.3249.

example 61: 4- ((6- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -6-oxohexyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 65%.¹H NMR(500MHz,CD₃OD)δ8.71(t,J＝8.2Hz,1H),8.00(s,2H),7.78(s,1H),7.71(s,1H),7.56–7.49(m,1H),7.32(t,J＝9.6Hz,2H),7.05(d,J＝7.1Hz,1H),6.97(d,J＝8.6Hz,1H),4.97(dd,J＝12.0,5.5Hz,1H),3.78–3.55(m,8H),3.34–3.29(m,2H),2.85–2.69(m,3H),2.51–2.40(m,2H),2.18–2.07(m,1H),2.06–1.97(m,1H),1.77–1.64(m,4H),1.55–1.44(m,2H),1.08–1.02(m,2H),0.99–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₄₂H₄₃FN₁₁O₆S⁺Of [ M + H]⁺Calculated values: 816.3375, respectively; the following are found: 816.3390.

example 62: 4- ((7- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -7-oxoheptyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 68%.¹H NMR(500MHz,CD₃OD)δ8.67(t,J＝8.1Hz,1H),8.06(s,2H),7.86(s,1H),7.81(s,1H),7.56–7.48(m,1H),7.39–7.29(m,2H),7.04(d,J＝7.0Hz,1H),6.99(d,J＝8.5Hz,1H),5.01(dd,J＝12.3,5.4Hz,1H),3.85–3.44(m,8H),2.85–2.68(m,3H),2.44(s,2H),2.17–2.01(m,2H),1.75–1.61(m,4H),1.54–1.39(m,4H),1.10–1.01(m,2H),1.00–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₄₃H₄₅FN₁₁O₆S⁺Of [ M + H]⁺Calculated values: 830.3533, respectively; the following are found: 830.3549.

example 65: 4- ((8- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -8-oxooctyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 62%.¹H NMR(500MHz,CD₃OD)δ8.75(t,J＝8.3Hz,1H),8.01(s,2H),7.79(s,1H),7.69(s,1H),7.56–7.44(m,1H),7.40–7.25(m,2H),7.09–7.00(m,1H),6.97(d,J＝8.6Hz,1H),4.99(dd,J＝12.2,5.3Hz,1H),3.82–3.49(m,8H),3.31–3.27(m,2H),2.86–2.69(m,3H),2.46–2.36(m,2H),2.19–2.08(m,1H),2.06–1.98(m,1H),1.78–1.53(m,4H),1.52–1.33(m,6H),1.10–1.00(m,2H),1.00–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₄₄H₄₇FN₁₁O₆S⁺Of [ M + H]⁺Calculated values: 844.3689, respectively; the following are found: 844.3671.

example 66: 4- ((2- (3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropanOxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 69%. ¹H NMR(500MHz,CD₃OD)δ8.71(t,J＝7.6Hz,1H),7.98(s,2H),7.76(s,1H),7.67(s,1H),7.58–7.48(m,1H),7.35–7.17(m,2H),7.07(d,J＝7.0Hz,1H),6.99(d,J＝8.5Hz,1H),4.96(dd,J＝11.9,5.2Hz,1H),3.83(t,J＝5.8Hz,2H),3.80–3.54(m,10H),3.48(t,J＝4.9Hz,2H),2.85–2.65(m,5H),2.14–2.05(m,1H),2.05–1.95(m,1H),1.09–1.01(m,2H),0.99–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₁H₄₁FN₁₁O₇S⁺Of [ M + H]⁺Calculated values: 818.3169, respectively; the following are found: 818.3178.

example 67: 4- ((2- (2- (3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl)) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 65%.¹H NMR(500MHz,CD₃OD)δ8.69(t,J＝8.3Hz,1H),8.00(s,2H),7.77(s,1H),7.70(s,1H),7.55–7.37(m,1H),7.28(t,J＝8.3Hz,2H),7.10–6.84(m,2H),4.96(dd,J＝12.2,5.4Hz,1H),3.79(t,J＝6.0Hz,2H),3.77–3.51(m,14H),3.51–3.40(m,2H),2.85–2.60(m,5H),2.16–2.06(m,1H),2.06–1.96(m,1H),1.09–1.00(m,2H),0.99–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₃H₄₅FN₁₁O₈S⁺Of [ M + H]⁺Calculated values: 862.3431, respectively; the following are found: 862.3453.

example 68: 4- ((2- (2- (2- (3- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl)) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -3-oxopropoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 60%.¹H NMR(500MHz,CD₃OD)δ8.66(t,J＝8.2Hz,1H),8.01(s,2H),7.79(s,1H),7.74(s,1H),7.53–7.45(m,1H),7.31(t,J＝10.1Hz,2H),6.99(dd,J＝21.6,6.9Hz,2H),4.97(dd,J＝12.3,5.5Hz,1H),3.78(t,J＝6.1Hz,2H),3.75–3.54(m,18H),3.51–3.42(m,2H),2.86–2.58(m,5H),2.17–2.07(m,1H),2.07–1.97(m,1H),1.07–1.01(m,2H),0.98–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₅H₄₉FN₁₁O₉S⁺Of [ M + H]⁺Calculated values: 906.3693, respectively; the following are found: 906.3688.

example 69: 4- ((15- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -15-oxo-3, 6,9, 12-tetraoxapentadecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 59%.¹H NMR(500MHz,CD₃OD)δ8.65(t,J＝8.1Hz,1H),8.03(s,2H),7.82(s,1H),7.77(s,1H),7.54–7.42(m,1H),7.34(t,J＝5.0Hz,2H),7.00(dd,J＝17.7,7.8Hz,2H),4.98(dd,J＝12.4,5.4Hz,1H),3.78(t,J＝6.1Hz,2H),3.76–3.54(m,22H),3.51–3.42(m,2H),2.88–2.59(m,5H),2.16–2.07(m,1H),2.08–2.00(m,1H),1.08–1.01(m,2H),1.01–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₄₇H₅₃FN₁₁O₁₀S⁺Of [ M + H]⁺Calculated values: 950.3955, respectively; the following are found: 950.3944.

example 70: 4- ((18- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -18-oxo-3, 6,9,12, 15-pentaoxaoctadecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione. The yield was 63%.¹H NMR(500MHz,CD₃OD)δ8.66(t,J＝8.3Hz,1H),7.99(s,2H),7.77(s,1H),7.73(s,1H),7.54–7.45(m,1H),7.42–7.23(m,2H),7.04(d,J＝7.1Hz,1H),6.97(d,J＝8.6Hz,1H),4.96(dd,J＝11.9,5.6Hz,1H),3.88–3.52(m,30H),3.52–3.44(m,2H),2.90–2.61(m,5H),2.12(dd,J＝8.9,5.2Hz,1H),2.07–1.95(m,1H),1.11–1.00(m,2H),1.00–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₉H₅₇FN₁₁O₁₁S⁺Of [ M + H]⁺Calculated values: 994.4218, respectively; the following are found: 994.4230.

example 71: (2S,4R) -1- ((S) -2- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2-oxoethoxy) ethoxy) acetylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 60%.¹H NMR(500MHz,CD₃OD)δ8.98(s,1H),8.60(t,J＝8.2Hz,1H),8.16(s,2H),7.97(s,1H),7.92(s,1H),7.53–7.20(m,6H),4.71(s,1H),4.64–4.35(m,6H),4.20(d,J＝15.1Hz,1H),4.11(d,J＝15.1Hz,1H),3.91(d,J＝10.9Hz,1H),3.83(dd,J＝11.0,3.7Hz,1H),3.80–3.50(m,8H),2.49(s,3H),2.29–2.21(m,1H),2.18–2.07(m,2H),1.08(s,9H),1.06–1.01(m,2H),1.01–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₄₉H₅₆FN₁₂O₇S⁺Of [ M + H]⁺Calculated values: 975.4094, respectively; the following are found: 975.4086.

example 72: (2S,4R) -1- ((S) -2- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2-oxoethoxy) ethoxy) acetylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 66%.¹H NMR(500MHz,CD₃OD)δ8.98(s,1H),8.59(t,J＝8.2Hz,1H),8.16(s,2H),7.98(s,1H),7.94(s,1H),7.40(ddd,J＝37.7,18.3,8.2Hz,6H),4.73(s,1H),4.65–4.42(m,3H),4.41–4.30(m,3H),4.13–4.03(m,2H),3.93–3.49(m,14H),2.48(s,3H),2.30–2.19(m,1H),2.19–2.05(m,2H),1.15–0.91(m,13H)。HRMS(ESI-TOF)m/z：C₅₁H₆₀FN₁₂O₈S⁺Of [ M + H]⁺Calculated values: 1019.4356, respectively; the following are found: 1019.4377.

example 73: (2S,4R) -1- ((S) -2- (tert-butyl) -14- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 14-dioxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 67%.¹H NMR(500MHz,CD₃OD)δ9.03(s,1H),8.58(t,J＝8.2Hz,1H),8.17(s,2H),8.01(s,1H),7.98(s,1H),7.55–7.23(m,6H),4.72(s,1H),4.65–4.48(m,3H),4.42–4.23(m,3H),4.11–3.95(m,2H),3.92–3.49(m,18H),2.50(s,3H),2.30–2.20(m,1H),2.20–2.05(m,2H),1.12–0.94(m,13H)。HRMS(ESI-TOF)m/z：C₅₃H₆₄FN₁₂O₉S⁺Of [ M + H]⁺Calculated values: 1063.4618, respectively; the following are found: 1063.4632.

example 74: (2S,4R) -1- ((S) -2- (tert-butyl) -20- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 20-dioxo-6, 9,12,15, 18-pentaoxa-3-azaeicosanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 56%.¹H NMR(500MHz,CD₃OD)δ9.11(s,1H),8.55(t,J＝8.0Hz,1H),8.18(s,2H),8.03(s,2H),7.56–7.32(m,6H),4.71(s,1H),4.64–4.49(m,3H),4.37(d,J＝15.6Hz,1H),4.31(s,2H),4.07(d,J＝4.1Hz,2H),3.94–3.48(m,26H),2.51(s,3H),2.29–2.20(m,1H),2.20–2.06(m,2H),1.13–0.93(m,13H)。HRMS(ESI-TOF)m/z：C₅₇H₇₂FN₁₂O₁₁S⁺Of [ M + H]⁺Calculated values: 1151.5143, respectively; the following are found: 1151.5117.

scheme 27 Synthesis of example 31

Example 31: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N⁷- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) pimelinamide. A solution of intermediate 8 in DCM/TFA (2:1, 1mL) was stirred at room temperature. After 2h, the solvent was removed under reduced pressure to give intermediate 9 as a brown oil. To a solution of intermediate 9(5mg, 0.009mmol) and linker 8(5mg, 0.008mmol) in DMF (0.5mL) was added DIEA (17. mu.L, 0.1mmol) and TBTU (4mg, 0.01 mmol). After stirring at room temperature for 12h, the mixture was purified by HPLC to give the title compound as a brown oil (7mg, 75%). ¹H NMR(600MHz,CD₃OD)δ8.98–8.91(m,1H),8.74(t,J＝8.2Hz,1H),8.15(s,2H),7.98(s,1H),7.86(s,1H),7.52–7.37(m,6H),4.66(s,1H),4.64–4.50(m,3H),4.38(d,J＝15.4Hz,1H),3.92(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.8Hz,1H),3.77–3.34(m,12H),2.50(s,3H),2.42–2.21(m,5H),2.21–2.05(m,2H),1.71–1.58(m,4H),1.43–1.33(m,2H),1.12–0.86(m,13H)。HRMS(ESI-TOF)m/z：C₅₄H₆₇FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1044.5037, respectively; the following are found: 1044.5060.

example compounds 75-101 were synthesized according to the procedure used to prepare example compound 28.

Example 75: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N⁴- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) succinamide. The yield was 70%.¹H NMR(500MHz,CD₃OD)δ8.98(s,1H),8.68(t,J＝8.2Hz,1H),8.15(s,2H),7.98(s,1H),7.90(s,1H),7.53–7.36(m,6H),4.63–4.49(m,4H),4.38(d,J＝15.5Hz,1H),3.87–3.77(m,2H),3.77–3.42(m,10H),3.38(t,J＝4.8Hz,2H),2.72–2.66(m,2H),2.53–2.46(m,5H),2.30–2.21(m,1H),2.17–2.06(m,2H),1.13–1.00(m,11H),1.00–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₅₁H₆₁FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1002.4567, respectively; the following are found: 1002.4587.

example 76: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N⁵- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) glutaramide. The yield was 73%.¹H NMR(500MHz,CD₃OD)δ8.96(s,1H),8.69(t,J＝8.2Hz,1H),8.15(s,2H),7.97(s,1H),7.87(s,1H),7.55–7.34(m,6H),4.63(s,1H),4.62–4.50(m,3H),4.39(d,J＝15.5Hz,1H),3.94(d,J＝11.0Hz,1H),3.83(dd,J＝11.0,3.8Hz,1H),3.71–3.41(m,10H),3.37(t,J＝5.8Hz,2H),2.48(s,3H),2.43–2.22(m,5H),2.17–2.08(m,2H),2.00–1.91(m,2H),1.10–1.02(m,11H),1.00–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₅₂H₆₃FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1016.4724, respectively; the following are found: 1016.4739.

example 77: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N⁶- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) adipamide. The yield was 55%. ¹H NMR(500MHz,CD₃OD)δ8.97(s,1H),8.70(t,J＝8.2Hz,1H),8.15(s,2H),7.97(s,1H),7.88(s,1H),7.53–7.29(m,6H),4.64(s,1H),4.63–4.49(m,3H),4.39(d,J＝15.4Hz,1H),3.92(d,J＝11.1Hz,1H),3.83(dd,J＝11.0,3.8Hz,1H),3.72–3.40(m,10H),3.37(t,J＝5.9Hz,2H),2.49(s,3H),2.38–2.19(m,5H),2.18–2.06(m,2H),1.74–1.57(m,4H),1.11–1.01(m,11H),1.01–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₅₃H₆₅FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1030.4880, respectively; the following are found: 1030.4897.

example 78: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N⁸- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) octanediamide. The yield was 73%.¹H NMR(500MHz,CD₃OD)δ8.99(s,1H),8.69(t,J＝8.2Hz,1H),8.15(s,2H),7.98(s,1H),7.90(s,1H),7.59–7.25(m,6H),4.65(s,1H),4.63–4.49(m,3H),4.38(d,J＝15.5Hz,1H),3.92(d,J＝11.0Hz,1H),3.83(dd,J＝10.9,3.8Hz,1H),3.71–3.40(m,10H),3.39–3.35(m,2H),2.49(s,3H),2.38–2.19(m,5H),2.19–2.05(m,2H),1.76–1.56(m,4H),1.47–1.31(m,4H),1.11–1.01(m,11H),1.01–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1058.5193, respectively; the following are found: 1058.5177.

example 79: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N⁹- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) nonanediamide. The yield was 69%.¹H NMR(500MHz,CD₃OD)δ8.95(s,1H),8.73(t,J＝8.2Hz,1H),8.14(s,2H),7.96(s,1H),7.84(s,1H),7.53–7.33(m,6H),4.65(s,1H),4.62–4.49(m,3H),4.38(d,J＝15.5Hz,1H),3.92(d,J＝11.1Hz,1H),3.82(dd,J＝10.9,3.9Hz,1H),3.73–3.40(m,10H),3.37–3.35(m,2H),2.49(s,3H),2.35–2.18(m,5H),2.16–2.05(m,2H),1.69–1.55(m,4H),1.36(s,6H),1.12–1.00(m,11H),1.00–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₅₆H₇₁FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1072.5350, respectively; the following are found: 1072.5371.

example 80: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N¹⁰- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) sebacamide. The yield was 63%. ¹H NMR(500MHz,CD₃OD)δ9.01(s,1H),8.68(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.91(s,1H),7.61–7.30(m,6H),4.66(s,1H),4.62–4.49(m,3H),4.38(d,J＝15.5Hz,1H),3.92(d,J＝11.0Hz,1H),3.82(dd,J＝10.9,3.8Hz,1H),3.68–3.39(m,10H),3.39–3.35(m,2H),2.50(s,3H),2.37–2.19(m,5H),2.19–2.06(m,2H),1.71–1.54(m,4H),1.42–1.27(m,8H),1.11–1.02(m,11H),1.02–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₅₇H₇₃FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1086.5506, respectively; the following are found: 1086.5519.

example 81: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N¹¹- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) undecanediamide. The yield was 67%.¹H NMR(500MHz,CD₃OD)δ9.00(s,1H),8.69(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.90(s,1H),7.53–7.31(m,6H),4.65(s,1H),4.61–4.50(m,3H),4.38(d,J＝15.5Hz,1H),3.92(d,J＝11.0Hz,1H),3.82(dd,J＝10.9,3.9Hz,1H),3.69–3.39(m,10H),3.38–3.34(m,2H),2.50(s,3H),2.36–2.19(m,5H),2.19–2.06(m,2H),1.73–1.54(m,4H),1.44–1.24(m,10H),1.11–0.95(m,13H)。HRMS(ESI-TOF)m/z：C₅₈H₇₅FN₁₃O₆S⁺Of [ M + H]⁺Calculated values: 1100.5663, respectively; the following are found: 1100.5655.

example 82: (2S,4R) -1- ((S) -2- (2- ((2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) amino) -2-oxoethoxy) acetylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 66%.¹H NMR(500MHz,CD₃OD)δ8.98(s,1H),8.66(t,J＝8.2Hz,1H),8.15(s,2H),7.98(s,1H),7.91(s,1H),7.56–7.32(m,6H),4.73(s,1H),4.63–4.44(m,3H),4.39(d,J＝15.5Hz,1H),4.25–4.09(m,4H),3.92(d,J＝11.0Hz,1H),3.84(dd,J＝11.0,3.7Hz,1H),3.76–3.37(m,12H),2.48(s,3H),2.31–2.23(m,1H),2.18–2.05(m,2H),1.11–1.02(m,11H),1.01–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₅₁H₆₁FN₁₃O₇S⁺Of [ M + H]⁺Calculated values: 1018.4516, respectively; the following are found: 1018.4516.

example 83: (2S,4R) -1- ((S) -2- (3- ((2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) amino) -3-oxopropoxy) propionylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 68%. ¹H NMR(500MHz,CD₃OD)δ8.98(s,1H),8.66(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.92(s,1H),7.53–7.34(m,6H),4.66(s,1H),4.63–4.48(m,3H),4.40(d,J＝15.4Hz,1H),3.91(d,J＝11.1Hz,1H),3.83(dd,J＝11.0,3.8Hz,1H),3.74(dd,J＝13.5,5.9Hz,4H),3.69–3.35(m,12H),2.61–2.50(m,4H),2.48(s,3H),2.31–2.20(m,1H),2.18–2.06(m,2H),1.10–1.01(m,11H),1.01–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₃H₆₅FN₁₃O₇S⁺Of [ M + H]⁺Calculated values: 1046.4829, respectively; the following are found: 1046.4813.

example 84: (2S,4R) -1- ((S) -2- (tert-butyl) -14- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 11-dioxo-6, 9-dioxa-3, 12-diazadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 61%.¹H NMR(500MHz,CD₃OD)δ8.98(s,1H),8.67(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.91(s,1H),7.52–7.33(m,6H),4.72(s,1H),4.61–4.55(m,1H),4.55–4.51(m,1H),4.46(s,2H),4.16(d,J＝15.6Hz,1H),4.12–4.05(m,3H),3.91(d,J＝11.1Hz,1H),3.84(dd,J＝11.1,3.6Hz,1H),3.82–3.72(m,14H),3.69(t,J＝5.6Hz,2H),3.40(dd,J＝11.0,5.3Hz,2H),2.49(s,3H),2.34–2.24(m,1H),2.21–2.03(m,2H),1.13–1.01(m,13H),1.01–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₃H₆₅FN₁₃O₈S⁺Of [ M + H]⁺Calculated values: 1062.4778, respectively; the following are found: 1062.4753.

example 85: (2S,4R) -1- ((S) -2- (tert-butyl) -16- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 13-dioxo-7, 10-dioxa-3, 14-diazahexadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 61%.¹H NMR(500MHz,CD₃OD)δ8.99(s,1H),8.66(t,J＝8.2Hz,1H),8.16(s,2H),7.98(s,1H),7.91(s,1H),7.57–7.34(m,6H),4.67(s,1H),4.63–4.49(m,3H),4.39(d,J＝15.5Hz,1H),3.91(d,J＝10.1Hz,1H),3.88–3.70(m,7H),3.70–3.42(m,12H),3.42–3.36(m,2H),2.65–2.44(m,7H),2.30–2.20(m,1H),2.20–2.06(m,2H),1.13–0.90(m,13H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₈S⁺Of [ M + H]⁺Calculated values: 1090.5091, respectively; the following are found: 1090.5083.

example 86: (2S,4R) -1- ((S) -2- (tert-butyl) -17- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 14-dioxo-6, 9, 12-trioxa-3, 15-diazaheptanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 67%. ¹H NMR(500MHz,CD₃OD)δ8.99(s,1H),8.66(t,J＝8.2Hz,1H),8.16(s,2H),7.99(s,1H),7.92(s,1H),7.54–7.38(m,6H),4.69(s,1H),4.61–4.50(m,3H),4.39(d,J＝15.5Hz,1H),4.18–4.10(m,2H),4.09–3.99(m,2H),3.90(d,J＝11.0Hz,1H),3.86–3.80(m,1H),3.80–3.44(m,18H),3.40(t,J＝5.6Hz,2H),2.49(s,3H),2.26(dd,J＝13.1,7.6Hz,1H),2.19–2.04(m,2H),1.18–1.00(m,11H),1.01–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₉FN₁₃O₉S⁺Of [ M + H]⁺Calculated values: 1106.5040, respectively; the following are found: 1106.5071.

example 87: (2S,4R) -1- ((S) -2- (tert-butyl) -19- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4, 16-dioxo-7, 10, 13-trioxa-3, 17-diaza-nonadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 64%.¹H NMR(500MHz,CD₃OD)δ9.07(s,1H),8.61(t,J＝8.2Hz,1H),8.18(s,2H),8.03(s,1H),8.00(s,1H),7.54–7.28(m,6H),4.66(s,1H),4.63–4.49(m,3H),4.39(d,J＝15.5Hz,1H),3.91(d,J＝11.0Hz,1H),3.82(dd,J＝11.0,3.8Hz,1H),3.80–3.70(m,6H),3.70–3.42(m,16H),3.41–3.36(m,2H),2.65–2.44(m,7H),2.29–2.21(m,1H),2.20–2.06(m,2H),1.10–1.02(m,11H),1.02–0.96(m,1H)。HRMS(ESI-TOF)m/z：C₅₇H₇₃FN₁₃O₉S⁺Of [ M + H]⁺Calculated values: 1134.5353, respectively; the following are found: 1134.5370.

example 88: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N¹⁶- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -4,7,10, 13-tetraoxahexadecanediamide. The yield was 60%.¹H NMR(500MHz,CD₃OD)δ9.03(s,1H),8.65(t,J＝8.2Hz,1H),8.17(s,2H),8.01(s,1H),7.96(s,1H),7.52–7.39(m,6H),4.66(s,1H),4.62–4.49(m,3H),4.38(d,J＝15.5Hz,1H),3.91(d,J＝11.0Hz,1H),3.82(dd,J＝11.0,3.8Hz,1H),3.80–3.69(m,6H),3.69–3.42(m,20H),3.42–3.36(m,2H),2.65–2.43(m,7H),2.29–2.19(m,1H),2.19–2.06(m,2H),1.11–1.01(m,11H),1.01–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₉H₇₇FN₁₃O₁₀S⁺Of [ M + H]⁺Calculated values: 1178.5616, respectively; the following are found: 1178.5627.

example 89: n is a radical of¹- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -N¹⁹- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -4,7,10,13, 16-pentaoxanonadecanediamide. The yield was 62%. ¹H NMR(500MHz,CD₃OD)δ9.06(s,1H),8.63(t,J＝8.2Hz,1H),8.17(s,2H),8.02(s,1H),7.98(s,1H),7.61–7.34(m,6H),4.66(s,1H),4.62–4.49(m,3H),4.38(d,J＝15.5Hz,1H),3.91(d,J＝10.8Hz,1H),3.85–3.71(m,7H),3.70–3.41(m,24H),3.41–3.37(m,2H),2.63–2.46(m,7H),2.29–2.20(m,1H),2.20–2.07(m,2H),1.14–0.95(m,13H)。HRMS(ESI-TOF)m/z：C₆₁H₈₁FN₁₃O₁₁S⁺Of [ M + H]⁺Calculated values: 1222.5878, respectively; the following are found: 1222.5899.

example 90: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) acetamide. The yield was 70%.¹H NMR(500MHz,CD₃OD)δ8.78(t,J＝8.2Hz,1H),7.98(s,2H),7.77(s,1H),7.67(s,1H),7.55(t,J＝7.5Hz,1H),7.36(m,2H),7.14(d,J＝7.1Hz,1H),6.88(d,J＝8.5Hz,1H),5.00(dd,J＝12.0,5.6Hz,1H),4.14–3.78(m,6H),3.65(t,J＝5.5Hz,2H),3.49–3.35(m,4H),3.32–3.29(m,2H),2.86–2.70(m,3H),2.17–2.08(m,1H),2.06–1.97(m,1H),1.08–1.00(m,2H),0.99–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₀H₄₀FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 803.3172, respectively; the following are found: 803.3178.

example 91: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) acrylamide. The yield was 71%.¹H NMR(500MHz,CD₃OD)δ8.69(t,J＝8.1Hz,1H),7.99(s,2H),7.79(s,1H),7.74(s,1H),7.57–7.50(m,1H),7.41–7.29(m,2H),7.06(dd,J＝17.8,7.8Hz,2H),4.98(dd,J＝12.3,5.6Hz,1H),4.20–3.70(m,4H),3.70–3.54(m,4H),3.53–3.37(m,4H),3.28(t,J＝5.6Hz,2H),2.89–2.67(m,3H),2.64–2.53(m,2H),2.18–2.08(m,1H),2.07–1.97(m,1H),1.08–0.99(m,2H),1.00–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₁H₄₂FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 817.3329, respectively; the following are found: 817.3311.

example 92: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butanamide. The yield was 73%.¹H NMR(500MHz,CD₃OD)δ8.73(t,J＝8.1Hz,1H),7.99(s,2H),7.77(s,1H),7.71(s,1H),7.56–7.47(m,1H),7.35(dd,J＝13.2,10.5Hz,2H),7.05(d,J＝7.1Hz,1H),7.00(d,J＝8.6Hz,1H),4.98(dd,J＝12.2,5.6Hz,1H),4.19–3.62(m,4H),3.56(t,J＝5.6Hz,2H),3.49–3.34(m,4H),3.28(t,J＝5.6Hz,2H),2.85–2.68(m,3H),2.37(t,J＝7.0Hz,2H),2.17–2.08(m,1H),2.07–1.95(m,3H),1.09–1.02(m,2H),0.99–0.91(m,2H)。HRMS(ESI-TOF)m/z：C₄₂H₄₄FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 831.3485, respectively; the following are found: 831.3499.

example 93: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentanamide. The yield was 69%. ¹H NMR(500MHz,CD₃OD)δ8.69(t,J＝8.1Hz,1H),8.00(s,2H),7.79(s,1H),7.75(s,1H),7.54–7.46(m,1H),7.41–7.30(m,2H),7.04(d,J＝7.1Hz,1H),6.96(d,J＝8.6Hz,1H),4.97(dd,J＝12.2,5.7Hz,1H),4.19–3.68(m,4H),3.59(t,J＝5.5Hz,2H),3.52–3.36(m,4H),3.32–3.23(m,2H),2.87–2.68(m,3H),2.30(t,J＝7.1Hz,2H),2.18–2.06(m,1H),2.06–1.97(m,1H),1.72(ddd,J＝20.9,12.7,7.6Hz,4H),1.09–1.01(m,2H),1.01–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₄₃H₄₆FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 845.3642, respectively; the following are found: 845.3655.

example 94: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanamide. The yield was 64%. HRMS (ESI-TOF) m/z: c₄₄H₄₈FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 859.3798, respectively; the following are found: 859.3811.

example 95: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptanamide. The yield was 70%.¹H NMR(500MHz,CD₃OD)δ8.73(t,J＝8.1Hz,1H),7.98(s,2H),7.77(s,1H),7.71(s,1H),7.50(dd,J＝8.5,7.2Hz,1H),7.43–7.30(m,2H),7.04(d,J＝7.1Hz,1H),6.94(d,J＝8.6Hz,1H),4.97(dd,J＝12.1,5.6Hz,1H),4.17–3.69(m,4H),3.59(t,J＝5.7Hz,2H),3.51–3.37(m,4H),3.32–3.26(m,4H),2.90–2.69(m,3H),2.24(t,J＝7.6Hz,2H),2.17–2.09(m,1H),2.05–1.98(m,1H),1.73–1.57(m,4H),1.50–1.33(m,4H),1.08–1.01(m,2H),0.99–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₄₅H₅₀FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 873.3955, respectively; the following are found: 873.3928.

example 96: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octanamide. The yield was 71%.¹H NMR(500MHz,CD₃OD)δ8.67(t,J＝8.1Hz,1H),8.01(s,2H),7.80(s,1H),7.76(s,1H),7.54–7.46(m,1H),7.41–7.31(m,2H),7.04(t,J＝7.9Hz,1H),6.93(d,J＝8.6Hz,1H),4.97(dd,J＝12.1,5.6Hz,1H),4.17–3.66(m,4H),3.59(t,J＝5.6Hz,2H),3.54–3.37(m,4H),3.33–3.21(m,4H),2.86–2.68(m,3H),2.22(t,J＝7.6Hz,2H),2.17–2.07(m,1H),2.08–1.96(m,1H),1.73–1.52(m,4H),1.49–1.29(m,6H),1.09–1.00(m,2H),1.01–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₆H₅₂FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 887.4111, respectively; the following are found: 887.4114.

example 97: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) acrylamide. The yield was 73%. HRMS (ESI-TOF) m/z: c ₄₃H₄₆FN₁₂O₇S⁺Of [ M + H]⁺Calculated values: 861.3591, respectively; the following are found: 861.3588.

example 98: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -3- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) acrylamide. The yield was 70%.¹H NMR(500MHz,CD₃OD)δ8.75(t,J＝8.2Hz,1H),7.98(s,2H),7.76(s,1H),7.67(s,1H),7.54–7.46(m,1H),7.41–7.25(m,2H),7.05(d,J＝7.0Hz,1H),6.98(d,J＝8.6Hz,1H),4.99(dd,J＝12.3,5.6Hz,1H),4.21–3.83(m,4H),3.77(t,J＝5.8Hz,2H),3.72(t,J＝5.1Hz,2H),3.65(s,4H),3.61–3.52(m,2H),3.52–3.36(m,6H),3.31–3.23(m,2H),2.90–2.70(m,3H),2.50(t,J＝5.8Hz,2H),2.18–2.09(m,1H),2.01(ddd,J＝12.9,8.3,4.2Hz,1H),1.06–1.00(m,2H),1.00–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₅H₅₀FN₁₂O₈S⁺Of [ M + H]⁺Calculated values: 905.3853, respectively; the following are found: 905.3829.

example 99: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -3- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoiso-Indolin-4-yl) amino) ethoxy) acrylamide. The yield was 68%.¹H NMR(500MHz,CD₃OD)δ8.72(t,J＝8.1Hz,1H),7.96(s,2H),7.74(s,1H),7.66(d,J＝12.2Hz,1H),7.49(dd,J＝8.4,7.2Hz,1H),7.34(dd,J＝17.0,5.7Hz,2H),7.05(d,J＝7.1Hz,1H),6.97(t,J＝8.8Hz,1H),4.97(dd,J＝12.3,5.6Hz,1H),4.12–3.80(m,4H),3.79–3.69(m,4H),3.69–3.53(m,10H),3.53–3.35(m,6H),3.31–3.27(m,2H),2.85–2.69(m,3H),2.48(t,J＝5.8Hz,2H),2.17–2.09(m,1H),2.02–1.95(m,1H),1.05–0.99(m,2H),0.98–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₄₇H₅₄FN₁₂O₉S⁺Of [ M + H]⁺Calculated values: 949.4115, respectively; the following are found: 949.4133.

example 100: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3,6,9, 12-tetraoxapentadecane-15-amide. The yield was 66%.¹H NMR(500MHz,CD₃OD)δ8.71(t,J＝8.1Hz,1H),7.99(s,2H),7.78(s,1H),7.72(s,1H),7.54–7.44(m,1H),7.36(dd,J＝17.1,5.9Hz,2H),7.04(d,J＝7.1Hz,1H),6.98(d,J＝8.6Hz,1H),4.98(dd,J＝12.4,5.6Hz,1H),4.15–3.80(m,4H),3.80–3.70(m,4H),3.70–3.53(m,14H),3.52–3.36(m,6H),3.32–3.29(m,2H),2.87–2.68(m,3H),2.49(t,J＝5.8Hz,2H),2.19–2.08(m,1H),2.08–1.97(m,1H),1.09–0.99(m,2H),1.00–0.90(m,2H)。HRMS(ESI-TOF)m/z：C₄₉H₅₈FN₁₂O₁₀S⁺Of [ M + H]⁺Calculated values: 993.4377, respectively; the following are found: 993.4369.

example 101: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a) ]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) ethyl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -3,6,9,12, 15-pentaoxaoctadecane-18-amide. The yield was 72%.¹H NMR(500MHz,CD₃OD)δ8.74(t,J＝8.1Hz,1H),7.97(s,2H),7.73(s,1H),7.66(s,1H),7.52–7.47(m,1H),7.39–7.29(m,2H),7.05(d,J＝7.1Hz,1H),6.98(d,J＝8.6Hz,1H),4.96(dd,J＝12.2,5.6Hz,1H),4.13–3.77(m,4H),3.79–3.69(m,4H),3.69–3.54(m,18H),3.52–3.35(m,6H),3.32–3.28(m,2H),2.86–2.68(m,3H),2.49(t,J＝5.8Hz,2H),2.13(dd,J＝9.6,5.9Hz,1H),2.04–1.92(m,1H),1.07–1.00(m,2H),1.00–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₅₁H₆₂FN₁₂O₁₁S⁺Of [ M + H]⁺Calculated values: 1037.4640, respectively; the following are found: 1037.4655.

scheme 28 Synthesis of example 108

Example 108: (2S,4R) -N- ((S) -3- ((2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) ethyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. Example 108 was synthesized according to the procedure used to prepare example 1. The yield was 61%.¹H NMR(500MHz,CD₃OD)δ8.99–8.92(m,1H),8.75–8.65(m,1H),8.16(s,2H),7.97(s,1H),7.91(s,1H),7.55–7.36(m,6H),5.43–5.29(m,1H),4.77–4.66(m,1H),4.64–4.55(m,1H),4.53–4.45(m,1H),4.10–3.91(m,6H),3.87(d,J＝11.2Hz,1H),3.78(dd,J＝11.1,3.5Hz,1H),3.57–3.40(m,6H),3.32–3.26(m,2H),2.88–2.70(m,2H),2.49(s,3H),2.25(dd,J＝13.1,7.6Hz,1H),2.17–2.07(m,1H),1.97(ddd,J＝13.5,9.5,4.4Hz,1H),1.44–1.27(m,4H),1.12(s,3H),1.10–1.02(m,9H),0.99–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₅H₆₅F₂N₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1103.4844; the following are found: 1103.4856.

example compounds 109-129 were synthesized according to the procedure used to prepare example compound 108.

Example 109: (2S,4R) -N- ((S) -3- ((3- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) propyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 68%. ¹H NMR(500MHz,CD₃OD)δ8.96(s,1H),8.75–8.63(m,1H),8.15(s,2H),7.98(s,1H),7.89(s,1H),7.54–7.36(m,6H),5.41–5.29(m,1H),4.75(d,J＝9.1Hz,1H),4.66–4.53(m,1H),4.47(s,1H),4.13–3.89(m,6H),3.85(d,J＝11.2Hz,1H),3.78(dd,J＝11.1,3.6Hz,1H),3.55–3.41(m,4H),3.27–3.09(m,4H),2.93–2.84(m,1H),2.82–2.70(m,1H),2.49(s,3H),2.30–2.17(m,1H),2.17–2.05(m,1H),2.02–1.91(m,1H),1.71–1.55(m,2H),1.45–1.25(m,4H),1.12(s,2H),1.10–1.00(m,9H),0.97(dd,J＝8.1,2.4Hz,2H)。HRMS(ESI-TOF)m/z：C₅₆H₆₇F₂N₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1117.5000, respectively; the following are found: 1117.4977.

example 110: (2S,4R) -N- ((S) -3- ((4- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) butyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 63%.¹H NMR(600MHz,CD₃OD)δ8.99–8.86(m,1H),8.76–8.65(m,1H),8.15(s,2H),8.00–7.93(m,1H),7.85(s,1H),7.52–7.36(m,6H),5.40–5.21(m,1H),4.78–4.71(m,1H),4.66–4.53(m,2H),4.51–4.37(m,1H),4.16–3.87(m,6H),3.85(d,J＝11.3Hz,1H),3.80–3.73(m,1H),3.58–3.37(m,4H),3.29–3.18(m,2H),3.18–3.09(m,2H),2.89–2.66(m,2H),2.49(s,3H),2.28–2.18(m,1H),2.16–2.05(m,1H),2.02–1.90(m,1H),1.55–1.25(m,8H),1.13(s,3H),1.10–1.01(m,8H),0.99–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₇H₆₉F₂N₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1131.5157, respectively; the following are found: 1131.5131.

example 111: (2S,4R) -N- ((S) -3- ((5- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) pentyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 59%.¹H NMR(600MHz,CD₃OD)δ8.92(s,1H),8.72(t,J＝8.3Hz,1H),8.15(s,2H),7.95(s,1H),7.84(s,1H),7.53–7.36(m,6H),5.42–5.23(m,1H),4.75(d,J＝9.2Hz,1H),4.67–4.53(m,2H),4.52–4.42(m,1H),4.17–3.89(m,6H),3.86(d,J＝11.1Hz,1H),3.80–3.73(m,1H),3.58–3.38(m,4H),3.28–3.04(m,4H),2.89–2.66(m,2H),2.48(s,3H),2.28–2.17(m,1H),2.15–2.06(m,1H),2.04–1.91(m,1H),1.57–1.19(m,10H),1.13(s,3H),1.10–1.00(m,8H),1.00–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₈H₇₁F₂N₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1145.5313, respectively; the following are found: 1145.5335.

example 112: (2S,4R) -N- ((S) -3- ((6- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazineOxazin-1-yl) acetylamino) hexyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 70%. ¹H NMR(600MHz,CD₃OD)δ8.93(s,1H),8.76–8.70(m,1H),8.15(s,2H),7.96(d,J＝1.6Hz,1H),7.84(s,1H),7.52–7.37(m,6H),5.38–5.24(m,1H),4.76(d,J＝8.9Hz,1H),4.66–4.53(m,2H),4.51–4.38(m,1H),4.15–3.88(m,6H),3.85(d,J＝11.2Hz,1H),3.78(dd,J＝11.1,3.6Hz,1H),3.57–3.39(m,4H),3.27–3.04(m,4H),2.91–2.67(m,2H),2.49(d,J＝2.2Hz,3H),2.28–2.17(m,1H),2.17–2.06(m,1H),2.05–1.94(m,1H),1.57–1.16(m,12H),1.13(s,2H),1.10–1.01(m,9H),0.98–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₅₉H₇₃F₂N₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1159.5470, respectively; the following are found: 1159.5439.

example 113: (2S,4R) -N- ((S) -3- ((7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) heptyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 60%.¹H NMR(600MHz,CD₃OD)δ8.96–8.88(m,1H),8.79–8.69(m,1H),8.15(s,2H),7.96(s,1H),7.82(s,1H),7.52–7.31(m,6H),5.41–5.22(m,1H),4.76(d,J＝9.1Hz,1H),4.67–4.52(m,2H),4.48(d,J＝13.4Hz,1H),4.16–3.88(m,6H),3.85(d,J＝11.1Hz,1H),3.82–3.71(m,1H),3.57–3.38(m,4H),3.29–3.00(m,4H),2.88–2.66(m,2H),2.49(s,3H),2.28–2.17(m,1H),2.17–2.06(m,1H),2.02–1.91(m,1H),1.56–1.15(m,14H),1.13(s,2H),1.09–1.01(m,9H),0.99–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₆₀H₇₅F₂N₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1173.5626, respectively; the following are found: 1173.5644.

example 114: (2S,4R) -N- ((S) -3- ((2- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) ethoxy) ethyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 66%.¹H NMR(600MHz,CD₃OD)δ8.93–8.87(m,1H),8.77–8.66(m,1H),8.16(s,2H),7.97(s,1H),7.85(d,J＝2.8Hz,1H),7.53–7.35(m,6H),5.43–5.33(m,1H),4.76(d,J＝9.0Hz,1H),4.65–4.56(m,2H),4.52–4.45(m,1H),4.12–3.89(m,6H),3.87(d,J＝11.3Hz,1H),3.78(dd,J＝11.1,3.6Hz,1H),3.62–3.36(m,12H),2.93–2.82(m,1H),2.82–2.72(m,1H),2.48(s,3H),2.30–2.20(m,1H),2.17–2.08(m,1H),2.02–1.94(m,1H),1.46–1.26(m,4H),1.14(s,2H),1.09–1.02(m,9H),0.99–0.94(m,2H)。HRMS(ESI-TOF)m/z：C₅₇H₆₉F₂N₁₄O₈S⁺Of [ M + H]⁺Calculated values: 1147.5106, respectively; the following are found: 1147.5124.

example 115: (2S,4R) -N- ((S) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -15- (4- (4-methylthiazol-5-yl) phenyl) -2, 13-dioxo-6, 9-dioxa-3, 12-diazepin-15-yl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 65%. ¹H NMR(600MHz,CD₃OD)δ8.91–8.88(m,1H),8.76–8.68(m,1H),8.15(s,2H),7.96(s,1H),7.84(s,1H),7.53–7.37(m,6H),5.45–5.32(m,1H),4.75(d,J＝9.0Hz,1H),4.63–4.54(m,2H),4.51–4.42(m,1H),4.12–3.88(m,6H),3.85(d,J＝11.2Hz,1H),3.78(dd,J＝10.9,3.5Hz,1H),3.65–3.54(m,7H),3.54–3.39(m,9H),2.91–2.70(m,2H),2.48(s,3H),2.28–2.18(m,1H),2.16–2.06(m,1H),2.03–1.93(m,1H),1.42–1.26(m,4H),1.13(s,2H),1.10–1.01(m,9H),0.99–0.92(m,2H)。HRMS(ESI-TOF)m/z：C₅₉H₇₃F₂N₁₄O₉S⁺Of [ M + H]⁺Calculated values: 1191.5368, respectively; the following are found: 1191.5355.

example 116: (2S,4R) -N- ((S) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -18- (4- (4-methylthiazol-5-yl) phenyl) -2, 16-dioxo-6, 9, 12-trioxa-3, 15-diazacyclooctadecan-18-yl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 63%.¹H NMR(600MHz,CD₃OD)δ8.94(s,1H),8.68(t,J＝8.1Hz,1H),8.17(s,2H),7.99(s,1H),7.91(s,1H),7.48–7.38(m,6H),5.41–5.31(m,1H),4.76(d,J＝8.7Hz,1H),4.62–4.48(m,2H),4.47–4.38(m,1H),4.12–3.88(m,6H),3.85(d,J＝11.2Hz,1H),3.80–3.72(m,1H),3.69–3.54(m,11H),3.54–3.39(m,9H),2.90–2.70(m,2H),2.49(s,3H),2.29–2.18(m,1H),2.18–2.07(m,1H),2.01–1.94(m,1H),1.43–1.27(m,6H),1.15–1.11(m,2H),1.10–1.02(m,9H),0.99–0.95(m,2H)。HRMS(ESI-TOF)m/z：C₆₁H₇₇F₂N₁₄O₁₀S⁺Of [ M + H]⁺Calculated values: 1235.5630, respectively; the following are found: 1235.5641.

example 117: (2S,4R) -N- ((S) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -21- (4- (4-methylthiazol-5-yl) phenyl) -2, 19-dioxo-6, 9,12, 15-tetraoxa-3, 18-diaza-heneicosane-21-yl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3,3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 61%.¹H NMR(600MHz,CD₃OD)δ8.91(s,1H),8.77–8.71(m,1H),8.15(s,2H),7.96(s,1H),7.83(s,1H),7.48–7.38(m,6H),5.40–5.30(m,1H),4.76(d,J＝9.0Hz,1H),4.63–4.49(m,2H),4.47–4.38(m,1H),4.13–3.88(m,6H),3.85(d,J＝11.2Hz,1H),3.78(dd,J＝11.2,3.8Hz,1H),3.68–3.52(m,16H),3.52–3.38(m,8H),2.90–2.68(m,2H),2.49(s,3H),2.30–2.20(m,1H),2.18–2.07(m,1H),2.06–1.91(m,1H),1.44–1.25(m,4H),1.13(s,2H),1.10–1.01(m,9H),0.99–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₆₃H₈₁F₂N₁₄O₁₁S⁺Of [ M + H]⁺Calculated values: 1279.5893, respectively; the following are found: 1279.5870.

example 118: (2S,4R) -N- ((S) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -24- (4- (4-methylthiazol-5-yl) phenyl) -2, 22-dioxo-6, 9,12,15, 18-pentaoxa-3, 21-diaza-tetracosan-24-yl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutanoyl) -4-hydroxypyrrolidine-2-carboxamide. The yield was 60%. ¹H NMR(600MHz,CD₃OD)δ8.93(s,1H),8.76–8.67(m,1H),8.15(s,2H),7.97(s,1H),7.85(s,1H),7.49–7.38(m,6H),5.42–5.30(m,1H),4.76(d,J＝9.2Hz,1H),4.66–4.48(m,2H),4.48–4.39(m,1H),4.14–3.89(m,6H),3.85(d,J＝11.3Hz,1H),3.81–3.72(m,1H),3.67–3.52(m,22H),3.52–3.36(m,6H),2.90–2.69(m,2H),2.49(s,3H),2.28–2.19(m,1H),2.15–2.07(m,1H),2.06–1.93(m,1H),1.35(ddt,J＝19.9,15.9,6.4Hz,4H),1.13(s,2H),1.10–1.01(m,9H),0.98–0.93(m,2H)。HRMS(ESI-TOF)m/z：C₆₅H₈₅F₂N₁₄O₁₂S⁺Of [ M + H]⁺Calculated values: 1323.6155, respectively; the following are found: 1323.6170.

example 119: (2S,4R) -N- ((S) -3- ((2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) ethyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butyryl) pyrrolidine-2-carboxamide. The yield was 68%.¹H NMR(500MHz,CD₃OD)δ8.93(s,1H),8.74–8.59(m,1H),8.15(s,2H),7.94(s,1H),7.86(s,1H),7.48–7.36(m,6H),6.28(s,1H),5.40–5.24(m,1H),4.62–4.57(m,1H),4.56–4.51(m,1H),4.47(s,1H),4.16–3.91(m,5H),3.89–3.77(m,2H),3.72–3.64(m,1H),3.64–3.41(m,6H),3.19–3.05(m,1H),2.84–2.61(m,2H),2.46(s,3H),2.27(s,3H),2.15–2.05(m,1H),2.00–1.89(m,1H),1.12–1.05(m,3H),1.05–0.90(m,4H),0.90–0.84(m,3H)。HRMS(ESI-TOF)m/z：C₅₄H₆₂FN₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1069.4625, respectively; the following are found: 1069.4635.

example 120: (2S,4R) -N- ((S) -3- ((3- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) propyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 60%.¹H NMR(600MHz,CD₃OD)δ8.99–8.93(m,1H),8.72–8.66(m,1H),8.16(s,2H),7.99(d,J＝2.7Hz,1H),7.91(s,1H),7.53–7.36(m,6H),6.26(d,J＝10.3Hz,1H),5.40–5.27(m,1H),4.62–4.49(m,1H),4.45(s,1H),4.10–3.61(m,9H),3.57–3.40(m,4H),3.27–3.13(m,4H),2.91–2.71(m,2H),2.49(d,J＝5.3Hz,3H),2.46–2.36(m,1H),2.31–2.23(m,3H),2.17–2.10(m,1H),2.02–1.91(m,1H),1.73–1.61(m,2H),1.12–1.02(m,5H),1.00–0.95(m,2H),0.91–0.85(m,3H)。HRMS(ESI-TOF)m/z：C₅₅H₆₄FN₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1083.4782, respectively; the following are found: 1083.4781.

example 121: (2S,4R) -N- ((S) -3- ((4- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) butyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 59%. ¹H NMR(600MHz,CD₃OD)δ8.91(d,J＝16.4Hz,1H),8.78–8.68(m,1H),8.15(s,2H),7.97–7.92(m,1H),7.83(s,1H),7.49–7.34(m,6H),6.25(d,J＝12.4Hz,1H),5.39–5.25(m,1H),4.61–4.48(m,1H),4.45(s,1H),4.18–3.57(m,9H),3.57–3.40(m,4H),3.28–3.07(m,4H),2.87–2.65(m,2H),2.47(d,J＝11.2Hz,3H),2.46–2.38(m,1H),2.26(d,J＝16.8Hz,3H),2.15–2.08(m,1H),2.01–1.94(m,1H),1.56–1.42(m,4H),1.12–0.99(m,5H),0.99–0.92(m,2H),0.88(dd,J＝13.1,6.7Hz,3H)。HRMS(ESI-TOF)m/z：C₅₆H₆₆FN₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1097.4938, respectively; the following are found: 1097.4928.

example 122: (2S,4R) -N- ((S) -3- ((5- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) pentyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 70%.¹H NMR(600MHz,CD₃OD)δ8.92–8.86(m,1H),8.78–8.69(m,1H),8.15(s,2H),7.94(d,J＝3.4Hz,1H),7.82(s,1H),7.50–7.34(m,6H),6.26(d,J＝27.8Hz,1H),5.37–5.27(m,1H),4.60–4.48(m,1H),4.46(s,1H),4.09–3.56(m,9H),3.55–3.41(m,4H),3.28–3.02(m,4H),2.87–2.65(m,2H),2.47(d,J＝10.7Hz,3H),2.45–2.38(m,1H),2.26(d,J＝11.4Hz,3H),2.18–2.09(m,1H),2.02–1.93(m,1H),1.61–1.23(m,6H),1.10–1.06(m,3H),1.05–0.99(m,2H),0.99–0.92(m,2H),0.91–0.85(m,3H)。HRMS(ESI-TOF)m/z：C₅₇H₆₈FN₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1111.5095, respectively; the following are found: 1111.5078.

example 123: (2S,4R) -N- ((S) -3- ((6- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) hexyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butyryl) pyrrolidine-2-carboxamide. The yield was 73%.¹H NMR(600MHz,CD₃OD)δ8.95–8.86(m,1H),8.78–8.69(m,1H),8.14(s,2H),7.94(d,J＝2.2Hz,1H),7.80(s,1H),7.49–7.37(m,6H),6.25(d,J＝21.7Hz,1H),5.38–5.25(m,1H),4.62–4.48(m,1H),4.46(s,1H),4.11–3.56(m,9H),3.55–3.38(m,4H),3.24(dd,J＝16.7,9.9Hz,2H),3.18–3.06(m,2H),2.91–2.68(m,2H),2.52–2.46(m,3H),2.46–2.36(m,1H),2.30–2.23(m,3H),2.21–2.06(m,1H),2.01–1.92(m,1H),1.52–1.45(m,2H),1.45–1.35(m,2H),1.35–1.28(m,2H),1.28–1.18(m,2H),1.11–1.00(m,5H),0.99–0.92(m,2H),0.92–0.85(m,3H)。HRMS(ESI-TOF)m/z：C₅₈H₇₀FN₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1125.5251, respectively; the following are found: 1125.5270.

example 124: (2S,4R) -N- ((S) -3- ((7- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) heptyl) amino) -1- (4- (4-methylthiazol-5-yl) benzene-3-oxopropyl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 63%. ¹H NMR(600MHz,CD₃OD)δ8.97–8.86(m,1H),8.77–8.66(m,1H),8.15(s,2H),7.97(d,J＝3.1Hz,1H),7.86(s,1H),7.51–7.36(m,6H),6.26(d,J＝24.9Hz,1H),5.38–5.27(m,1H),4.60–4.48(m,1H),4.46(s,1H),4.13–3.57(m,9H),3.57–3.40(m,4H),3.27–3.18(m,2H),3.18–3.04(m,2H),2.88–2.68(m,2H),2.49(d,J＝9.4Hz,3H),2.46–2.34(m,1H),2.26(d,J＝12.3Hz,3H),2.22–2.09(m,1H),2.02–1.91(m,1H),1.55–1.44(m,2H),1.44–1.34(m,2H),1.34–1.25(m,4H),1.25–1.16(m,2H),1.10–1.01(m,5H),0.99–0.93(m,2H),0.93–0.85(m,3H)。HRMS(ESI-TOF)m/z：C₅₉H₇₂FN₁₄O₇S⁺Of [ M + H]⁺Calculated values: 1139.5408, respectively; the following are found: 1139.5411.

example 125: (2S,4R) -N- ((S) -3- ((2- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) ethoxy) ethyl) amino) -1- (4- (4-methylthiazol-5-yl) phenyl) -3-oxopropyl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 65%.¹H NMR(600MHz,CD₃OD)δ8.89–8.81(m,1H),8.78–8.66(m,1H),8.15(d,J＝1.9Hz,2H),7.95(d,J＝3.1Hz,1H),7.82(s,1H),7.50–7.32(m,6H),6.26(d,J＝31.5Hz,1H),5.40–5.28(m,1H),4.62–4.49(m,1H),4.47(s,1H),4.12–3.67(m,9H),3.67–3.38(m,12H),2.92–2.70(m,2H),2.48–2.37(m,4H),2.29–2.23(m,3H),2.15–2.06(m,1H),2.03–1.94(m,1H),1.11–0.99(m,5H),0.99–0.92(m,2H),0.89(dd,J＝20.6,6.7Hz,3H)。HRMS(ESI-TOF)m/z：C₅₆H₆₆FN₁₄O₈S⁺Of [ M + H]⁺Calculated values: 1113.4887, respectively; the following are found: 1113.4899.

example 126: (2S,4R) -N- ((S) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -15- (4- (4-methylthiazol-5-yl) phenyl) -2, 13-dioxo-6, 9-dioxa-3, 12-diazepin-15-yl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 60%. HRMS (ESI-TOF) m/z: c₅₈H₇₀FN₁₄O₉S⁺Of [ M + H]⁺Calculated values: 1157.5149, respectively; the following are found: 1157.5177.

example 127: (2S,4R) -N- ((S) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -18- (4- (4-methylthiazol-5-yl) phenyl) -2, 16-dioxo-6, 9, 12-trioxa-3, 15-diazadenan-18-yl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 63%. ¹H NMR(600MHz,CD₃OD)δ8.89(d,J＝15.4Hz,1H),8.75–8.65(m,1H),8.15(s,2H),7.96(d,J＝2.5Hz,1H),7.85(s,1H),7.52–7.34(m,6H),6.32–6.21(m,1H),5.41–5.30(m,1H),4.61–4.48(m,1H),4.46(s,1H),4.12–3.68(m,9H),3.68–3.54(m,8H),3.54–3.41(m,8H),2.90–2.71(m,2H),2.53–2.45(m,3H),2.45–2.37(m,1H),2.31–2.22(m,3H),2.16–2.09(m,1H),2.02–1.94(m,1H),1.12–0.99(m,5H),0.99–0.93(m,2H),0.93–0.84(m,3H)。HRMS(ESI-TOF)m/z：C₆₀H₇₄FN₁₄O₁₀S⁺Of [ M + H]⁺Calculated values: 1201.5412, respectively; the following are found: 1201.5431.

example 128: (2S,4R) -N- ((S) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo)[1,2-a]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -21- (4- (4-methylthiazol-5-yl) phenyl) -2, 19-dioxo-6, 9,12, 15-tetraoxa-3, 18-diazicosane-21-yl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 60%.¹H NMR(600MHz,CD₃OD)δ8.95–8.88(m,1H),8.76–8.65(m,1H),8.16(s,2H),7.97(d,J＝4.0Hz,1H),7.87(s,1H),7.52–7.31(m,6H),6.25(d,J＝22.2Hz,1H),5.40–5.27(m,1H),4.60–4.48(m,1H),4.46(s,1H),4.11–3.69(m,9H),3.68–3.55(m,12H),3.55–3.43(m,8H),2.90–2.72(m,2H),2.54–2.45(m,3H),2.45–2.35(m,1H),2.33–2.22(m,3H),2.18–2.09(m,1H),2.03–1.90(m,1H),1.15–1.00(m,5H),1.00–0.92(m,2H),0.92–0.84(m,3H)。HRMS(ESI-TOF)m/z：C₆₂H₇₈FN₁₄O₁₁S⁺Of [ M + H]⁺Calculated values: 1245.5674, respectively; the following are found: 1245.5677.

example 129: (2S,4R) -N- ((S) -1- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -24- (4- (4-methylthiazol-5-yl) phenyl) -2, 22-dioxo-6, 9,12,15, 18-pentaoxa-3, 21-diaza-tetracos-3-yl) -4-hydroxy-1- ((R) -3-methyl-2- (3-methylisoxazol-5-yl) butanoyl) pyrrolidine-2-carboxamide. The yield was 67%.¹H NMR(600MHz,CD₃OD)δ8.94–8.87(m,1H),8.77–8.68(m,1H),8.16(s,2H),7.96(d,J＝3.3Hz,1H),7.85(d,J＝2.1Hz,1H),7.51–7.34(m,6H),6.26(d,J＝22.2Hz,1H),5.39–5.27(m,1H),4.60–4.48(m,1H),4.46(s,1H),4.12–3.68(m,9H),3.68–3.53(m,16H),3.53–3.41(m,8H),2.92–2.70(m,2H),2.52–2.46(m,3H),2.46–2.35(m,1H),2.31–2.23(m,3H),2.23–2.09(m,1H),2.03–1.92(m,1H),1.12–1.00(m,5H),1.00–0.93(m,2H),0.93–0.84(m,2H)。HRMS(ESI-TOF)m/z：C₆₄H₈₂FN₁₄O₁₂S⁺Of [ M + H]⁺Calculated values: 1289.5636, respectively; the following are found: 1289.5661.

scheme 29 Synthesis of example 135

Example 135: (2S,4R) -1- ((S) -2- (8- (7- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) -2, 7-diazaspiro [3.5 ]Nonan-2-yl) -8-oxooctanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. Example 135 was synthesized according to the procedure used to prepare example 1. The yield was 63%.¹H NMR(600MHz,CD₃OD)δ9.03(s,1H),8.58(t,J＝8.1Hz,1H),8.18(s,2H),8.02(s,1H),7.98(s,1H),7.49(d,J＝8.1Hz,2H),7.44(d,J＝8.0Hz,2H),7.39(d,J＝11.3Hz,1H),7.34(d,J＝8.4Hz,1H),4.66(s,1H),4.63–4.49(m,3H),4.38(d,J＝15.5Hz,1H),4.06–3.96(m,2H),3.92(d,J＝10.9Hz,1H),3.82(dd,J＝10.9,3.8Hz,1H),3.80–3.67(m,4H),3.62–3.42(m,2H),2.50(s,3H),2.36–2.20(m,3H),2.20–2.13(m,3H),2.13–2.07(m,1H),1.97–1.75(m,4H),1.69–1.57(m,4H),1.43–1.33(m,4H),1.11–1.03(m,11H),1.01–0.97(m,2H)。HRMS(ESI-TOF)m/z：C₅₆H₆₇FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1055.5084, respectively; the following are found: 1055.5099.

example compound 136 was synthesized according to the procedure used to prepare example compound 135.

Example 136: (2S,4R) -1- ((S) -2- (9- (7- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) -2, 7-diazaspiro [3.5]Nonan-2-yl) -9-oxononanoylamino) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide. The yield was 66%.¹H NMR(600MHz,CD₃OD)δ9.00(s,1H),8.61(t,J＝8.2Hz,1H),8.17(s,2H),8.01(s,1H),7.96(s,1H),7.49(d,J＝8.2Hz,2H),7.44(d,J＝8.3Hz,2H),7.39(dd,J＝11.2,1.8Hz,1H),7.34(d,J＝9.7Hz,1H),4.66(s,1H),4.61–4.50(m,3H),4.38(d,J＝15.5Hz,1H),4.05–3.96(m,2H),3.92(d,J＝11.2Hz,1H),3.82(dd,J＝10.9,3.9Hz,1H),3.80–3.63(m,4H),3.62–3.43(m,2H),2.50(s,3H),2.35–2.21(m,3H),2.20–2.12(m,3H),2.12–2.07(m,1H),1.97–1.75(m,4H),1.68–1.57(m,4H),1.41–1.31(m,6H),1.09–1.04(m,11H),1.01–0.96(m,2H)。HRMS(ESI-TOF)m/z：C₅₇H₆₇FN₁₂O₆S⁺Of [ M + H]⁺Calculated values: 1055.5084, respectively; the following are found: 1055.5099.

scheme 30 Synthesis of example 137

Example 137: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- ((2- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) nicotinamide. To a solution of intermediate 22(10mg, 0.017mmol) and linking group 27(9mg, 0.017mmol) in DMSO (0.5mL) were added NMM (10 μ L, 0.085mmol), EDCI (5mg, 0.026mmol) and HOAt (3.5mg, 0.026 mmol). After stirring at room temperature for 12h, the mixture was concentrated and purified by HPLC to give the title compound as a brown oil (6mg, 32% yield). ¹H NMR(600MHz,CD₃OD)δ9.01(s,1H),8.90(s,1H),8.65(s,1H),8.57(s,1H),8.04(s,1H),7.43(d,J＝8.3Hz,2H),7.40(d,J＝8.2Hz,2H),7.37(d,J＝7.9Hz,2H),7.25(d,J＝8.2Hz,2H),5.69–5.59(m,1H),4.83–4.76(m,1H),4.71(s,1H),4.59–4.53(m,1H),4.52–4.46(m,2H),4.38(d,J＝15.5Hz,1H),4.30(t,J＝7.0Hz,2H),4.07(d,J＝15.2Hz,1H),4.04–3.97(m,2H),3.92–3.86(m,3H),3.83–3.76(m,3H),3.68–3.56(m,3H),3.46–3.34(m,2H),2.46(s,3H),2.34(t,J＝7.0Hz,2H),2.29–2.17(m,4H),2.13–2.04(m,1H),1.91–1.75(m,1H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₃H₆₃F₄N₁₀O₁₀S⁺Of [ M + H]⁺Calculated values: 1107.4380, respectively; the following are found: 1107.4449.

example compound 138-189 was synthesized according to the procedure used to prepare example compound 137.

Example 138: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- ((2- (3- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -3-oxopropoxy) ethyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) nicotinamide. The yield was 40%.¹H NMR(500MHz,CD₃OD)δ9.03(s,1H),8.91(s,1H),8.71–8.63(m,1H),8.58(dd,J＝4.9,2.5Hz,1H),8.05(t,J＝1.6Hz,1H),7.44(d,J＝8.3Hz,2H),7.41–7.39(m,2H),7.37(d,J＝8.4Hz,2H),7.24(d,J＝8.2Hz,2H),5.70–5.58(m,1H),4.57(dd,J＝9.1,7.6Hz,2H),4.52–4.47(m,2H),4.38(d,J＝15.5Hz,1H),4.31(t,J＝7.0Hz,2H),4.18–3.98(m,1H),3.94–3.84(m,3H),3.83–3.76(m,3H),3.75–3.68(m,3H),3.64–3.56(td,J＝12.1,11.6,4.4Hz,1H),3.52(t,J＝5.4Hz,2H),3.38–3.33(m,2H),2.59–2.50(m,2H),2.46(s,3H),2.32(t,J＝7.4Hz,2H),2.28–2.17(m,4H),2.09(ddd,J＝13.3,9.2,4.5Hz,1H),1.92–1.75(m,1H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₄H₆₅F₄N₁₀O₁₀S⁺Of [ M + H]⁺Calculated values: 1121.4536, respectively; the following are found: 1121.4535.

example 139: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 14-dioxo-7, 10-dioxa-4, 13-diazepan-17-Yl) -1H-imidazol-4-yl) nicotinamide. The yield was 33%.¹H NMR(600MHz,CD₃OD)δ9.01(s,1H),8.90(s,1H),8.65(s,1H),8.58(s,1H),8.04(s,1H),7.43(d,J＝11.3Hz,2H),7.40(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),7.25(d,J＝8.1Hz,2H),5.68–5.59(m,1H),4.83–4.78(m,1H),4.75(d,J＝8.1Hz,1H),4.55(t,J＝8.5Hz,1H),4.52–4.46(m,2H),4.39(d,J＝15.5Hz,1H),4.28(t,J＝7.0Hz,2H),4.16–4.08(m,1H),4.06–3.98(m,2H),3.88(t,J＝5.7Hz,3H),3.84–3.77(m,3H),3.73–3.69(m,3H),3.66–3.60(m,3H),3.58–3.54(m,2H),3.49–3.43(m,1H),2.46(s,3H),2.33(dt,J＝14.7,7.1Hz,2H),2.29–2.23(m,2H),2.20(t,J＝7.1Hz,2H),2.13–2.04(m,1H),1.91–1.77(m,1H),1.04(s,9H)。HRMS(ESI-TOF)m/z：C₅₅H₆₇F₄N₁₀O₁₁S⁺Of [ M + H]⁺Calculated values: 1151.4642, respectively; the following are found: 1151.4634.

example 140: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 15-dioxo-8, 11-dioxa-4, 14-diazadenan-18-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 41%. ¹H NMR(600MHz,CD₃OD)δ9.06(s,1H),8.93(s,1H),8.67(dd,J＝4.7,2.6Hz,1H),8.60–8.54(m,1H),8.08(s,1H),7.46(d,J＝8.0Hz,2H),7.41(d,J＝8.1Hz,2H),7.37(d,J＝8.0Hz,2H),7.24(d,J＝8.2Hz,2H),5.69–5.61(m,1H),4.83–4.77(m,1H),4.65(s,1H),4.56(t,J＝8.4Hz,1H),4.53–4.48(m,2H),4.37(d,J＝15.4Hz,1H),4.31(t,J＝6.9Hz,2H),4.16–3.99(m,1H),3.94–3.84(m,3H),3.84–3.76(m,3H),3.75–3.69(m,2H),3.65–3.57(m,5H),3.53(t,J＝5.3Hz,2H),3.34(t,J＝5.4Hz,2H),2.61–2.52(m,1H),2.50–2.44(d,J＝3.8Hz,4H),2.31(t,J＝6.9Hz,2H),2.23(p,J＝7.2Hz,4H),2.08(ddd,J＝13.3,9.4,4.5Hz,1H),1.91–1.75(m,1H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₆H₆₉F₄N₁₀O₁₁S⁺Of [ M + H]⁺Calculated values: 1165.4799, respectively; the following are found: 1165.4808.

example 141: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 17-dioxo-7, 10, 13-trioxa-4, 16-diaza-eicosan-20-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 31%.¹H NMR(600MHz,CD₃OD)δ9.07(s,1H),8.96(s,1H),8.67(dd,J＝4.8,2.7Hz,1H),8.59(dd,J＝6.0,2.6Hz,1H),8.08(s,1H),7.45(t,J＝7.7Hz,2H),7.42(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),7.24(d,J＝8.1Hz,2H),5.69–5.60(s,1H),4.83–4.77(m,1H),4.69(s,1H),4.59–4.55(m,1H),4.54–4.48(m,2H),4.37(d,J＝15.5Hz,1H),4.31(t,J＝6.9Hz,2H),4.16–4.06(m,1H),4.04–3.98(m,2H),3.92–3.84(m,3H),3.80(dd,J＝11.1,3.9Hz,3H),3.72–3.64(m,7H),3.62(q,J＝5.1,4.6Hz,2H),3.55–3.48(m,2H),3.37–3.32(m,2H),2.48(s,3H),2.29(d,J＝6.6Hz,2H),2.27–2.18(m,4H),2.13–2.04(m,1H),1.92–1.76(m,1H),1.04(s,9H)。HRMS(ESI-TOF)m/z：C₅₇H₇₁F₄N₁₀O₁₂S⁺Of [ M + H]⁺Calculated values: 1195.4904, respectively; the following are found: 1195.4888.

example 142: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 18-dioxo-8, 11, 14-trioxa-4, 17-diaza-heneicosane-21-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 35%.¹H NMR(500MHz,CD₃OD)δ8.97(s,1H),8.89(d,J＝4.9Hz,1H),8.66(q,J＝4.3,3.8Hz,1H),8.60–8.54(m,1H),8.04(s,1H),7.45(td,J＝7.9,6.9,3.1Hz,2H),7.40(dt,J＝6.2,1.9Hz,2H),7.36(dd,J＝7.9,4.8Hz,2H),7.24(d,J＝7.9Hz,2H),5.64(brs,1H),4.60–4.52(m,2H),4.51–4.46(m,2H),4.40–4.34(m,1H),4.32–4.27(m,2H),4.19–3.97(m,1H),3.92–3.82(m,3H),3.81–3.76(m,3H),3.74–3.66(m,3H),3.65–3.55(m,9H),3.52(q,J＝5.1Hz,2H),3.38–3.33(m,2H),2.59–2.50(m,1H),2.49–2.42(m,4H),2.30(p,J＝5.6,5.2Hz,2H),2.27–2.17(m,4H),2.09(ddd,J＝13.3,9.0,4.5Hz,1H),1.91–1.73(d,J＝41.5Hz,1H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₈H₇₃F₄N₁₀O₁₂S⁺Of [ M + H]⁺Calculated values: 1209.5061, respectively; the following are found: 1209.5067.

example 143: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 18-dioxo-8, 11, 14-trioxa-4, 17-diaza-heneicosane-21-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 45%. ¹H NMR(500MHz,CD₃OD)δ9.07(d,J＝3.5Hz,1H),8.96(d,J＝3.5Hz,1H),8.67(q,J＝3.3Hz,1H),8.59(dt,J＝6.3,3.0Hz,1H),8.09(d,J＝3.8Hz,1H),7.46(dd,J＝8.2,3.4Hz,2H),7.43–7.39(m,2H),7.37(dd,J＝8.5,3.3Hz,2H),7.24(d,J＝8.1Hz,2H),5.65(brs,1H),4.60–4.53(m,2H),4.52–4.47(m,2H),4.40–4.29(m,3H),4.17–3.98(m,1H),3.91–3.85(m,3H),3.83–3.76(m,3H),3.75–3.66(m,3H),3.64–3.56(m,14H),3.53(td,J＝5.4,3.5Hz,3H),2.60–2.51(m,1H),2.49–2.42(m,4H),2.34–2.29(m,2H),2.28–2.17(m,4H),2.12–2.05(m,1H),1.92–1.76(m,1H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₆₀H₇₇F₄N₁₀O₁₃S⁺Of [ M + H]⁺Calculated values: 1253.5323, respectively; the following are found: 1253.5312.

example 144: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 24-dioxo-8, 11,14,17, 20-pentaoxa-4, 23-diaza-heptacosan-27-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 34%.¹H NMR(600MHz,CD₃OD)δ9.07(s,1H),8.93(s,1H),8.67(s,1H),8.60(d,J＝5.9Hz,1H),8.09(s,1H),7.47(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),7.37(d,J＝8.1Hz,2H),7.25(d,J＝8.1Hz,2H),5.70–5.60(m,1H),4.83–4.77(m,2H),4.65(s,1H),4.57(dd,J＝16.9,8.6Hz,1H),4.53–4.47(m,1H),4.40–4.30(m,3H),4.17–4.00(s,1H),3.93–3.84(m,3H),3.83–3.77(m,3H),3.75–3.67(m,3H),3.65–3.56(m,16H),3.53(t,J＝5.3Hz,2H),3.34(t,J＝5.4Hz,2H),2.60–2.53(m,1H),2.51–2.43(m,4H),2.32(t,J＝6.9Hz,2H),2.29–2.17(m,4H),2.12–2.02(m,1H),1.91–1.75(m,1H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₆₂H₈₁F₄N₁₀O₁₄S⁺Of [ M + H]⁺Calculated values: 1297.5585, respectively; the following are found: 1297.5596.

example 145: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- ((2- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) nicotinamide. The yield was 39%.¹H NMR(500MHz,CD₃OD)δ9.10(s,1H),8.93(s,1H),8.66(t,J＝3.4Hz,1H),8.58(dd,J＝4.7,2.7Hz,1H),8.11(s,1H),7.45(dt,J＝8.2,3.0Hz,2H),7.41–7.35(m,4H),7.24(d,J＝7.8Hz,2H),5.64(brs,1H),4.66–4.62(m,1H),4.59–4.52(m,2H),4.50(d,J＝4.2Hz,2H),4.39–4.32(m,3H),4.20–3.98(m,1H),3.94–3.84(m,5H),3.83–3.75(m,3H),3.71–3.54(m,1H),2.52–2.42(m,3H),2.40–2.34(m,2H),2.32–2.17(m,4H),2.09(ddd,J＝13.3,9.0,4.4Hz,1H),1.93–1.73(m,1H),1.04(s,9H)。HRMS(ESI-TOF)m/z：C₅₁H₅₉F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1063.4118, respectively; the following are found: 1063.4128.

example 146: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- ((3- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -3-oxopropyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) nicotinamide. The yield was 37%. ¹H NMR(600MHz,CD₃OD)δ8.97(s,1H),8.89(s,1H),8.66(s,1H),8.57(s,1H),8.05(s,1H),7.44(d,J＝7.5Hz,2H),7.41–7.34(m,4H),7.25(d,J＝8.2Hz,2H),5.69–5.59(m,1H),4.60(s,1H),4.56–4.54(m,1H),4.52(d,J＝6.4Hz,1H),4.51–4.48(m,1H),4.37(d,J＝15.6Hz,1H),4.29(t,J＝7.0Hz,2H),4.15–3.99(m,1H),3.94(d,J＝11.1Hz,1H),3.90–3.86(m,2H),3.83–3.76(m 3H),3.65–3.56(m,1H),3.48–3.42(m,1H),3.42–3.35(m,1H),2.60–2.43(m,5H),2.29–2.25(m,3H),2.24–2.17(m,4H),2.11–2.05(m,1H),1.91–1.76(m,1H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₂H₆₁F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1077.4274, respectively; the following are found: 1077.4290.

example 147: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- ((4- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -4-oxobutyl) -1H-imidazole-4-yl) nicotinamide. The yield was 41%.¹H NMR(600MHz,CD₃OD)δ9.09(s,1H),8.96(s,1H),8.66(dd,J＝4.6,2.6Hz,1H),8.57(dd,J＝6.0,2.6Hz,1H),8.09(s,1H),7.46(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),7.37(d,J＝8.1Hz,2H),7.24(d,J＝8.1Hz,2H),5.69–5.60(m,1H),4.82–4.73(m,1H),4.62(s,1H),4.57(d,J＝8.4Hz,1H),4.55(d,J＝7.1Hz,1H),4.52–4.48(m,1H),4.36(d,J＝15.5Hz,1H),4.33(t,J＝7.1Hz,2H),4.18–3.99(m,1H),3.94–3.87(m,3H),3.85–3.76(m,3H),3.64–3.57(m,1H),3.18(t,J＝6.9Hz,2H),2.47(s,3H),2.31(q,J＝7.3Hz,3H),2.29–2.19(m,5H),2.09(ddd,J＝13.4,9.3,4.6Hz,1H),1.92–1.79(m,1H),1.76(p,J＝7.2Hz,2H),1.04(s,9H)。HRMS(ESI-TOF)m/z：C₅₃H₆₃F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1091.4431, respectively; the following are found: 1091.4445.

example 148: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- ((5- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -5-oxopentyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) nicotinamide. The yield was 33%.¹H NMR(600MHz,CD₃OD)δ9.04(s,1H),8.90(s,1H),8.67(s,1H),8.59(s,1H),8.07(s,1H),7.46(d,J＝8.0Hz,2H),7.40(d,J＝8.2Hz,2H),7.37(d,J＝7.9Hz,2H),7.25(d,J＝8.4Hz,2H),5.68–5.61(m,1H),4.62(s,1H),4.56(d,J＝8.4Hz,1H),4.55–4.53(m,1H),4.52–4.48(m,2H),4.36(d,J＝15.5Hz,1H),4.32(t,J＝7.0Hz,3H),3.92–3.86(m,4H),3.83–3.76(m,3H),3.66–3.57(m,1H),3.21–3.09(m,3H),2.48–2.45(m,5H),2.32–2.27(m,4H),2.26–2.19(m,3H),1.91–1.76(m,1H),1.64–1.57(m,1H),1.53–1.46(m,1H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₄H₆₅F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1105.4587, respectively; the following are found: 1105.4638.

example 149: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- ((6- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -6-oxohexyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) nicotinamide. The yield was 39%. ¹H NMR(600MHz,CD₃OD)δ9.03(s,1H),8.90(s,1H),8.66(s,1H),8.58(d,J＝5.8Hz,1H),8.06(s,1H),7.46(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),7.25(d,J＝8.2Hz,2H),5.69–5.60(m,1H),4.64–4.62(m,1H),4.59–4.53(m,1H),4.52–4.48(m,1H),4.39–4.33(m,1H),4.32–4.26(m,3H),3.92–3.87(m,4H),3.83–3.77(m,3H),3.66–3.62(m,1H),3.43–3.41(m,1H),3.21–3.18(m,1H),3.14(t,J＝7.1Hz,3H),2.48–2.45(m,4H),2.29(d,J＝7.0Hz,4H),2.25–2.19(m,4H),2.11–2.06(m,1H),1.62–1.57(m,1H),1.51–1.47(m,1H),1.36–1.30(m,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₅H₆₇F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1119.4744, respectively; the following are found: 1119.4838.

example 150: 5- (1- (4- ((2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 33%.¹H NMR(600MHz,CD₃OD)δ8.81(s,1H),8.60(s,1H),8.52(s,1H),7.92(s,1H),7.50(s,1H),7.38(d,J＝7.7Hz,2H),7.25(d,J＝8.2Hz,2H),7.03(d,J＝8.4Hz,1H),6.99(d,J＝7.8Hz,1H),5.67–5.57(m,1H),5.04(dd,J＝12.8,5.4Hz,1H),4.23(t,J＝7.0Hz,2H),3.89(d,J＝5.5Hz,2H),3.84–3.77(m,2H),3.72(t,J＝5.2Hz,3H),,3.61(t,J＝5.2Hz,3H),3.50–3.46(m,2H),3.44–3.37(m,2H),2.89–2.81(m,1H),2.76–2.70(m,1H),2.68–2.64(m,1H),2.29(t,J＝6.8Hz,2H),2.22–2.17(m,2H),2.12–2.06(m,1H),1.92–1.84(m,1H),1.83–1.75(m,1H)。HRMS(ESI-TOF)m/z：C₄₄H₄₆F₄N₉O₁₀ ⁺Of [ M + H]⁺Calculated values: 936.3298, respectively; the following are found: 936.3292.

example 151: 5- (1- (4- ((2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 37%.¹H NMR(600MHz,CD₃OD)δ9.01(s,1H),8.59(dd,J＝5.1,2.6Hz,1H),8.52(dd,J＝6.0,2.6Hz,1H),8.01(s,1H),7.54–7.45(m,1H),7.37(d,J＝8.0Hz,2H),7.25(d,J＝8.1Hz,2H),7.06–6.88(m,1H),5.68–5.57(m,1H),5.04(dd,J＝12.8,5.4Hz,1H),4.27(t,J＝6.6Hz,2H),4.19–3.99(m,1H),3.94–3.85(m,2H),3.84–3.76(m,2H),3.72(t,J＝5.0Hz,2H),3.69(dd,J＝6.3,2.7Hz,2H),3.66(dd,J＝6.2,2.8Hz,2H),3.63–3.58(m,1H),3.57(t,J＝5.3Hz,2H),3.45(t,J＝5.3Hz,2H),3.35(td,J＝5.2,2.3Hz,2H),2.85(ddd,J＝18.7,13.9,5.4Hz,1H),2.74(dt,J＝17.4,3.2Hz,1H),2.67(qd,J＝13.2,4.6Hz,1H),2.31–2.18(m,5H),2.12–2.05(m,1H),1.92–1.76(m,1H)。HRMS(ESI-TOF)m/z：C₄₆H₅₀F₄N₉O₁₁ ⁺Of [ M + H]⁺Calculated values: 980.3560, respectively; the following are found: 980.3641.

example 152: 5- (1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -13-oxo-3, 6, 9-trioxa-12-azahexadecan-16-yl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1-yl)- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 36%.¹H NMR(600MHz,CD₃OD)δ8.99(s,1H),8.60(dd,J＝5.6,2.6Hz,1H),8.55–8.50(m,1H),8.00(s,1H),7.59–7.44(m,1H),7.37(d,J＝8.1Hz,2H),7.25(d,J＝8.1Hz,2H),7.12–6.87(m,2H),5.67–5.57(m,1H),5.05(dd,J＝12.7,5.5Hz,1H),4.83–4.78(m,1H),4.27(t,J＝6.7Hz,2H),4.19–4.00(m,1H),3.94–3.85(m,2H),3.84–3.75(m,2H),3.73–3.65(m,10H),3.63–3.58(m,2H),3.52(t,J＝5.2Hz,2H),3.45–3.40(m,2H),2.87(ddd,J＝18.8,14.0,5.4Hz,1H),2.77–2.71(m,1H),2.71–2.61(m,1H),2.30–2.26(m,2H),2.25–2.19(m,3H),2.14–2.07(m,1H),1.92–1.75(m,1H)。HRMS(ESI-TOF)m/z：C₄₈H₅₄F₄N₉O₁₂ ⁺Of [ M + H]⁺Calculated values: 1024.3823, respectively; the following are found: 1024.3845.

Example 153: 5- (1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -19-oxo-3, 6,9,12, 15-pentaoxa-18-azadocosan-22-yl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 34%.¹H NMR(500MHz,CD₃OD)δ9.02(s,1H),8.63(dd,J＝4.0,2.5Hz,1H),8.56(dd,J＝4.9,2.6Hz,1H),8.04(s,1H),7.51(dd,J＝8.6,7.1Hz,1H),7.40–7.33(m,2H),7.24(d,J＝8.2Hz,2H),7.04(d,J＝8.6Hz,1H),7.01(d,J＝7.1Hz,1H),5.68–5.57(m,1H),5.03(dd,J＝12.8,5.4Hz,1H),4.30(t,J＝6.9Hz,2H),4.20–3.98(m,1H),3.93–3.84(m,2H),3.83–3.75(m,2H),3.71(t,J＝5.2Hz,2H),3.67–3.64(m,4H),3.63–3.59(m,5H),3.58–3.55(m,6H),3.53(t,J＝5.3Hz,2H),3.46(t,J＝5.1Hz,2H),3.34(t,J＝5.3Hz,2H),2.85(ddd,J＝17.7,14.0,5.3Hz,1H),2.77–2.71(m,1H),2.70–2.62(m,1H),2.29(t,J＝6.4Hz,2H),2.23(t,J＝6.6Hz,3H),2.10(ddt,J＝13.1,5.5,2.7Hz,1H),1.95–1.84(m,1H),1.83–1.74(m,1H)。HRMS(ESI-TOF)m/z：C₅₂H₆₂F₄N₉O₁₄ ⁺Of [ M + H]⁺Calculated values: 1112.4347, respectively; the following are found: 1112.4816.

example 154: 5- (1- (4- ((2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) benzamide. The yield was 40%.¹H NMR(500MHz,CD₃OD)δ8.85(s,1H),8.63(dd,J＝4.8,2.5Hz,1H),8.55(dd,J＝4.8,2.5Hz,1H),7.95(s,1H),7.59–7.50(m,1H),7.41–7.33(m,2H),7.24(d,J＝8.2Hz,2H),7.10(d,J＝8.6Hz,1H),7.02(d,J＝7.1Hz,1H),5.69–5.58(m,1H),5.01(dd,J＝12.4,5.4Hz,1H),4.23(t,J＝7.1Hz,2H),4.16–3.98(m,1H),3.94–3.85(m,3H),3.83–3.73(m,2H),3.65–3.57(m,1H),3.48–3.43(m,4H),2.81(ddd,J＝18.0,14.2,5.4Hz,1H),2.73–2.70(m,1H),2.68–2.61(m,1H),2.29(t,J＝7.0Hz,2H),2.21–2.16(m,2H),2.12–2.04(m,1H),1.93–1.74(m,1H)。HRMS(ESI-TOF)m/z：C₄₂H₄₂F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 892.3036, respectively; the following are found: 892.3066.

example 155: 5- (1- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 33%.¹H NMR(600MHz,CD₃OD)δ9.00(s,1H),8.75–8.62(m,1H),8.60–8.52(m,1H),8.04(s,1H),7.53(t,J＝7.8Hz,1H),7.37(d,J＝7.9Hz,2H),7.25(d,J＝8.1Hz,2H),7.07–6.96(m,2H),5.68–5.57(m,1H),5.05(dd,J＝12.7,5.5Hz,1H),4.30(t,J＝7.1Hz,2H),4.16–3.99(m,1H),3.94–3.84(m,3H),3.82–3.72(m,2H),3.63–3.57(m,1H),3.37–3.34(m,2H),2.85(ddd,J＝18.1,13.9,5.3Hz,1H),2.79–2.63(m,2H),2.32(t,J＝7.1Hz,2H),2.22(q,J＝7.2Hz,3H),2.13–2.06(m,1H),1.95–1.85(m,1H),1.82(t,J＝6.5Hz,3H)。HRMS(ESI-TOF)m/z：C₄₃H₄₄F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 906.3193, respectively; the following are found: 906.3197.

example 157: 5- (1- (4- ((5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 37%. ¹H NMR(600MHz,CD₃OD)δ9.02(s,1H),8.65(dd,J＝4.4,2.6Hz,1H),8.57(dd,J＝6.5,2.6Hz,1H),8.03(s,1H),7.61–7.48(m,1H),7.37(d,J＝8.2Hz,2H),7.24(d,J＝8.1Hz,2H),7.03(d,J＝8.6Hz,1H),7.00(d,J＝7.1Hz,1H),5.69–5.60(m,1H),5.04(dd,J＝12.8,5.5Hz,1H),4.83–4.76(m,1H),4.28(t,J＝7.1Hz,2H),4.17–3.98(m,1H),3.93–3.84(m,3H),3.83–3.70(m,2H),3.63–3.56(m,1H),3.18(t,J＝6.9Hz,2H),2.93–2.79(m,1H),2.76–2.71(m,1H),2.71–2.64(m,1H),2.29(t,J＝7.0Hz,2H),2.22(q,J＝6.9Hz,3H),2.13–2.04(m,1H),1.92–1.75(m,1H),1.69–1.63(m,2H),1.57–1.51(m,2H),1.47–1.40(m,2H)。HRMS(ESI-TOF)m/z：C₄₅H₄₈F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 934.3506, respectively; the following are found: 934.3521.

example 158: 5- (1- (4- ((6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 36%.¹H NMR(600MHz,CD₃OD)δ8.98(s,1H),8.65(d,J＝3.7Hz,1H),8.58(d,J＝6.3Hz,1H),8.03(s,1H),7.54(dd,J＝8.6,7.1Hz,1H),7.37(d,J＝8.3Hz,2H),7.24(d,J＝8.2Hz,2H),7.03(d,J＝4.2Hz,1H),7.02(d,J＝2.6Hz,1H),5.69–5.60(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.82–4.78(m,1H),4.30(t,J＝7.0Hz,2H),4.17–3.98(m,1H),3.94–3.84(m,3H),3.83–3.73(m,2H),3.62–3.56(m,1H),3.15(t,J＝7.0Hz,2H),2.93–2.81(m,1H),2.79–2.64(m,2H),2.29(t,J＝7.1Hz,2H),2.25–2.17(m,3H),2.13–2.07(m,1H),1.92–1.76(m,1H),1.65(t,J＝7.5Hz,2H),1.50(t,J＝7.3Hz,2H),1.46–1.40(m,2H),1.39–1.35(m,2H)。HRMS(ESI-TOF)m/z：C₄₆H₅₀F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 948.3662, respectively; the following are found: 948.3695.

example 159: 5- (1- (4- ((7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 34%.¹H NMR(600MHz,CD₃OD)δ9.00(s,1H),8.65(d,J＝3.7Hz,1H),8.60–8.53(m,1H),8.04(s,1H),7.54(dd,J＝8.6,7.1Hz,1H),7.37(d,J＝8.2Hz,2H),7.24(d,J＝8.2Hz,2H),7.03(d,J＝5.1Hz,1H),7.01(d,J＝3.5Hz,1H),5.69–5.60(m,1H),5.05(dd,J＝12.8,5.5Hz,1H),4.30(t,J＝7.0Hz,2H),4.18–3.95(m,1H),3.95–3.84(m,3H),3.83–3.73(m,2H),3.62–3.55(m,1H),3.13(t,J＝7.0Hz,2H),2.91–2.80(m,1H),2.77–2.64(m,2H),2.29(t,J＝6.9Hz,2H),2.23(q,J＝7.1Hz,3H),2.13–2.06(m,1H),1.95–1.75(m,1H),1.69–1.58(m,2H),1.50–1.45(m,2H),1.44–1.39(m,2H),1.38–1.28(s,5H)。HRMS(ESI-TOF)m/z：C₄₇H₅₂F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 962.3819, respectively; the following are found: 962.3863.

example 160: 5- (1- (4- ((8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octyl) amino) -4-oxobutyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 38%.¹H NMR(600MHz,CD₃OD)δ9.05(s,1H),8.65(dd,J＝4.6,2.6Hz,1H),8.57(dd,J＝6.2,2.5Hz,1H),8.06(s,1H),7.53(dd,J＝9.1,6.8Hz,1H),7.37(d,J＝8.1Hz,2H),7.24(d,J＝8.0Hz,2H),7.02(d,J＝7.7Hz,2H),5.71–5.60(m,1H),5.08–4.97(m,2H),4.31(t,J＝7.0Hz,2H),4.17–3.99(m,1H),3.92–3.84(m,3H),3.83–3.74(m,2H),3.62–3.49(m,1H),3.13(t,J＝7.1Hz,2H),2.90–2.80(m,1H),2.77–2.64(m,2H),2.35–2.27(m,2H),2.26–2.18(m,3H),2.13–2.08(m,1H),1.98–1.84(m,1H),1.68–1.61(m,3H),1.52–1.38(m,4H),1.37–1.31(m,5H)。HRMS(ESI-TOF)m/z：C₄₈H₅₄F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 976.3975, respectively; the following are found: 976.4135.

example 161: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- (2- (2- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) acetamido) butyl) -1H-imidazol-4-yl) nicotinamide. The yield was 35%. ¹H NMR(600MHz,CD₃OD)δ9.09(s,1H),9.01(s,1H),8.66(dd,J＝4.8,2.5Hz,1H),8.57(dd,J＝6.1,2.6Hz,1H),8.09(d,J＝2.0Hz,1H),7.46(d,J＝8.3Hz,2H),7.41(d,J＝8.2Hz,2H),7.39–7.34(m,2H),7.24(d,J＝8.0Hz,2H),5.64(brs,1H),4.83–4.76(m,1H),4.71(d,J＝6.9Hz,1H),4.61–4.55(m,1H),4.54–4.47(m,2H),4.38–4.34(m,1H),4.35–4.27(m,2H),4.16–4.11(m,3H),4.10–4.05(m,2H),3.93–3.85(m,3H),3.84–3.75(m,3H),3.66–3.55(m,1H),3.36–3.31(m,2H),2.48(s,3H),2.31–2.16(m,2H),2.12–2.05(m,1H),2.02–1.93(m,2H),1.91–1.76(m,1H),1.62(p,J＝7.0Hz,2H),1.04(s,9H)。HRMS(ESI-TOF)m/z：C₅₃H₆₃F₄N₁₀O₁₀S⁺Of [ M + H]⁺Calculated values: 1107.4380, respectively; the following are found: 1107.4389.

example 162: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- (4- (3- (3- (((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -3-oxopropoxy) propionylamino) butyl) -1H-imidazol-4-yl) nicotinamide. The yield was 31%.¹H NMR(600MHz,CD₃OD)δ9.07(s,1H),8.94(s,1H),8.66(dd,J＝4.7,2.6Hz,1H),8.58(dd,J＝6.0,2.6Hz,1H),8.09(s,1H),7.46(d,J＝8.1Hz,2H),7.41(d,J＝8.2Hz,2H),7.37(d,J＝7.8Hz,2H),7.24(d,J＝8.0Hz,2H),5.69–5.61(m,1H),4.84–4.75(m,1H),4.64(s,1H),4.60–4.54(m,1H),4.54–4.48(m,2H),4.36(d,J＝15.5Hz,1H),4.31(t,J＝7.3Hz,2H),4.22–3.94(m,1H),3.93–3.84(m,3H),3.83–3.75(m,3H),3.74–3.64(ddq,J＝18.5,10.1,4.9,4.4Hz,5H),3.62–3.56(m,1H),3.28–3.20(h,J＝6.7Hz,2H),2.57–2.49(m,1H),2.47(s,3H),2.45–2.41(m,2H),2.29–2.17(m,2H),2.11–2.05(m,1H),1.94(q,J＝7.5Hz,2H),1.91–1.76(m,1H),1.57(p,J＝7.1Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₅H₆₇F₄N₁₀O₁₀S⁺Of [ M + H]⁺Calculated values: 1135.4693, respectively; the following are found: 1135.4730.

example 163: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 12-dioxo-7, 10-dioxa-4, 13-diazepinan-17-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 39%.¹H NMR(600MHz,CD₃OD)δ9.06(s,1H),8.92(s,1H),8.65(dd,J＝4.8,2.7Hz,1H),8.57(dd,J＝5.9,2.6Hz,1H),8.08(s,1H),7.45–7.39(m,4H),7.38–7.36(m,2H),7.25(d,J＝8.1Hz,2H),5.68–5.59(m,1H),4.83–4.76(m,1H),4.73–4.66(m,1H),4.57(t,J＝8.5Hz,1H),4.52–4.46(m,1H),4.45–4.38(m,2H),4.34–4.27(m,2H),4.15–4.07(m,2H),4.07–3.97(m,4H),3.93–3.83(m,3H),3.82–3.77(m,3H),3.76–3.69(m,5H),3.64–3.54(m,1H),2.47(s,3H),2.26(dd,J＝13.2,7.6Hz,1H),2.22–2.12(m,1H),2.08(ddd,J＝13.4,9.4,4.3Hz,1H),2.00–1.91(m,2H),1.90–1.75(m,1H),1.66–1.53(m,2H),1.02(s,9H)。HRMS(ESI-TOF)m/z：C₅₅H₆₇F₄N₁₀O₁₁S⁺Of [ M + H]⁺Calculated values: 1151.4642, respectively; the following are found: 1151.4645.

example 164: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 14-dioxo-8, 11-dioxa-4, 15-diaza-nonadin-19-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 38%. ¹H NMR(600MHz,CD₃OD)δ9.07(s,1H),8.96(s,1H),8.67(dd,J＝4.7,2.6Hz,1H),8.59(dd,J＝6.1,2.6Hz,1H),8.09(d,J＝2.0Hz,1H),7.46(d,J＝8.0Hz,2H),7.41(d,J＝8.2Hz,2H),7.38–7.35(m,2H),7.24(d,J＝8.0Hz,2H),5.69–5.60(m,1H),4.83–4.77(m,1H),4.64(s,1H),4.60–4.52(m,1H),4.52–4.47(m,2H),4.36(d,J＝15.5Hz,1H),4.31(t,J＝7.3Hz,2H),4.15–3.99(m,1H),3.93–3.84(m,3H),3.80(dd,J＝11.0,4.0Hz,3H),3.75–3.64(m,5H),3.61–3.51(m,5H),3.26(t,J＝6.8Hz,2H),2.57–2.51(m,1H),2.47(s,4H),2.44–2.39(m,2H),2.28–2.17(m,1H),2.08(ddd,J＝13.4,9.3,4.4Hz,1H),1.97(p,J＝7.5Hz,2H),1.84(d,J＝49.2Hz,1H),1.57(p,J＝7.0Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₇H₇₁F₄N₁₀O₁₁S⁺Of [ M + H]⁺Calculated values: 1179.4955, respectively; the following are found: 1179.5066.

example 165: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 15-dioxo-7, 10, 13-trioxa-4, 16-diaza-eicosan-20-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 30%.¹H NMR(600MHz,CD₃OD)δ9.07(s,1H),8.95(s,1H),8.66(dd,J＝4.7,2.6Hz,1H),8.58(dd,J＝6.1,2.6Hz,1H),8.09(d,J＝2.1Hz,1H),7.46(d,J＝8.1Hz,2H),7.42(t,J＝7.6Hz,2H),7.39–7.35(m,2H),7.24(d,J＝8.0Hz,2H),5.64(brs,1H),4.82–4.73(m,1H),4.70(s,1H),4.60–4.54(m,2H),4.53–4.47(m,2H),4.36(d,J＝15.5Hz,1H),4.33–4.27(m,2H),4.11–3.98(m,3H),3.98–3.91(m,2H),3.91–3.84(m,3H),3.83–3.76(m,3H),3.75–3.65(m,9H),3.30–3.28(m,1H),2.47(s,3H),2.29–2.17(m,2H),2.09(ddd,J＝13.4,9.4,4.4Hz,1H),1.95(p,J＝7.4Hz,2H),1.90–1.76(m,1H),1.58(p,J＝7.2Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₇H₇₁F₄N₁₀O₁₂S⁺Of [ M + H]⁺Calculated values: 1195.4904, respectively; the following are found: 1195.5010.

example 166: 2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) -5- (1- ((S) -3- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidine-1-carbonyl) -2, 2-dimethyl-5, 17-dioxo-8, 11, 14-trioxa-4, 18-diaza-docosan-22-yl) -1H-imidazol-4-yl) nicotinamide. The yield was 30%.¹H NMR(600MHz,CD₃OD)δ9.05(s,1H),8.91(s,1H),8.67(dd,J＝4.7,2.5Hz,1H),8.59(dd,J＝6.0,2.6Hz,1H),8.09(t,J＝1.9Hz,1H),7.46(d,J＝8.0Hz,2H),7.40(d,J＝8.1Hz,2H),7.39–7.34(m,2H),7.24(d,J＝8.5Hz,2H),5.65(brs,1H),4.85–4.76(m,1H),4.64(s,1H),4.60–4.54(m,1H),4.52–4.47(m,1H),4.36(d,J＝15.5Hz,1H),4.31(t,J＝7.3Hz,2H),4.15–3.99(m,1H),3.93–3.83(m,3H),3.80(dd,J＝11.0,4.0Hz,2H),3.70(dt,J＝13.7,6.0Hz,4H),3.63–3.51(m,8H),3.35(s,4H),3.27(t,J＝6.7Hz,2H),2.56(ddd,J＝15.0,7.3,5.3Hz,1H),2.47(s,3H),2.42(t,J＝6.0Hz,2H),2.29–2.18(m,2H),2.08(ddd,J＝13.3,9.3,4.5Hz,1H),1.97(p,J＝7.4Hz,2H),1.91–1.76(m,1H),1.57(p,J＝7.0Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₉H₇₅F₄N₁₀O₁₂S⁺Of [ M + H]⁺Calculated values: 1223.5217, respectively; the following are found: 1223.5263.

example 167: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N¹⁶- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -4,7,10, 13-tetraoxahexadecanediamide. The yield was 31%. ¹H NMR(600MHz,CD₃OD)δ9.06(s,1H),8.91(s,1H),8.67(dd,J＝4.6,2.5Hz,1H),8.59(dd,J＝6.2,2.6Hz,1H),8.10(d,J＝2.1Hz,1H),7.46(d,J＝8.1Hz,2H),7.41(d,J＝8.2Hz,2H),7.38–7.34(m,2H),7.27–7.20(m,2H),5.75–5.58(m,1H),4.84–4.75(m,1H),4.64(s,1H),4.60–4.54(m,1H),4.53–4.47(m,1H),4.36(d,J＝15.5Hz,1H),4.32(t,J＝7.3Hz,2H),4.17–3.97(m,1H),3.94–3.84(m,3H),3.80(dd,J＝11.0,3.9Hz,2H),3.75–3.66(m,5H),3.65–3.52(m,13H),3.35(s,2H),3.27(t,J＝6.7Hz,2H),2.59–2.52(m,1H),2.47(s,3H),2.42(t,J＝6.0Hz,2H),2.32–2.18(m,2H),2.08(ddd,J＝13.3,9.2,4.4Hz,1H),1.97(p,J＝7.4Hz,2H),1.91–1.76(m,1H),1.58(p,J＝6.9Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₆₁H₇₉F₄N₁₀O₁₃S⁺Of [ M + H]⁺Calculated values: 1267.5479, respectively; the following are found: 1267.5484.

example 168: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N¹⁸- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) -3,6,9,12, 15-pentaoxaoctadecanediamide. The yield was 31%.¹H NMR(600MHz,CD₃OD)δ9.09(s,1H),8.95(s,1H),8.67(dd,J＝4.7,2.6Hz,1H),8.59(dd,J＝5.8,2.6Hz,2H),8.10(s,1H),7.46(d,J＝8.1Hz,3H),7.44–7.40(m,4H),7.37(d,J＝8.0Hz,4H),7.24(d,J＝8.1Hz,4H),5.69–5.61(m,1H),4.84–4.76(m,1H),4.69(s,1H),4.59–4.56(m,1H),4.55(d,J＝5.4Hz,1H),4.53–4.48(m,2H),4.36(d,J＝15.6Hz,1H),4.32(t,J＝7.3Hz,2H),4.09–4.00(m,3H),3.97(s,2H),3.91–3.84(m,3H),3.83–3.76(m,3H),3.71–3.67(m,5H),3.66–3.62(m,10H),3.61–3.57(m,5H),2.48(s,3H),2.36–2.16(m,2H),2.08(ddd,J＝13.2,9.3,4.3Hz,1H),1.97(p,J＝7.4Hz,2H),1.91–1.76(m,1H),1.61(q,J＝7.5Hz,2H),1.04(s,9H)。HRMS(ESI-TOF)m/z：C₆₂H₈₁F₄N₁₀O₁₄S⁺Of [ M + H]⁺Calculated values: 1297.5585, respectively; the following are found: 1297.5586.

example 169: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N¹⁹- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl1-oxobutan-2-yl) -4,7,10,13, 16-pentaoxanonadecane diamide. The yield was 33%.¹H NMR(600MHz,CD₃OD)δ9.08(s,1H),8.94(s,1H),8.68(dd,J＝4.5,2.5Hz,1H),8.60(dd,J＝6.3,2.6Hz,1H),8.11(t,J＝1.8Hz,1H),7.47(d,J＝8.1Hz,2H),7.41(d,J＝8.2Hz,2H),7.37(dd,J＝8.6,1.9Hz,2H),7.28–7.15(m,2H),5.70–5.61(m,1H),4.83–4.75(m,1H),4.65(s,1H),4.60–4.54(m,1H),4.53–4.48(m,1H),4.36(d,J＝15.5Hz,1H),4.32(t,J＝7.3Hz,2H),4.18–3.97(m,1H),3.94–3.83(m,3H),3.80(dd,J＝11.0,3.8Hz,3H),3.74–3.66(m,5H),3.61–3.58(m,8H),3.57–3.54(m,9H),3.28(t,J＝6.7Hz,2H),2.56(ddd,J＝14.9,7.4,5.1Hz,1H),2.47(s,4H),2.42(t,J＝5.9Hz,2H),2.29–2.18(m,2H),2.08(ddd,J＝13.3,9.2,4.5Hz,1H),1.98(p,J＝7.4Hz,2H),1.91–1.76(m,1H),1.58(p,J＝6.9Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₆₃H₈₃F₄N₁₀O₁₄S⁺Of [ M + H]⁺Calculated values: 1311.5742, respectively; the following are found: 1311.5700.

example 170: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N ⁴- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) succinamide. The yield was 37%.¹H NMR(600MHz,CD₃OD)δ9.07(s,1H),8.91(s,1H),8.67(dd,J＝4.7,2.6Hz,1H),8.59(dd,J＝6.3,2.5Hz,1H),8.12(d,J＝2.9Hz,1H),7.46(d,J＝8.0Hz,2H),7.40(d,J＝8.1Hz,2H),7.38–7.35(m,2H),7.24(d,J＝8.1Hz,2H),5.69–5.60(m,1H),4.82–4.72(m,1H),4.59(s,1H),4.57–4.53(m,1H),4.52–4.46(m,1H),4.36(d,J＝15.5Hz,1H),4.31(t,J＝7.3Hz,2H),4.21–3.96(m,1H),3.94–3.83(m,4H),3.82–3.74(m,3H),3.66–3.55(m,1H),3.24(t,J＝6.8Hz,2H),2.66–2.59(m,1H),2.56–2.50(m,1H),2.49–2.45(m,5H),2.31–2.17(m,2H),2.07(ddd,J＝13.3,9.2,4.4Hz,1H),1.96(p,J＝7.5Hz,2H),1.90–1.74(m,1H),1.56(p,J＝7.1Hz,2H),1.01(s,9H)。HRMS(ESI-TOF)m/z：C₅₃H₆₃F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1091.4431, respectively; the following are found: 1091.4437.

example 171: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N⁵- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) glutaramide. The yield was 35%.¹H NMR(600MHz,CD₃OD)δ9.09(s,1H),8.96(s,1H),8.67(dd,J＝4.7,2.6Hz,1H),8.58(dd,J＝6.2,2.6Hz,1H),8.09(d,J＝2.3Hz,1H),7.46(d,J＝8.1Hz,2H),7.41(d,J＝8.1Hz,2H),7.38–7.33(m,2H),7.24(d,J＝8.1Hz,2H),5.69–5.60(m,1H),4.83–4.76(m,1H),4.61(s,1H),4.59–4.55(m,1H),4.55–4.52(m,1H),4.51–4.48(m,1H),4.36(d,J＝15.5Hz,1H),4.31(t,J＝7.3Hz,2H),4.16–3.97(m,1H),3.92(d,J＝10.8Hz,1H),3.90–3.87(d,J＝9.3Hz,2H),3.84–3.76(m,2H),3.65–3.55(m,1H),3.24(t,J＝6.9Hz,2H),2.47(s,3H),2.38–2.25(m,3H),2.25–2.18(m,3H),2.16(s,2H),2.08(ddd,J＝13.3,9.2,4.4Hz,1H),1.99–1.92(m,2H),1.91–1.85(m,2H),1.57(p,J＝7.1Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₄H₆₅F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1105.4587, respectively; the following are found: 1105.4619.

example 172: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N⁶- ((S) -1- ((2S,4R) -4-hydroxy-2)- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) hexanediamide. The yield was 39%.¹H NMR(600MHz,CD₃OD)δ9.10(s,1H),8.97(s,1H),8.67(dd,J＝4.6,2.5Hz,1H),8.58(dd,J＝6.2,2.6Hz,1H),8.10(t,J＝1.9Hz,1H),7.47(d,J＝8.0Hz,2H),7.41(d,J＝8.1Hz,2H),7.38–7.35(m,2H),7.24(d,J＝8.1Hz,2H),5.69–5.60(m,1H),4.83–4.76(m,1H),4.62(s,1H),4.60–4.54(m,1H),4.53(d,J＝15.8Hz,1H),4.51–4.48(m,1H),4.36(d,J＝15.5Hz,1H),4.32(t,J＝7.2Hz,2H),4.19–3.96(m,1H),3.93–3.83(m,3H),3.80(dd,J＝11.1,4.1Hz,3H),3.64–3.54(m,1H),3.24(t,J＝6.8Hz,2H),2.47(s,3H),2.37–2.24(m,3H),2.23–2.18(m,3H),2.08(ddd,J＝13.3,9.1,4.4Hz,1H),1.96(p,J＝7.3Hz,2H),1.91–1.76(m,1H),1.67–1.59(m,4H),1.56(q,J＝7.5Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₅H₆₇F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1119.4744, respectively; the following are found: 1119.4723.

example 173: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N ⁷- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) pimelinamide. The yield was 30%.¹H NMR(600MHz,CD₃OD)δ9.10(s,1H),9.02(s,1H),8.67(dd,J＝4.7,2.6Hz,1H),8.58(dd,J＝6.3,2.6Hz,1H),8.10(d,J＝1.9Hz,1H),7.47(d,J＝8.0Hz,2H),7.42(d,J＝8.2Hz,2H),7.39–7.34(m,2H),7.29–7.16(m,2H),5.69–5.60(m,1H),4.83–4.75(m,1H),4.63(s,1H),4.59–4.56(m,1H),4.53(d,J＝16.2Hz,1H),4.51–4.48(m,1H),4.36(d,J＝15.5Hz,1H),4.32(t,J＝7.1Hz,2H),4.17–3.97(m,1H),3.93–3.83(m,3H),3.80(dd,J＝11.0,4.0Hz,3H),3.66–3.55(m,1H),3.23(t,J＝7.0Hz,2H),2.48(s,3H),2.33–2.25(m,1H),2.26–2.20(m,3H),2.18(t,J＝7.5Hz,2H),2.08(ddd,J＝13.4,9.2,4.5Hz,1H),1.96(p,J＝7.3Hz,2H),1.91–1.76(m,1H),1.66–1.53(m,6H),1.33(p,J＝7.7Hz,2H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₆H₆₉F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1133.4900, respectively; the following are found: 1133.4889.

example 174: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N⁸- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) octanediamide. The yield was 38%.¹H NMR(600MHz,CD₃OD)δ9.05(s,1H),8.91(s,1H),8.67(dd,J＝4.6,2.6Hz,1H),8.58(dd,J＝6.2,2.6Hz,1H),8.08(d,J＝1.8Hz,1H),7.46(d,J＝8.0Hz,2H),7.41(d,J＝8.2Hz,2H),7.38–7.34(m,2H),7.29–7.20(m,2H),5.78–5.57(m,1H),4.83–4.76(d,J＝17.3Hz,1H),4.63(s,1H),4.60–4.55(m,1H),4.53(d,J＝15.5Hz,1H),4.51–4.48(m,1H),4.36(d,J＝15.5Hz,1H),4.31(t,J＝7.3Hz,2H),4.19–3.95(m,1H),3.94–3.84(m,3H),3.80(dd,J＝11.0,4.0Hz,3H),3.66–3.55(m,1H),3.24(t,J＝7.0Hz,2H),2.47(s,3H),2.31–2.27(m,1H),2.26–2.19(m,3H),2.17(t,J＝7.5Hz,2H),2.08(ddd,J＝13.2,9.2,4.5Hz,1H),1.95(p,J＝7.3Hz,2H),1.91–1.76(m,1H),1.64–1.52(m,6H),1.43–1.23(m,4H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₇H₇₁F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1147.5057, respectively; the following are found: 1147.5161.

example 175: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N⁹- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) nonanediamide. The yield was 37%.¹H NMR(600MHz,CD₃OD)δ9.12(s,1H),9.05(s,1H),8.69(dd,J＝4.6,2.6Hz,1H),8.60(dd,J＝6.3,2.6Hz,1H),8.11(d,J＝2.0Hz,1H),7.49(d,J＝8.0Hz,2H),7.44(d,J＝8.2Hz,2H),7.40–7.35(m,2H),7.26(d,J＝8.0Hz,2H),5.71–5.62(m,1H),4.85–4.77(m,1H),4.65(s,1H),4.61–4.57(m,1H),4.55(d,J＝15.5Hz,1H),4.52–4.50(m,1H),4.38(d,J＝15.5Hz,1H),4.34(t,J＝7.2Hz,2H),4.20–4.00(m,1H),3.96–3.85(m,3H),3.82(dd,J＝11.0,4.0Hz,2H),3.66–3.58(m,1H),3.25(t,J＝6.9Hz,2H),2.50(s,3H),2.30(dq,J＝15.3,7.6Hz,2H),2.24(dd,J＝13.6,7.4Hz,2H),2.20–2.16(m,4H),2.10(ddd,J＝13.3,9.2,4.5Hz,1H),1.97(p,J＝7.3Hz,2H),1.93–1.78(m,1H),1.67–1.51(m,6H),1.38–1.26(m,5H),1.05(s,9H)。HRMS(ESI-TOF)m/z：C₅₈H₇₃F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1161.5213, respectively; the following are found: 1161.5303.

example 176: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N ¹⁰- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) sebacamide. The yield was 30%.¹H NMR(600MHz,CD₃OD)δ9.07(s,1H),8.92(s,1H),8.67(dd,J＝4.6,2.6Hz,1H),8.58(dd,J＝6.2,2.6Hz,1H),8.09(t,J＝2.0Hz,1H),7.47(d,J＝8.0Hz,2H),7.41(d,J＝8.2Hz,2H),7.39–7.35(m,2H),7.24(d,J＝8.1Hz,2H),5.69–5.60(m,1H),4.83–4.76(m,1H),4.64(s,1H),4.59–4.55(m,1H),4.55–4.52(s,1H),4.51–4.48(m,1H),4.36(d,J＝15.5Hz,1H),4.32(t,J＝7.3Hz,2H),4.21–3.96(m,1H),3.95–3.84(m,3H),3.80(dd,J＝11.0,4.1Hz,3H),3.68–3.56(m,1H),3.24(t,J＝6.9Hz,2H),2.47(s,3H),2.28(dq,J＝15.6,7.8Hz,2H),2.22(dd,J＝13.4,7.1Hz,2H),2.17(t,J＝7.5Hz,2H),2.08(ddd,J＝13.3,9.1,4.5Hz,1H),1.96(p,J＝7.4Hz,2H),1.91–1.76(m,1H),1.64–1.52(m,6H),1.34–1.25(m,8H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₅₉H₇₅F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1175.5370, respectively; the following are found: 1175.5453.

example 177: n is a radical of¹- (4- (4- (5-carbamoyl-6- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) pyridin-3-yl) -1H-imidazol-1-yl) butyl) -N¹¹- ((S) -1- ((2S,4R) -4-hydroxy-2- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) undecanediamide. The yield was 31%.¹H NMR(600MHz,CD₃OD)δ9.02(s,1H),8.90(s,1H),8.67(dd,J＝4.6,2.6Hz,1H),8.58(dd,J＝6.3,2.6Hz,1H),8.07(t,J＝1.9Hz,1H),7.46(d,J＝8.1Hz,2H),7.41(d,J＝8.2Hz,2H),7.39–7.34(m,2H),7.24(d,J＝8.5Hz,2H),5.69–5.60(m,1H),4.83–4.75(m,1H),4.63(s,1H),4.60–4.55(m,1H),4.54–4.51(m,1H),4.51–4.47(m,1H),4.35(d,J＝15.5Hz,1H),4.31(t,J＝7.3Hz,2H),4.16–3.99(m,1H),3.94–3.84(m,3H),3.83–3.76(m,3H),3.65–3.56(m,1H),3.24(t,J＝6.9Hz,2H),2.47(s,3H),2.28(td,J＝15.3,14.9,7.7Hz,2H),2.23–2.19(m,2H),2.17(t,J＝7.5Hz,2H),2.08(ddd,J＝13.3,9.1,4.5Hz,1H),1.95(p,J＝7.4Hz,2H),1.91–1.76(m,1H),1.57(q,J＝7.4Hz,6H),1.35–1.22(m,10H),1.03(s,9H)。HRMS(ESI-TOF)m/z：C₆₀H₇₇F₄N₁₀O₉S⁺Of [ M + H]⁺Calculated values: 1189.5526, respectively; the following are found: 1189.5613.

example 178: 5- (1-(4- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) acetamido) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 35%.¹H NMR(600MHz,CD₃OD)δ9.05(s,1H),8.62(dd,J＝5.2,2.6Hz,1H),8.55(dd,J＝6.5,2.6Hz,1H),8.00(d,J＝1.8Hz,1H),7.52(t,J＝7.8Hz,1H),7.37(dd,J＝8.5,2.0Hz,2H),7.25(d,J＝8.1Hz,2H),7.05(d,J＝7.1Hz,1H),6.86(d,J＝8.5Hz,1H),5.69–5.60(m,1H),5.05(dd,J＝12.9,5.5Hz,1H),4.28(t,J＝7.3Hz,2H),4.17–4.02(m,1H),4.00(s,2H),3.94–3.84(m,3H),3.84–3.72(m,2H),3.64–3.58(m,1H),2.85(ddd,J＝17.7,14.0,5.3Hz,1H),2.77–2.72(m,1H),2.72–2.65(m,1H),2.31–2.17(m,1H),2.10(ddt,J＝12.3,6.9,3.9Hz,1H),1.90(p,J＝7.4Hz,3H),1.84–1.77(m,1H),1.57(p,J＝7.0Hz,2H)。HRMS(ESI-TOF)m/z：C₄₂H₄₂F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 892.3036, respectively; the following are found: 892.4059.

example 179: 5- (1- (4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propionylamino) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 33%. ¹H NMR(600MHz,CD₃OD)δ8.96(s,1H),8.61(dd,J＝5.1,2.5Hz,1H),8.53(dd,J＝5.6,2.5Hz,1H),7.96(s,1H),7.58–7.46(m,1H),7.42–7.34(m,2H),7.28–7.21(m,2H),7.09(d,J＝8.6Hz,1H),6.96(dd,J＝7.1,2.2Hz,1H),5.69–5.59(m,1H),4.99(dd,J＝12.7,5.5Hz,1H),4.24(t,J＝7.4Hz,2H),4.17–3.97(m,1H),3.95–3.84(m,2H),3.84–3.71(m,2H),3.67–3.58(m,3H),3.27(dt,J＝8.2,4.0Hz,2H),2.80(ddd,J＝17.1,13.7,5.3Hz,1H),2.72–2.58(m,2H),2.54(q,J＝5.6Hz,2H),2.33–2.18(m,1H),2.06(ddd,J＝12.6,7.0,4.3Hz,1H),1.92–1.78(m,3H),1.52(p,J＝6.9Hz,2H)。HRMS(ESI-TOF)m/z：C₄₃H₄₄F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 906.3193, respectively; the following are found: 906.4594.

example 180: 5- (1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyrylamino) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 34%.¹H NMR(600MHz,CD₃OD)δ9.06(s,1H),8.63(dd,J＝5.0,2.5Hz,1H),8.58–8.51(m,1H),8.06(s,1H),7.54–7.44(m,1H),7.40–7.33(m,2H),7.24(d,J＝8.1Hz,2H),7.09–7.00(m,1H),6.98(dd,J＝7.1,2.7Hz,1H),5.77–5.50(m,1H),5.04(dd,J＝12.8,5.5Hz,1H),4.29(t,J＝7.2Hz,2H),4.17–3.99(m,1H),3.93–3.84(m,2H),3.84–3.69(m,2H),3.63–3.55(m,1H),3.34(t,J＝6.9Hz,2H),3.23(t,J＝6.9Hz,2H),2.85(ddd,J＝17.6,14.0,5.4Hz,1H),2.76–2.61(m,2H),2.31(t,J＝7.1Hz,2H),2.28–2.17(m,1H),2.13–2.06(m,1H),1.94(h,J＝7.8,7.3Hz,4H),1.90–1.74(m,1H),1.54(p,J＝7.1Hz,2H)。HRMS(ESI-TOF)m/z：C₄₄H₄₆F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 920.3349, respectively; the following are found: 920.3956.

example 181: 5- (1- (4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentanoylamino) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 35%.¹H NMR(600MHz,CD₃OD)δ8.96(s,1H),8.63(dd,J＝4.7,2.6Hz,1H),8.55(dd,J＝5.9,2.5Hz,1H),8.01(d,J＝2.2Hz,1H),7.51(t,J＝7.8Hz,1H),7.37(d,J＝8.1Hz,2H),7.24(d,J＝7.9Hz,2H),7.00(d,J＝7.4Hz,2H),5.67–5.58(m,1H),5.03(dd,J＝12.7,5.5Hz,1H),4.82–4.75(m,1H),4.28(t,J＝7.2Hz,2H),4.18–3.98(m,1H),3.93–3.83(m,3H),3.82–3.69(m,2H),3.63–3.56(m,1H),3.25(t,J＝6.8Hz,2H),2.84(ddd,J＝18.2,13.8,5.2Hz,1H),2.76–2.61(m,2H),2.32–2.17(m,3H),2.12–2.06(m,1H),1.94(p,J＝7.4Hz,2H),1.90–1.77(m,1H),1.73(p,J＝7.1Hz,2H),1.69–1.62(m,2H),1.56(p,J＝7.0Hz,2H)。HRMS(ESI-TOF)m/z：C₄₅H₄₈F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 934.3506, respectively; the following are found: 934.4065.

example 182: 5- (1- (4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoylamino) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 38%.¹H NMR(600MHz,CD₃OD)δ9.06(s,1H),8.64(dd,J＝5.2,2.5Hz,1H),8.55(dd,J＝6.3,2.6Hz,1H),8.06(d,J＝2.1Hz,1H),7.49(td,J＝7.8,3.3Hz,1H),7.39–7.35(m,2H),7.24(d,J＝8.1Hz,2H),6.98(ddd,J＝13.3,7.7,3.6Hz,2H),5.68–5.58(m,1H),5.05(dd,J＝12.9,5.5Hz,1H),4.29(t,J＝7.3Hz,2H),4.19–3.97(m,1H),3.95–3.83(m,2H),3.83–3.67(m,2H),3.62–3.56(m,1H),3.30–3.26(m,2H),3.24(t,J＝6.9Hz,2H),2.85(ddd,J＝18.8,14.0,5.3Hz,1H),2.77–2.63(m,2H),2.22(t,J＝7.2Hz,3H),2.12–2.06(m,1H),1.94(p,J＝7.5Hz,2H),1.89–1.75(m,1H),1.66(dt,J＝12.4,6.8Hz,4H),1.55(p,J＝7.1Hz,2H),1.46–1.38(m,2H)。HRMS(ESI-TOF)m/z：C₄₆H₅₀F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 948.3662, respectively; the following are found: 948.4017.

example 183: 5- (1- (4- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptanoylamino) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethyl) amino) Oxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 39%.¹H NMR(600MHz,CD₃OD)δ9.05(s,1H),8.65(dd,J＝4.6,2.6Hz,1H),8.56(dd,J＝6.3,2.5Hz,1H),8.06(s,1H),7.52(t,J＝7.8Hz,1H),7.37(d,J＝8.1Hz,2H),7.24(d,J＝8.1Hz,2H),7.00(dd,J＝11.0,7.9Hz,2H),5.68–5.57(m,1H),5.05(dd,J＝12.8,5.5Hz,1H),4.30(t,J＝7.3Hz,2H),4.18–3.96(m,1H),3.93–3.83(m,3H),3.82–3.68(m,2H),3.28(t,J＝6.7Hz,2H),3.23(t,J＝6.9Hz,2H),2.85(ddd,J＝18.9,14.1,5.3Hz,1H),2.77–2.61(m,2H),2.19(t,J＝7.3Hz,3H),2.13–2.07(m,1H),1.95(p,J＝7.5Hz,2H),1.90–1.75(m,1H),1.62(p,J＝7.3Hz,4H),1.56(p,J＝7.1Hz,2H),1.43(p,J＝7.4Hz,2H),1.37(q,J＝7.6Hz,2H)。HRMS(ESI-TOF)m/z：C₄₇H₅₂F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 962.3819, respectively; the following are found: 962.4877.

example 184: 5- (1- (4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octanoylamino) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 31%.¹H NMR(600MHz,CD₃OD)δ9.07(s,1H),8.65(dd,J＝4.6,2.6Hz,1H),8.57(dd,J＝6.4,2.6Hz,1H),8.06(d,J＝2.2Hz,1H),7.53(t,J＝7.8Hz,1H),7.37(d,J＝8.2Hz,2H),7.24(d,J＝8.1Hz,2H),7.04–6.90(m,2H),5.63(brs,1H),5.05(dd,J＝12.8,5.5Hz,1H),4.30(t,J＝7.3Hz,2H),4.19–3.97(m,1H),3.93–3.82(m,2H),3.82–3.66(m,2H),3.64–3.49(m,1H),3.29–3.26(m,2H),3.24(t,J＝7.0Hz,2H),2.91–2.80(m,1H),2.78–2.64(m,2H),2.30–2.20(s,1H),2.18(t,J＝7.3Hz,2H),2.14–2.06(m,1H),1.95(p,J＝7.4Hz,2H),1.90–1.75(m,1H),1.65–1.58(m,4H),1.55(q,J＝7.3Hz,2H),1.43–1.35(s,4H),1.35–1.31(m,2H)。HRMS(ESI-TOF)m/z：C₄₈H₅₄F₄N₉O₉ ⁺Of [ M + H]⁺Calculated values: 976.3975, respectively; the following are found: 976.4222.

example 186: 5- (1- (4- (3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) propionylamino) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 40%.¹H NMR(600MHz,CD₃OD)δ8.97(s,1H),8.58(dd,J＝5.3,2.6Hz,1H),8.51(dd,J＝5.5,2.5Hz,1H),7.99(s,1H),7.48–7.43(m,1H),7.41–7.34(m,2H),7.25(d,J＝8.0Hz,2H),7.00–6.94(m,2H),5.68–5.58(m,1H),5.04(dd,J＝12.7,5.5Hz,1H),4.25(t,J＝7.4Hz,2H),4.19–4.00(m,1H),3.96–3.82(m,3H),3.78(t,J＝5.8Hz,3H),3.67(t,J＝5.2Hz,2H),3.63–3.56(m,1H),3.42(s,2H),3.25(q,J＝6.7Hz,2H),2.85(ddd,J＝18.6,13.9,5.4Hz,1H),2.76–2.61(m,2H),2.46(t,J＝5.7Hz,2H),2.35–2.16(m,1H),2.13–2.05(m,1H),1.91(p,J＝7.5Hz,2H),1.84–1.75(m,1H),1.53(p,J＝7.0Hz,2H)。HRMS(ESI-TOF)m/z：C₄₅H₄₈F₄N₉O₁₀ ⁺Of [ M + H]⁺Calculated values: 950.3455, respectively; the following are found: 950.3895.

example 186: 5- (1- (4- (3- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) propionylamino) butyl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 29%.¹H NMR(600MHz,CD₃OD)δ9.01(s,1H),8.60(dd,J＝5.0,2.6Hz,1H),8.53(dd,J＝6.4,2.5Hz,1H),8.02(s,1H),7.49(td,J＝7.8,3.1Hz,1H),7.40–7.32(m,2H),7.25(d,J＝8.0Hz,2H),7.02–6.95(m,2H),5.68–5.57(m,1H),5.03(dd,J＝12.8,5.5Hz,1H),4.26(t,J＝7.3Hz,2H),4.18–3.96(m,1H),3.95–3.84(m,2H),3.84–3.76(m,2H),3.74(t,J＝5.8Hz,2H),3.69(t,J＝5.2Hz,2H),3.64(q,J＝5.2Hz,4H),3.62–3.56(m,1H),3.42(q,J＝4.2,3.6Hz,2H),3.24(t,J＝6.7Hz,2H),2.85(ddd,J＝17.3,13.8,5.4Hz,1H),2.77–2.70(m,1H),2.66(td,J＝13.4,4.5Hz,1H),2.42(t,J＝5.8Hz,2H),2.31–2.18(m,1H),2.12–2.06(m,1H),1.93(p,J＝7.5Hz,2H),1.90–1.76(m,1H),1.53(p,J＝6.9Hz,2H)。HRMS(ESI-TOF)m/z：C₄₇H₅₂F₄N₉O₁₁ ⁺Of [ M + H]⁺Calculated values: 994.3717, respectively; the following are found: 994.4232.

Example 187: 5- (1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -12-oxo-3, 6, 9-trioxa-13-azaheptadecan-17-yl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 36%.¹H NMR(600MHz,CD₃OD)δ8.99(s,1H),8.60(dd,J＝5.1,2.5Hz,1H),8.53(dd,J＝6.1,2.5Hz,1H),8.02(s,1H),7.49(ddd,J＝9.6,7.4,2.7Hz,1H),7.37(d,J＝8.0Hz,2H),7.25(d,J＝8.1Hz,2H),6.99(ddd,J＝10.6,7.9,2.7Hz,2H),5.67–5.57(m,1H),5.04(dd,J＝12.7,5.5Hz,1H),4.27(t,J＝7.3Hz,2H),4.19–3.97(m,1H),3.94–3.84(m,2H),3.83–3.75(m,2H),3.70(t,J＝5.6Hz,5H),3.68–3.63(m,4H),3.61(dd,J＝6.2,3.1Hz,2H),3.58(dd,J＝5.9,3.1Hz,2H),3.48–3.40(m,2H),3.25(t,J＝6.6Hz,2H),2.86(ddd,J＝18.5,13.8,5.3Hz,1H),2.78–2.70(m,1H),2.67(td,J＝13.1,4.3Hz,1H),2.40(t,J＝5.8Hz,2H),2.30–2.18(m,1H),2.10(td,J＝7.8,7.2,3.3Hz,1H),1.94(p,J＝7.3Hz,2H),1.90–1.74(m,1H),1.55(p,J＝6.9Hz,2H)。HRMS(ESI-TOF)m/z：C₄₉H₅₆F₄N₉O₁₂ ⁺Of [ M + H]⁺Calculated values: 1038.3979, respectively; the following are found: 1038.4780.

example 188: 5- (1- ((2- (2, 6-dioxopipa)Pyridin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -15-oxo-3, 6,9, 12-tetraoxa-16-azaeicosan-20-yl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 29%.¹H NMR(600MHz,CD₃OD)δ9.04(s,1H),8.61(dd,J＝5.0,2.5Hz,1H),8.54(dd,J＝6.5,2.5Hz,1H),8.04(s,1H),7.49(ddd,J＝9.9,7.3,2.8Hz,1H),7.37(d,J＝8.0Hz,2H),7.24(d,J＝8.1Hz,2H),7.06–6.93(m,2H),5.68–5.58(m,1H),5.04(dd,J＝12.7,5.5Hz,1H),4.28(t,J＝7.3Hz,2H),4.22–3.96(m,1H),3.94–3.84(m,2H),3.83–3.74(m,2H),3.72–3.68(m,5H),3.67–3.64(m,4H),3.63–3.60(m,2H),3.59–3.56(m,2H),3.55–3.52(m,4H),3.46–3.41(m,2H),3.26(t,J＝6.6Hz,2H),2.86(ddd,J＝17.3,13.8,5.3Hz,1H),2.74(dt,J＝17.6,3.2Hz,1H),2.67(td,J＝13.2,4.4Hz,1H),2.41(t,J＝5.8Hz,2H),2.31–2.18(m,1H),2.12–2.07(m,1H),1.95(p,J＝7.4Hz,2H),1.92–1.74(m,1H),1.56(p,J＝6.9Hz,2H)。HRMS(ESI-TOF)m/z：C₅₁H₆₀F₄N₉O₁₃ ⁺Of [ M + H]⁺Calculated values: 1082.4241, respectively; the following are found: 1082.4686.

example 189: 5- (1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -18-oxo-3, 6,9,12, 15-pentaoxa-19-azaeicosatrien-23-yl) -1H-imidazol-4-yl) -2- (((3R,4R) -3-fluoro-1- (2- (4- (trifluoromethoxy) phenyl) acetyl) piperidin-4-yl) oxy) nicotinamide. The yield was 30%.¹H NMR(600MHz,CD₃OD)δ9.04(s,1H),8.62(dd,J＝5.0,2.5Hz,1H),8.56(dd,J＝5.5,2.6Hz,1H),8.05(s,1H),7.50(t,J＝7.9Hz,1H),7.37(d,J＝8.1Hz,2H),7.25(d,J＝8.1Hz,2H),7.01(t,J＝9.4Hz,2H),5.62(brs,1H),5.05(dd,J＝12.7,5.5Hz,1H),4.29(t,J＝7.4Hz,2H),4.19–4.00(m,1H),3.93–3.84(m,2H),3.84–3.75(m,2H),3.70(q,J＝5.0,4.4Hz,5H),3.66(s,4H),3.63(dd,J＝6.1,3.3Hz,2H),3.59(dd,J＝6.1,3.4Hz,2H),3.55–3.51(m,8H),3.44(t,J＝4.9Hz,2H),3.27(t,J＝6.7Hz,2H),2.86(ddd,J＝18.2,13.9,5.4Hz,1H),2.77–2.72(m,1H),2.71–2.64(m,1H),2.41(t,J＝5.8Hz,2H),2.31–2.18(m,1H),2.12–2.06(m,1H),1.96(p,J＝7.4Hz,2H),1.90–1.76(m,1H),1.56(p,J＝7.0Hz,2H)。HRMS(ESI-TOF)m/z：C₅₃H₆₄F₄N₉O₁₄ ⁺Of [ M + H]⁺Calculated values: 1126.4503, respectively; the following are found: 1126.5436.

scheme 31 Synthesis of example 190

Example 190: (3R,5S) -1- ((S) -2- (12- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -12-oxododecanoylamino) -3, 3-dimethylbutyryl) -5- ((4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-3-yl acetate. The title compound can be synthesized according to the following procedure: to a solution of intermediate 7(1 eq) and linking group 28(1.1 eq) in DMSO were added DIEA (7 eq) and TBTU (1.1 eq). After stirring at room temperature for 1h, the mixture was purified by HPLC to give the title compound.

Example compounds 191 and 192 will be synthesized from intermediate 7 and the corresponding linking groups according to the procedure used to prepare example compound 190.

Scheme 32 Synthesis of example 193

Example 193: (S) -N- ((S) -1-cyclohexyl-2- ((S) -2- (4- (3- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1, 2-a)]Pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2-oxoethoxy) benzoyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) acrylamide. The title compound can be synthesized according to the following procedure: to a solution of intermediate 7(1 eq) and linking group 29(1.1 eq) in DMSO were added DIEA (7 eq) and TBTU (1.1 eq). In the roomAfter stirring at room temperature for 1h, the mixture was purified by HPLC. The purified compound was dissolved in MeOH, then Pd/C (0.1 eq.) was added and the reaction was quenched in H₂Stirring is carried out for a further 2h under an atmosphere. Then, the mixture was filtered, and the filtrate was concentrated to give the title compound.

Example compound 194-208 will be synthesized from intermediate 7 and the corresponding linking group according to the procedure used to prepare example compound 193.

Scheme 33 Synthesis of example 209

Example 209: 2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- ((4- (4- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -4-oxobutanoyl) piperazin-1-yl) sulfonyl) -3, 3-dimethylbutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid. The title compound can be synthesized according to the following procedure: to a solution of intermediate 7(1 eq) and linking group 30(1.1 eq) in DMSO were added DIEA (7 eq) and TBTU (1.1 eq). After stirring at room temperature for 1h, the mixture was diluted with DCM and TFA. The resulting solution was stirred at room temperature for a further 1 h. After concentration, the residue was purified by HPLC to give the title compound.

Example compound 210-223 will be synthesized from intermediate 7 and the corresponding linking group according to the procedure used to prepare example compound 209.

Scheme 34 Synthesis of example 224

Example 224: n- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) -2-oxoethyl) -3- (N- (1, 3-dimethyl-2-oxo-6- (3-propoxyphenoxy) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) sulfamoyl) benzamide. The title compound can be synthesized according to the following procedure: to a solution of intermediate 7(1 eq) and linking group 31(1.1 eq) in DMSO were added DIEA (7 eq) and TBTU (1.1 eq). After stirring at room temperature for 1h, the mixture was purified by HPLC to give the title compound.

Example compound 225-239 will be synthesized from intermediate 7 and the corresponding linking group according to the procedure used to prepare example compound 209.

Scheme 35 Synthesis of example 240

Example 240: (S) -N- ((S) -1-cyclohexyl-2- ((S) -2- (4- (3- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) ethoxy) benzoyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) acrylamide. The title compound can be synthesized according to the following procedure: to a solution of intermediate 4(1 eq) and linking group 32(1.1 eq) in DMSO were added DIEA (7 eq) and TBTU (1.1 eq). After stirring at room temperature for 1h, the mixture was diluted with DCM and TFA. The resulting solution was stirred at room temperature for a further 1 h. After concentration, the residue was purified by HPLC to give the title compound.

Example compound 241-250 will be synthesized from intermediate 4 and the corresponding linking group according to the procedure used to prepare example compound 240.

Scheme 36 Synthesis of example 251

Example 251: 2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- ((4- (3- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) propionyl) piperazin-1-yl) sulfonyl) -3, 3-dimethylbutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid. The title compound can be synthesized according to the following procedure: to a solution of intermediate 4(1 eq) and linking group 33(1.1 eq) in DMSO were added DIEA (7 eq) and TBTU (1.1 eq). After stirring at room temperature for 1h, the mixture was diluted with DCM and TFA. The resulting solution was stirred at room temperature for a further 1 h. After concentration, the residue was purified by HPLC to give the title compound.

Example compound 252-259 will be synthesized from intermediate 4 and the corresponding linking group according to the procedure used to prepare example compound 251.

Scheme 37 Synthesis of example 260

Example 260: 3- (N- (6- (3-butoxyphenoxy) -1, 3-dimethyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) sulfamoyl) -N- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetylamino) ethyl) benzamide. The title compound can be synthesized according to the following procedure: to a solution of intermediate 4(1 eq) and linking group 34(1.1 eq) in DMSO were added DIEA (7 eq) and TBTU (1.1 eq). After stirring at room temperature for 1h, the mixture was purified by HPLC to give the title compound.

Example compound 261-269 will be synthesized from intermediate 4 and the corresponding linking group according to the procedure used to prepare example compound 260.

Scheme 38 Synthesis of example 270

Example 270: (2S,4R) -N- (2- (2- (2- (4- (4- ((6-cyclopropyl-3- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-yl) amino) -3-fluorobenzoyl) piperazin-1-yl) acetamido) ethoxy) -4- (4-methylthiazol-5-yl) benzyl) -1- ((S) -2- (1-fluorocyclopropane-1-carboxamido) -3, 3-dimethylbutyryl) -4-hydroxypyrrolidine-2-carboxamide. To a solution of intermediate 4(1 eq) and linking group 35(1.1 eq) in DMSO were added DIEA (7 eq) and TBTU (1.1 eq). After stirring at room temperature for 1h, the mixture was purified by HPLC to give the title compound.

Example compound 271-280 will be synthesized from intermediate 4 and the corresponding linking group according to the procedure used to prepare example compound 270.

The example compounds are shown in table 1 below.

TABLE 1

In table 1, the left part of the structure of PTK6 disruptor/degrader binds to PTK6 (as, e.g., compound 21d (Zeng et al, 2011), compound 4f (Mahmoud et al, 2014), compound 1(Yamamoto, 2016), XMU-MP-2(Jiang et al, 2017), and compound 3s (Cardenas et al, 2018), and analogs thereof), and the right part of the structure recruits the ubiquitination mechanism to PTK6, which induces polyubiquitination and degradation of PTK6 at the proteasome.

Compounds corresponding to examples 1 to 189 have been synthesized and the compound codes are provided in table 1. The compounds in table 1 corresponding to examples 190 to 280 have not been synthesized and no compound code is provided. These compounds can be synthesized according to the above scheme.

As used herein, structure will be controlled in the event that the structure provided for a particular compound does not correspond to a chemical name.

Example 281. evaluation of the effect of selected compounds on reducing the level of PTK6 protein in cancer cells (fig. 2-5).

MDA-MB231 cells were treated with DMSO or 2.5. mu.M, 2. mu.M or 500nM of the indicated compounds for 24 hours. Western blot results showed that various compounds significantly reduced PTK6 protein levels.

Example 282.PTK6 degradant inhibits growth and invasive branching of triple negative MDA-MB231 breast cancer cells in 3-D culture (FIG. 6).

In 3D cultures, MDA-MB231 cells were treated with 1. mu.M of the indicated compound for 3 days. YX39-103 and YX39-105 significantly inhibited the growth and invasive branching of these cells, whereas the negative control compound and the inhibitor of PTK6 kinase activity did not.

Example 283.YX39-103 and YX39-105 inhibit the viability of MCF7 ER + breast cancer cells in 3-D culture (FIG. 7).

MCF7 cells were treated with YX39-103, YX39-105 and compound 21D at 0. mu.M, 1. mu.M, 2. mu.M and 5. mu.M for 4 days using 3D Cell Titer Glo (Promega) assay conditions. YX39-103 and YX39-105 significantly impaired the viability of MCF7 cells in a dose-dependent manner, whereas the effect of PTK6 kinase inhibitor compound 21 was less pronounced.

Example 284.YX39-103 and YX39-105 inhibit the viability of ovarian cancer cells (CP70) that are resistant to chemotherapy (FIG. 8).

Platinum-resistant ovarian cancer cells CP70 were treated with PTK6 degradant or kinase inhibitor P21D (2 μ M) in 3D cultures for 6 days. Viability after 6 days was assessed by 3D Cell Titer glo.

Example 285 MG132 pretreatment prevents PTK6 degradation by YX39-105 in MDA-MB231 cells (FIG. 9).

MDA-MB231 cells were pre-treated with MG132 (10. mu.M) or DMSO for 2 hours, and then re-treated with PTK6 degradants YX39-105 or DMSO for 4 hours. Cells were lysed and expression of PTK6 was assessed by Western analysis.

Example 286 PTK6 inhibitor pretreatment prevented PTK6 from being degraded by YX39-105 in MDA-MB231 cells (FIG. 10).

MDA-MB231 cells pretreated for 2 hours with DMSO or the inhibitor of the kinase activity of PTK 6P 21d (5. mu.M) were subsequently treated for 24 hours with the PTK6 degradant YX 39-105. Expression of PTK6 was assessed by Western analysis.

Example 287.PTK6 degrading agents down-regulate PTK6 in ER + MCF7/EDR cells resistant to endocrine therapy (fig. 11).

MCF7/EDR cells in monolayer cultures were treated with PTK6 degradant at the indicated concentration for 24 hours. Cells were lysed and expression of PTK6 was assessed.

Example 288.PTK6 degradants, but not inhibitors of kinase activity, inhibited viability in 3D cultures (figure 12).

After 24 hours treatment with 1 μ M compound in monolayer cultures, expression of PTK6 in cells treated with PTK6 degradant, negative control compound, or PTK6 kinase activity inhibitor was assessed (fig. 12A). Cells were lysed and proteins were isolated and probed with anti-PTK 6 antibody (Cell Signaling).

MDA-MB231 triple negative breast cancer cells were inoculated into 3D matrigel cultures (4X 10)³Individual cells/well) and treated with 1 μ M of the indicated PTK6 degradant, negative control compound or PTK6 kinase activity inhibitor for 6 days, with compound re-added to the culture after 3 days (fig. 12B). 3D Cell Titer glo (Promega) was used to evaluate viability.

Example 289 PTK6 degrading agents inhibited PTK6 protein levels in MDA-MB231 cells (fig. 13).

In monolayer cultures, MDA-MB231 cells were treated with compound (500nM or 1. mu.M) for 24 hours. Cells were lysed and lysates probed with anti-PTK 6 antibody.

Materials and methods:

the general chemical method comprises the following steps:

all chemicals and reagents were purchased from commercial suppliers and used without further purification. HPLC profiles of all compounds were obtained using an Agilent 1200 series system with DAD detector. Chromatography was carried out on a 2.1X 150mm Zorbax 300 SB-C185 μm column using water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 0.4 ml/min. The linear gradient is as follows: 1% B (0-1min), 1-99% B (1-4min) and 99% B (4-8 min). High Resolution Mass Spectrometry (HRMS) data were obtained in positive ion mode using Agilent G1969A API-TOF with electrospray ionization (ESI) source. Proton Nuclear Magnetic Resonance (NMR) was recorded on a Bruker DRX-600 spectrometer¹H-NMR) spectrum, and recording the carbon nuclear magnetism at 150MHz¹³C NMR). Chemical shifts are expressed in parts per million (ppm) and are reported as δ values (chemical shifts δ). Coupling constants are reported in hertz (J value, Hz; integration mode and splitting mode: where s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, brs ═ broad singlet, m ═ multiplet). Preparative HPLC was performed on Agilent Prep 1200 series with UV detector set to 254 nm. Samples were injected at room temperature onto a Phenomenex Luna 75 × 30mm, 5 μm, C18 column. The flow rate was 40 ml/min. At H ₂A linear gradient was used in the case of 10% (or 50%) meoh (a) in O (with 0.1% TFA) (B) to 100% meoh (a). HPLC was used to determine the purity of the target compound. All compounds showed purity using the HPLC method described above>95％。

Antibodies and reagents

Antibodies purchased from Cell Signaling Technology were: GAPDH (14C10), β -tubulin (9F3), E-cadherin (24E10), and PTK 6. The antibodies obtained from Santa Cruz Biotechnology were: BRK antibodies (C-18 and D-7), goat anti-rabbit IgG-HRP, and goat anti-mouse IgG-HRP. PTK6 inhibitors (pyrazine-21 d, P21d) were synthesized according to the published description [24 ]. MDA231 cells, MCF7 cells, UACC893 cells, and MCFA-10A cells were obtained from ATCC. OV2008 was purchased from ThermoFisher Scientific. HeyC2 was purchased from cellulose Biosystems, Inc. All cell lines were cultured according to the media guidelines recommended by the ATCC or the individual supplier's instructions. MDA-MB231 cells (ATCC) were cultured in RPMI-1640 supplemented with 10% FBS. MCF7TamR cells, EDR cells, FulvR cells and MMTV-myc cells were cultured according to the published protocol (Ito et al, 2017; Ito et al, 2016).

RNAi knockdown

siRNA targeting PTK6 was obtained from GE Healthcare Dharmacon. Transfection was performed using Oligofectamine (Life technologies) following the manufacturer's protocol. Short hairpin-RNA targeting PTK6 was purchased from Sigma-Aldrich. Lentiviruses were generated by co-transfecting 293T cells with shRNA vectors and packaging plasmids (Delta 8.9 and pCMV-VSV-G) using Lipofectamine 2000 and Plus reagents (Life Technologies). The supernatant was collected and stored at-80 ℃. The cells were infected with the virus supernatant.

Immunoblotting

Cells were incubated with NaF, Na as described previously (Irie et al, 2010)₃VO₄Leupeptin, PMSF, aprotinin and phosphatase inhibitors (PhosSTOP, Roche) in 1% NP-40 lysis buffer. The clarified cell lysates were stored at-80 ℃ and analyzed by Western analysis as described previously (Irie et al, 2010).

3D cell growth assay

MDA-MB231 cells, MCF-7 cells, OV2008 cells and Hey C2 cells (3,000 cells) were added to Matrigel covered with 50. mu.l growth factor-reduced Matrigel^TM8-well chamber slides (BD Biosciences) of matrix basement membrane (Corning). Treatment with the degradation agent was started later in the day. The medium was changed every 3 days. Cells were imaged using an Axiovert 25 inverted microscope (Carl Zeiss AB). Matrigel in 96-well plates using the CellTiter-Glo 3D cell viability assay (Promega)^TMThe viability of the growing cells was quantified.

Apoptosis detection

The medium containing the floating cells was transferred to a 15ml conical tube. The parietal cells were collected by trypsinization at 37 ℃ in the same tube and then spun at 360 × g for 3 min. The cell pellet was washed once with ice-cold PBS and resuspended in 250. mu.l of 1 × binding buffer (BD Biosciences, #556547) containing 5. mu.l of FITC-annexin V and PI. After incubation at room temperature for 15min in the dark, 250 μ l of 1 × binding buffer was added and flow cytometry analysis was performed as previously described (Park et al, 2015).

Tumor xenograft study

Six-week-old female nude (nu/nu) mice (Charles River Laboratories) were injected subcutaneously with MCF-7 cells or UACC893R cells infected with control or PTK6 shRNA lentivirus. Cancer cells expressing PTK6 shRNA or vector control shRNA were generated in vitro prior to subcutaneous injection into nude mice. Mice from the combination purchased cages were randomly assigned to inject cells expressing PTK6 or control shRNA. Tumor growth was monitored twice weekly and tumor volume was determined [ V ═ 1/2 (lxw)²)]. Tumor measurements were performed by a second investigator blinded to shRNA treatment. Mice were euthanized when tumor diameter reached 10mm in any direction according to the approved IACUC protocol. All procedures and studies using mice were performed according to protocols approved by the Institutional Animal Care and Use Committee of Icahn School of Medicine at Mount Sinai.

Lung colonization (Lung colonization) detection

MDA-MB231 cells or MMTV-myc cells were transduced with PTK6 shRNA virus for 72 hours. For the PTK6 inhibitor experiments, MMTV-myc cells were treated in vitro with the PTK6 inhibitor P21d for 48 h. shRNA-infected cells or inhibitor-treated cells were washed three times with PBS. MDA-MB231 cells (2X 10 per mouse) in 100. mu.l PBS ⁶Individual) or MMTV-myc cells (5X 10 per mouse)⁴Individually) were injected into the tail vein of 6-week-old NOD-SCID or FVB female mice (Charles River Labs), respectively. Lung tissue was harvested after four weeks for MDA-MB231 and three weeks for MMTV-myc and fixed in Bouin's solution. The number of superficial lung metastases (size greater than 0.5mm in diameter for MDA-MB231 and greater than 1mm in diameter for MMTV-myc cells) was counted. All animal procedures were performed according to the guidelines of the IACUC committee of the western kaempa medical college.

Other embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Reference to the literature

Aguilar,A.,Lu,J.,Liu,L.,Du,D.,Bernard,D.,McEachern,D.,Przybranowski,S.,Li,X.,Luo,R.,Wen,B.,et al.(2017).Discovery of 4-((3'R,4'S,5'R)-6”-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2”-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3”-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid(AA-115/APG-115):A Potent and Orally Active Murine Double Minute 2(MDM2)Inhibitor in Clinical Development.J Med Chem 60,2819-2839.

Bondeson,D.P.,Mares,A.,Smith,I.E.,Ko,E.,Campos,S.,Miah,A.H.,Mulholland,K.E.,Routly,N.,Buckley,D.L.,Gustafson,J.L.,et al.(2015).Catalytic in vivo protein knockdown by small-molecule PROTACs.Nat Chem Biol 11,611-617.

Brauer,P.M.,and Tyner,A.L.(2010).Building a better understanding of the intracellular tyrosine kinase PTK6-BRK by BRK.Biochim Biophys Acta 1806,66-73.

Buckley,D.L.,and Crews,C.M.(2014).Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system.Angew Chem Int Ed Engl 53,2312-2330.

Buckley,D.L.,Gustafson,J.L.,Van Molle,I.,Roth,A.G.,Tae,H.S.,Gareiss,P.C.,Jorgensen,W.L.,Ciulli,A.,and Crews,C.M.(2012a).Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha.Angew Chem Int Ed Engl 51,11463-11467.

Buckley,D.L.,Raina,K.,Darricarrere,N.,Hines,J.,Gustafson,J.L.,Smith,I.E.,Miah,A.H.,Harling,J.D.,and Crews,C.M.(2015).HaloPROTACS:Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins.ACS Chem Biol 10,1831-1837.

Buckley,D.L.,Van Molle,I.,Gareiss,P.C.,Tae,H.S.,Michel,J.,Noblin,D.J.,Jorgensen,W.L.,Ciulli,A.,and Crews,C.M.(2012b).Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction.J Am Chem Soc 134,4465-4468.

Cardenas,M.M.,Toenjes,S.T.,Nalbandian,C.J.,and Gustafson,J.L.(2018).Enantioselective Synthesis of Pyrrolopyrimidine Scaffolds through Cation-Directed Nucleophilic Aromatic Substitution.Org Lett 20,2037-2041.

Castro,N.E.,and Lange,C.A.(2010).Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells.Breast Cancer Res 12,R60.

Chamberlain,P.P.,Lopez-Girona,A.,Miller,K.,Carmel,G.,Pagarigan,B.,Chie-Leon,B.,Rychak,E.,Corral,L.G.,Ren,Y.J.,Wang,M.,et al.(2014).Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs.Nat Struct Mol Biol 21,803-809.

Chen,X.,Song,B.,Lin,Y.,Cao,L.,Feng,S.,Zhang,L.,and Wang,F.(2016).PTK6 promotes hepatocellular carcinoma cell proliferation and invasion.Am J Transl Res 8,4354-4361.

Davies,T.G.,Wixted,W.E.,Coyle,J.E.,Griffiths-Jones,C.,Hearn,K.,McMenamin,R.,Norton,D.,Rich,S.J.,Richardson,C.,Saxty,G.,et al.(2016).Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1:Nuclear Factor Erythroid 2-Related Factor 2(KEAP1:NRF2)Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.J Med Chem59,3991-4006.

Derry,J.J.,Prins,G.S.,Ray,V.,and Tyner,A.L.(2003).Altered localization and activity of the intracellular tyrosine kinase BRK/Sik in prostate tumor cells.Oncogene 22,4212-4220.

E.Wakeling,A.(1995).Use of pure antioestrogens to elucidate the mode of action of oestrogens.Biochem Pharmacol 49,1545-1549.

Fan,Q.,Aksoy,O.,Wong,R.A.,Ilkhanizadeh,S.,Novotny,C.J.,Gustafson,W.C.,Truong,A.Y.,Cayanan,G.,Simonds,E.F.,Haas-Kogan,D.,et al.(2017).A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.Cancer Cell 31,424-435.

Fischer,E.S.,Bohm,K.,Lydeard,J.R.,Yang,H.,Stadler,M.B.,Cavadini,S.,Nagel,J.,Serluca,F.,Acker,V.,Lingaraju,G.M.,et al.(2014).Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide.Nature 512,49-53.

Galdeano,C.,Gadd,M.S.,Soares,P.,Scaffidi,S.,Van Molle,I.,Birced,I.,Hewitt,S.,Dias,D.M.,and Ciulli,A.(2014).Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau(VHL)E3 ubiquitin ligase and the hypoxia inducible factor(HIF)alpha subunit with in vitro nanomolar affinities.J Med Chem 57,8657-8663.

Haegebarth,A.,Bie,W.,Yang,R.,Crawford,S.E.,Vasioukhin,V.,Fuchs,E.,and Tyner,A.L.(2006).Protein tyrosine kinase 6 negatively regulates growth and promotes enterocyte differentiation in the small intestine.Mol Cell Biol 26,4949-4957.

Han,X.,Wang,C.,Qin,C.,Xiang,W.G.,Fernandez-Salas,E.,Yang,C.Y.,Wang,M.,Zhao,L.J.,Xu,T.F.,Chinnaswamy,K.,et al.(2019).Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera(PROTAC)Degrader of Androgen Receptor(AR)for the Treatment of Prostate Cancer.J Med Chem62,941-964.

Harvey,A.J.,and Crompton,M.R.(2003).Use of RNA interference to validate Brk as a novel therapeutic target in breast cancer:Brk promotes breast carcinoma cell proliferation.Oncogene 22,5006-5010.

Harvey,A.J.,Pennington,C.J.,Porter,S.,Burmi,R.S.,Edwards,D.R.,Court,W.,Eccles,S.A.,and Crompton,M.R.(2009).Brk protects breast cancer cells from autophagic cell death induced by loss of anchorage.Am J Pathol 175,1226-1234.

Hiroyuki Suda,Tomohisa Takita,Takaaki Aoyagi,and Umezawa,H.(1976).The structure of bestatin.

The Journal of Antibiotic 20,100-101.

Irie,H.Y.,Shrestha,Y.,Selfors,L.M.,Frye,F.,Iida,N.,Wang,Z.,Zou,L.,Yao,J.,Lu,Y.,Epstein,C.B.,et al.(2010).PTK6 regulates IGF-1-induced anchorage-independent survival.PLoS One 5,e11729.

Ito,K.,Park,S.H.,Katsyv,I.,Zhang,W.,De Angelis,C.,Schiff,R.,and Irie,H.Y.(2017).PTK6 regulates growth and survival of endocrine therapy-resistant ER+breast cancer cells.NPJ Breast Cancer 3,45.

Ito,K.,Park,S.H.,Nayak,A.,Byerly,J.H.,and Irie,H.Y.(2016).PTK6Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation.Cancer Res 76,4406-4417.

Ito,T.,Ando,H.,Suzuki,T.,Ogura,T.,Hotta,K.,Imamura,Y.,Yamaguchi,Y.,and Handa,H.(2010).Identification of a primary target of thalidomide teratogenicity.Science 327,1345-1350.

Jiang,J.,Gui,F.,He,Z.,Li,L.,Li,Y.,Li,S.,Wu,X.,Deng,Z.,Sun,X.,Huang,X.,et al.(2017).Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors.Cancer Res 77,175-186.

Lai,A.C.,Toure,M.,Hellerschmied,D.,Salami,J.,Jaime-Figueroa,S.,Ko,E.,Hines,J.,and Crews,C.M.(2016).Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL.Angew Chem Int Ed Engl 55,807-810.

Liu,J.,Farmer,J.D.,Jr.,Lane,W.S.,Friedman,J.,Weissman,I.,and Schreiber,S.L.(1991).Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.Cell 66,807-815.

Lu,J.,Qian,Y.,Altieri,M.,Dong,H.,Wang,J.,Raina,K.,Hines,J.,Winkler,J.D.,Crew,A.P.,Coleman,K.,et al.(2015).Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.Chemistry&biology 22,755-763.

Mahmoud,K.A.,Krug,M.,Wersig,T.,Slynko,I.,Schachtele,C.,Totzke,F.,Sippl,W.,and Hilgeroth,A.(2014).Discovery of 4-anilino alpha-carbolines as novel Brk inhibitors.Bioorg Med Chem Lett 24,1948-1951.

Maniaci,C.,Hughes,S.J.,Testa,A.,Chen,W.,Lamont,D.J.,Rocha,S.,Alessi,D.R.,Romeo,R.,and Ciulli,A.(2017).Homo-PROTACs:bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation.Nat Commun 8,830.

Mitchell,P.J.,Barker,K.T.,Martindale,J.E.,Kamalati,T.,Lowe,P.N.,Page,M.J.,Gusterson,B.A.,and Crompton,M.R.(1994).Cloning and characterisation of cDNAs encoding a novel non-receptor tyrosine kinase,brk,expressed in human breast tumours.Oncogene 9,2383-2390.

Ohoka,N.,Okuhira,K.,Ito,M.,Nagai,K.,Shibata,N.,Hattori,T.,Ujikawa,O.,Shimokawa,K.,Sano,O.,Koyama,R.,et al.(2017).In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein(IAP)-dependent Protein Erasers(SNIPERs).J Biol Chem 292,4556-4570.

Okuhira,K.,Ohoka,N.,Sai,K.,Nishimaki-Mogami,T.,Itoh,Y.,Ishikawa,M.,Hashimoto,Y.,and Naito,M.(2011).Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1and the target protein.FEBS Lett 585,1147-1152.

Ono,H.,Basson,M.D.,and Ito,H.(2014).PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling.PLoS One 9,e96060.

Ostrander,J.H.,Daniel,A.R.,and Lange,C.A.(2010).Brk/PTK6 signaling in normal and cancer cell models.Curr Opin Pharmacol 10,662-669.

Park,S.H.,Ito,K.,Olcott,W.,Katsyv,I.,Halstead-Nussloch,G.,and Irie,H.Y.(2015).PTK6 inhibition promotes apoptosis of Lapatinib-resistant Her2(+)breast cancer cells by inducing Bim.Breast Cancer Res 17,86.

Peng,M.,Ball-Kell,S.M.,and Tyner,A.L.(2015).Protein tyrosine kinase 6promotes ERBB2-induced mammary gland tumorigenesis in the mouse.Cell Death Dis 6,e1848.

Rodrik-Outmezguine,V.S.,Okaniwa,M.,Yao,Z.,Novotny,C.J.,McWhirter,C.,Banaji,A.,Won,H.,Wong,W.,Berger,M.,de Stanchina,E.,et al.(2016).Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor.Nature 534,272-276.

Schmandt,R.E.,Bennett,M.,Clifford,S.,Thornton,A.,Jiang,F.,Broaddus,R.R.,Sun,C.C.,Lu,K.H.,Sood,A.K.,and Gershenson,D.M.(2006).The BRK tyrosine kinase is expressed in high-grade serous carcinoma of the ovary.Cancer Biol Ther 5,1136-1141.

Shibata,N.,Miyamoto,N.,Nagai,K.,Shimokawa,K.,Sameshima,T.,Ohoka,N.,Hattori,T.,Imaeda,Y.,Nara,H.,Cho,N.,et al.(2017).Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands.Cancer Sci 108,1657-1666.

Sun,D.,Li,Z.,Rew,Y.,Gribble,M.,Bartberger,M.D.,Beck,H.P.,Canon,J.,Chen,A.,Chen,X.,Chow,D.,et al.(2014).Discovery of AMG 232,a potent,selective,and orally bioavailable MDM2-p53 inhibitor in clinical development.J Med Chem 57,1454-1472.

Varfolomeev,E.,Blankenship,J.W.,Wayson,S.M.,Fedorova,A.V.,Kayagaki,N.,Garg,P.,Zobel,K.,Dynek,J.N.,Elliott,L.O.,Wallweber,H.J.,et al.(2007).IAP antagonists induce autoubiquitination of c-IAPs,NF-kappaB activation,and TNFalpha-dependent apoptosis.Cell 131,669-681.

Vassilev,L.T.,Vu,B.T.,Graves,B.,Carvajal,D.,Podlaski,F.,Filipovic,Z.,Kong,N.,Kammlott,U.,Lukacs,C.,Klein,C.,et al.(2004).In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Science 303,844-848.

Vu,B.,Wovkulich,P.,Pizzolato,G.,Lovey,A.,Ding,Q.,Jiang,N.,Liu,J.J.,Zhao,C.,Glenn,K.,Wen,Y.,et al.(2013).Discovery of RG7112:A Small-Molecule MDM2 Inhibitor in Clinical Development.ACS Med Chem Lett4,466-469.

Weisberg,E.,Ray,A.,Barrett,R.,Nelson,E.,Christie,A.L.,Porter,D.,Straub,C.,Zawel,L.,Daley,J.F.,Lazo-Kallanian,S.,et al.(2010).Smac mimetics:implications for enhancement of targeted therapies in leukemia.Leukemia 24,2100-2109.

Winter,G.E.,Buckley,D.L.,Paulk,J.,Roberts,J.M.,Souza,A.,Dhe-Paganon,S.,and Bradner,J.E.(2015).Phthalimide conjugation as a strategy for in vivo target protein degradation.Science 348,1376-1381.

Xie,T.,Lim,S.M.,Westover,K.D.,Dodge,M.E.,Ercan,D.,Ficarro,S.B.,Udayakumar,D.,Gurbani,D.,Tae,H.S.,Riddle,S.M.,et al.(2014).Pharmacological targeting of the pseudokinase Her3.Nat Chem Biol 10,1006-1012.

Yamamoto,S.T.,Hiroshi；Kurono,Masakuni；Nomura,Yoshinori；Hotta,Shingo(2016).BRK INHIBITORY COMPOUND(ONO PHARMACEUTICAL CO.,LTD.(1-5 Doshomachi 2-chome,Chuo-ku Osaka-sh,Osaka 26,〒5418526,JP),).

Zeng,H.,Belanger,D.B.,Curran,P.J.,Shipps,G.W.,Jr.,Miao,H.,Bracken,J.B.,Arshad Siddiqui,M.,Malkowski,M.,and Wang,Y.(2011).Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors.Bioorg Med Chem Lett 21,5870-5875.

Zengerle,M.,Chan,K.H.,and Ciulli,A.(2015).Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4.ACS Chem Biol10,1770-1777.

Zheng,Y.,Wang,Z.,Bie,W.,Brauer,P.M.,Perez White,B.E.,Li,J.,Nogueira,V.,Raychaudhuri,P.,Hay,N.,Tonetti,D.A.,et al.(2013).PTK6activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer.Cancer Res 73,5426-5437.

291页详细技术资料下载

上一篇：一种医用注射器针头装配设备

下一篇：用于治疗睡眠呼吸中止的α2-肾上腺素受体亚型C(α-2C)拮抗剂

Protein tyrosine kinase 6(PTK6) degradation/disruption compounds and methods of use

相关技术

网友询问留言