Novel small molecule inhibitors of TEAD transcription factor

文档序号：411079 发布日期：2021-12-17 浏览：10次中文

阅读说明：本技术 Tead转录因子的新型小分子抑制剂 (Novel small molecule inhibitors of TEAD transcription factor ) 是由 P·迈蒂 C·阿比奈尼 K·C·塔鲁里 S·K·帕尼格拉希吴旭 G·K·雅鲁古米利孙于 2020-03-13 设计创作，主要内容包括：本公开化合物以及其组合物和使用方法。所述化合物抑制TEAD转录因子的活性,并且可用于治疗与TEAD转录因子的活性相关的疾病,包含例如癌症和其它疾病。(Disclosed are compounds, compositions and methods of use thereof. The compounds inhibit the activity of TEAD transcription factors and are useful in the treatment of diseases associated with the activity of TEAD transcription factors, including, for example, cancer and other diseases.)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

L¹is absent or of the formula N (R)^N) Or the group of C (O);

d is a group of formula (D1), (D2), (D3), (D4), (D5), (D6) or (D7):

m is 1,2 or 3;

A¹is C (O) R¹、S(O)₂R¹、NHC(O)R¹、(C_1-3Alkylene) -C (O) R¹、NH(C_1-3Alkylene) -C (O) R¹、CN、NO₂5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C)_1-3Alkylene) -5-to 10-membered heteroaryl or (C)_1-3Alkylene) -4-to 10-membered heterocycloalkyl, in which A is formed¹Is (C)_1-3Alkylene) -C (O) R¹Of group (C)_1-3Alkylene) group unsubstituted OR substituted with 1,2,3,4 OR 5 substituents each independently selected from halogen, OR^a1、NR^c1R^d1、NR^a1(CO)(C_1-6Alkyl) and NR^a1(CO)O(C_1-6Alkyl groups); and wherein form A¹5-to 10-membered heteroaryl, 4-to 10-membered heterocycloalkyl, (C)_1-3Alkylene) -5-to 10-membered heteroaryl or (C)_1-3Alkylene) -4-10 membered heterocycloalkyl unsubstituted OR substituted with 1,2,3,4 OR 5 substituents each independently selected from halogen, OR^a1、SR^a1、C(O)OR^a1、NR^c1R^d1And C (O) NR^c1R^d1；

L²Is absent or of the formula N (R)^N) A group of O or C (O);

L³is absent or of the formula CH₂、C≡C、N(R^N) Or the group of C (O);

each R^NIndependently H, C_1-6Alkyl, C (O) C_1-6Alkyl or C (O) OC_1-6An alkyl group;

R¹is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, Cy^1A、OH、OC_1-6Alkyl radical OCy^1A、O(C_1-3Alkylene) Cy^1A、NH₂、NHC_1-6Alkyl, N (C)_1-6Alkyl radical)₂、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1AWherein R is formed¹Each C of_1-6Alkyl is unsubstituted OR substituted with 1,2,3,4 OR 5 substituents each independently selected from halogen, OR^a1、SR^a1And NR^c1R^d1；

Cy^1AIs C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^1AC of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 Cy^1BAnd 0, 1,2,3,4 or 5 substituents, each independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

each Cy^1BIs C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^1BC of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1,2,3,4 or 5 substituents each independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1(ii) a And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

A²is CR²Or N;

A³is CR³Or N;

A⁴is CR⁴Or N;

A⁵is CR⁵Or N;

A⁶is CR⁶Or N;

A⁷is CR⁷Or N;

A⁸is CR⁸Or N;

A⁹is CR⁹Or N;

A¹⁰is CR¹⁰Or N;

A^D41is CH, C (C)_1-6Alkyl) or N;

A^D42is CH₂NH or NC_1-6An alkyl group;

R²is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁴is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁵is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、S(O)₂R^b1、S(O)₂NR^c1R^d1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1、Cy^7A、OCy^7A、O(C_1-3Alkylene) Cy^7A、C(O)OCy^7A、C(O)O(C_1-3Alkylene) Cy^7A、NHCy^7A、NH(C_1-3Alkylene) Cy^7A、N(C_1-6Alkyl) Cy^7A、N(C(O)C_1-6Alkyl) Cy^7A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7A、C(O)NHCy^7A、C(O)NH(C_1-3Alkylene) Cy^7A、C(O)N(C_1-6Alkyl) Cy^7A、C(O)N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、S(O)₂NR^c1R^d1、C(O)NR^c1R^d1、Cy^7A、OCy^7A、O(C_1-3Alkylene) Cy^7A、C(O)OCy^7A、C(O)O(C_1-3Alkylene) Cy^7A、NHCy^7A、NH(C_1-3Alkylene) Cy^7A、N(C_1-6Alkyl) Cy^7A、N(C(O)C_1-6Alkyl) Cy^7A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7A、C(O)NHCy^7A、C(O)NH(C_1-3Alkylene) Cy^7A、C(O)N(C_1-6Alkyl) Cy^7A、C(O)N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

Cy^7Ais C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^7AC of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 members selected from Cy^7B、OCy^7B、NHCy^7BAnd C (O) NHCy^7BAnd 0, 1,2,3,4, or 5 substituents each independently selected from the group consisting of: unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

each Cy^7BIs C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^7BC of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1,2,3,4 or 5 substituents each independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、S(O)₂NR^c1R^d1、SR^a1、NR^c1R^d1、NR^c1S(O)₂R^b1、C(O)OR^a1、C(O)NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、C(O)OCy^8A、C(O)O(C_1-3Alkylene) Cy^8A、NHCy^8A、N(Cy^8A)₂、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8A、N(C(O)C_1-6Alkyl) Cy^8A、SO₂NHCy^8A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^8A、C(O)NHCy^8A、C_1-3alkylene-C (O) NHCy^8A、C(O)NH(C_1-3Alkylene) Cy^8A、C(O)N(C_1-6Alkyl) Cy^8A、C(O)N(C_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

Cy^8Ais C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^8AC of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 members selected from Cy^8B、OCy^8B、NHCy^8BAnd C (O) NHCy^8BAnd 0, 1,2,3,4, or 5 substituents each independently selected from the group consisting of: unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

each Cy^8BIs C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkylIn which Cy is formed^8BC of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1,2,3,4 or 5 substituents each independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、NR^c1C(O)R^b1、C(O)OR^a1、C(O)NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹⁰is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

Cy^D71is C_6-10Aryl radical, C_3-15Cycloalkyl, 5-14 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^D71C of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 members selected from Cy^D72、CH₂Cy^D72、OCy^D72、NHCy^D72、O-C_1-6alkylene-Cy^D72、N(C_1-6Alkyl) Cy^D72、N(C(O)C_1-6Alkyl) Cy^D72And C (O) NHCy^D72And 0, 1,2,3,4, or 5 substituents each independently selected from the group consisting of: unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、S(hal)₅、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、C(O)OR^a1And NR^c1R^d1C substituted by a substituent of_1-6Alkyl or C_2-6An alkenyl group;

each Cy^D72Is C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^D72C of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1,2,3,4 or 5 substituents each independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl radical, C_3-15Cycloalkyl, 4-10 membered heterocycloalkyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 each independently of the other from C_6-10Aryl radical, C_3-15Cycloalkyl, 4-10 membered heterocycloalkyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、C(O)OR^a1And NR^c1R^d1C substituted by a substituent of_1-6Alkyl radical, wherein said C_6-10Aryl radical, C_3-15Cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1,2 or 3 independently selected from C_1-6Alkyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1And C (O) NR^c1R^d1Substituted with the substituent(s); and is

R^a1、R^b1、R^c1And R^d1Each independently selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, HO-C_1-6Alkylene, amino-C_1-6Alkylene radical, C_1-6alkylamino-C_1-6Alkylene, di (C)_1-6Alkyl) amino-C_1-6Alkylene radical, C_1-6alkoxy-C_1-6Alkylene radical, C_6-10Aryl radical, C_2-6Alkenyl and C_2-6An alkynyl group; or

R^c1And R^d1And the nitrogen atoms to which they are both attached together form a 4-10 membered unsubstituted heterocycloalkyl ring or a heterocycle substituted with 1,2 or 3 substituents independently selected from C_1-6Alkyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1And C (O) NR^c1R^d1；

With the following conditions:

when L is²When is C (O), L¹Is of the formula N (R)^N) A group of (a);

when L is²Is N (R)^N) When L is¹Is a group of formula C (O);

when L is¹When is C (O), L²Is absent or of the formula N (R)^N) A group of (a);

when L is¹Is N (R)^N) When L is²Absent or a group of formula C (O);

when A is^D42Is NH or NC_1-6When there is alkyl, A^D41Is CH, C (C)_1-6Alkyl groups);

when A is^D41Is NH or NC_1-6When there is alkyl, A^D42Is CH₂；

A²、A³、A⁴And A⁵No more than two of N;

A⁶、A⁷、A⁸、A⁹and A¹⁰No more than two of N; and is

R¹Is present and is Cy^1A、OCy^1A、O(C_1-3Alkylene) Cy^1A、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1A(ii) a Or

R⁷Is Cy^7A、OCy^7A、O(C_1-3Alkylene) Cy^7A、C(O)OCy^7A、C(O)O(C_1-3Alkylene) Cy^7A、NHCy^7A、NH(C_1-3Alkylene) Cy^7A、N(C_1-6Alkyl) Cy^7A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7A、C(O)NHCy^7A、C(O)NH(C_1-3Alkylene) Cy^7A、C(O)N(C_1-6Alkyl) Cy^7AOr C (O) N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7A(ii) a Or

R⁸Is Cy^8A、OCy^8A、O(C_1-3Alkylene) Cy^8A、C(O)OCy^8A、C(O)O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^8A、C(O)NHCy^8A、C(O)NH(C_1-3Alkylene) Cy^8A、C(O)N(C_1-6Alkyl) Cy^8AOr C (O) N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8A。

2. The compound of claim 1, wherein:

R⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1、Cy^7A、OCy^7A、O(C_1-3Alkylene) Cy^7A、C(O)OCy^7A、C(O)O(C_1-3Alkylene) Cy^7A、NHCy^7A、NH(C_1-3Alkylene) Cy^7A、N(C_1-6Alkyl) Cy^7A、N(C(O)C_1-6Alkyl) Cy^7A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7A、C(O)NHCy^7A、C(O)NH(C_1-3Alkylene) Cy^7A、C(O)N(C_1-6Alkyl) Cy^7A、C(O)N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、C(O)OCy^8A、C(O)O(C_1-3Alkylene) Cy^8A、NHCy^8A、N(Cy^8A)₂、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8A、N(C(O)C_1-6Alkyl) Cy^8A、SO₂NHCy^8A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^8A、C(O)NHCy^8A、C_1-3alkylene-C (O) NHCy^8A、C(O)NH(C_1-3Alkylene) Cy^8A、C(O)N(C_1-6Alkyl) Cy^8A、C(O)N(C_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

Cy^D71is C_6-10Aryl radical, C_3-15Cycloalkyl, 5-14 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^D71C of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 members selected from Cy^D72、CH₂Cy^D72、OCy^D72、NHCy^D72、O-C_1-6alkylene-Cy^D72、N(C_1-6Alkyl) Cy^D72、N(C(O)C_1-6Alkyl) Cy^D72And C (O) NHCy^D72And 0, 1,2,3,4, or 5 substituents each independently selected from the group consisting of: unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、C(O)OR^a1And NR^c1R^d1C substituted by a substituent of_1-6Alkyl or C_2-6An alkenyl group;

R^a1、R^b1、R^c1And R^d1Each independently selected from H, C_1-6Alkyl, HO-C_1-6Alkylene radical, C_1-6alkoxy-C_1-6Alkylene radical, C_6-10Aryl radical, C_2-6Alkenyl and C_2-6An alkynyl group; or

R^c1And R^d1And the nitrogen atoms to which they are both attached together form a 4-10 membered unsubstituted heterocycloalkyl ring.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L¹Is N (R)^N)。

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L¹Is C (O).

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein D is a group of formula (D1).

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein D is a group of formula (D2).

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein D is a group of formula (D3).

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein A¹Is C (O) R¹。

9. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A¹Is (C)_1-3Alkylene) -C (O) R¹In which form A¹Said (C) of_1-3Alkylene) -C (O) R¹Of group (C)_1-3Alkylene) group is unsubstituted OR substituted with 0, 1,2,3,4 OR 5 substituents each independently selected from halogen, OR^a1、NR^c1R^d1、NR^a1(CO)(C_1-6Alkyl) and NR^a1(CO)O(C_1-6Alkyl groups).

10. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein A¹Is (C)_1-3Alkylene) -C (O) R¹In which form A¹Said (C) of_1-3Alkylene) -C (O) R¹Of group (C)_1-3Alkylene) groups are substituted with: NR (nitrogen to noise ratio)^c1R^d1、NR^a1(CO)(C_1-6Alkyl) or NR^a1(CO)O(C_1-6Alkyl) such as CH₂CH(NH₂)C(O)OH。

11. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A¹Is CN.

12. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A¹Is NO₂。

13. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A¹Is a 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C) unsubstituted or substituted with 0, 1,2,3,4 or 5 substituents_1-3Alkylene) -5-to 10-membered heteroaryl or (C)_1-3Alkylene) -4-10 membered heterocycloalkyl, each of said substituents being independently selected from halogen, OR^a1、SR^a1、C(O)OR^a1、NR^c1R^d1And C (O) NR^c1R^d1。

14. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein A¹Is S (O) unsubstituted or substituted by 1,2,3,4 or 5 substituents₂R¹、NHC(O)R¹、NH(C_1-3Alkylene) -C (O) R¹5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CH₂(5-10 membered heteroaryl) or CH₂(4-10 membered heterocycloalkyl), each of said substituents being independently selected from halogen, OR^a1、SR^a1、C(O)OR^a1、NR^c1R^d1And C (O) NR^c1R^d1。

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein a²Is CR²。

16. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R²Is H.

17. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein a²Is N.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein a³Is CR³。

19. According to claim18 or a pharmaceutically acceptable salt thereof, wherein R³Is H, C_1-6Alkyl or C_1-6A haloalkyl group.

20. A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R³Is H, methyl or trifluoroethyl.

21. A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R³Is H.

22. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein a³Is N.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein a⁴Is CR⁴。

24. A compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein R⁴Is H.

25. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein a⁴Is N.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein a⁵Is CR⁵。

27. A compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein R⁵Is H.

28. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein a⁵Is N.

29. According to claims 1 to14 or a pharmaceutically acceptable salt thereof, wherein a²Is CR²，A³Is CR³，A⁴Is CR⁴And A is⁵Is CR⁵。

30. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein a²Is CR²，A³Is CR³，A⁴Is CR⁴And A is⁵Is N.

31. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein D is a group of formula (D4).

32. A compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein a^D41Is CH.

33. A compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein a^D41Is C (C)_1-6Alkyl groups).

34. A compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein a^D41Is N.

35. The compound of any one of claims 31 to 34, or a pharmaceutically acceptable salt thereof, wherein a^D42Is NH.

36. The compound of any one of claims 31 to 34, or a pharmaceutically acceptable salt thereof, wherein a^D42Is NC_1-6An alkyl group.

37. The compound of any one of claims 31 to 36, or a pharmaceutically acceptable salt thereof, wherein a^D42Is CH₂。

38. The compound of any one of claims 31 to 37, or a pharmaceutically acceptable salt thereof, wherein m is 1.

39. The compound of any one of claims 31 to 37, or a pharmaceutically acceptable salt thereof, wherein m is 2.

40. The compound of any one of claims 31 to 37, or a pharmaceutically acceptable salt thereof, wherein m is 3.

41. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein D is a group of formula (D5).

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein m is 1.

43. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein m is 2.

44. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein m is 3.

45. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein D is a group of formula (D6).

46. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein m is 1.

47. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein m is 2.

48. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein m is 3.

49. According to claims 1 to 10 or15 to 48, or a pharmaceutically acceptable salt thereof, wherein R¹Is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, Cy^1A、OH、OC_1-6Alkyl radical OCy^1A、O(C_1-3Alkylene) Cy^1A、NH₂、NHC_1-6Alkyl, N (C)_1-6Alkyl radical)₂、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1A。

50. A compound or pharmaceutically acceptable salt thereof according to claim 47, wherein R¹Is Cy^1A、OCy^1A、O(C_1-3Alkylene) Cy^1A、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1A。

51. A compound or pharmaceutically acceptable salt thereof according to claim 47, wherein R¹Is NHCy^1A。

52. The compound of any one of claims 1 to 10 or 15 to 48, or a pharmaceutically acceptable salt thereof, wherein R¹Is C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, Cy^1AOH or OC_1-6An alkyl group.

53. A compound or pharmaceutically acceptable salt thereof according to claim 52, wherein R¹Is OH.

54. A compound or pharmaceutically acceptable salt thereof according to claim 51, wherein R¹A group of one of the following formulae:

wherein:

R¹¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹²is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr is covered1.2 or 3 are each independently selected from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹⁴is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹⁵is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹⁷is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group; and is

R¹⁸Is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

55. A compound or pharmaceutically acceptable salt thereof according to claim 54, wherein R¹A group of one of the following formulae:

56. the compound of any one of claims 1 to 10 or 15 to 51, or a pharmaceutically acceptable salt thereof, wherein Cy^1AUnsubstituted or substituted by 0, 1 or 2 Cy^1BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein Cy^1AIs unsubstituted or substituted by 1 Cy^1BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

58. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein Cy^1AIs unsubstituted or substituted by 1 Cy^1BSubstituted C_6-10Aryl radicals, for example phenyl.

59. The compound of any one of claims 1 to 10, 15 to 51, or 56 to 58, or a pharmaceutically acceptable salt thereof, wherein each Cy is^1BIs C unsubstituted or substituted by 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein each Cy is^1BIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl).

61. The compound of any one of claims 1 to 10 or 15 to 51, or a pharmaceutically acceptable salt thereof, wherein Cy^1AA group of one of the following formulae:

wherein:

R¹³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein Cy^1AA group of one of the following formulae:

63. the compound of any one of claims 1 to 10, 15 to 51, or a pharmaceutically acceptable salt thereof, wherein Cy^1AUnsubstituted or substituted by 0, 1 or 2 Cy^1BAnd C substituted with 0, 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Alkyl halidesRadical, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

64. The compound of any one of claims 50, 51, or 54-63, or a pharmaceutically acceptable salt thereof, wherein:

R⁷is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group; and is

R⁸Is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

65. A compound or pharmaceutically acceptable salt thereof according to claim 64, wherein R⁷Is H, and R⁸Is H.

66. The compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein L²Is absent.

67. The compound of any one of claims 1 or 4 to 65, or a pharmaceutically acceptable salt thereof, wherein L²Is N (R)^N)。

68. The compound of any one of claims 1,3, or 5 to 65, or a pharmaceutically acceptable salt thereof, wherein L²Is C (O).

69. The compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein each R^NIs H.

70. The compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein A⁶Is CR⁶。

71. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R⁶Is H.

72. The compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt thereof, wherein A⁶Is N.

73. The compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof, wherein A⁷Is CR⁷。

74. A compound or pharmaceutically acceptable salt thereof according to claim 73, wherein R⁷Is H.

75. A compound or pharmaceutically acceptable salt thereof according to claim 73, wherein R⁷Is Cy^7A、OCy^7A、O(C_1-3Alkylene) Cy^7A、C(O)OCy^7A、C(O)O(C_1-3Alkylene) Cy^7A、NHCy^7A、NH(C_1-3Alkylene) Cy^7A、N(C_1-6Alkyl) Cy^7A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7A、C(O)NHCy^7A、C(O)NH(C_1-3Alkylene) Cy^7A、C(O)N(C_1-6Alkyl) Cy^7AOr C (O) N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7A。

76. The method of claim 73A compound or a pharmaceutically acceptable salt thereof, wherein R⁷Is Cy^7A、OCy^7A、O(C_1-3Alkylene) Cy^7A、NHCy^7A、NH(C_1-3Alkylene) Cy^7A、N(C_1-6Alkyl) Cy^7AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7A。

77. A compound or pharmaceutically acceptable salt thereof according to claim 73, wherein R⁷Is NHCy^7A。

78. A compound or pharmaceutically acceptable salt thereof according to claim 77, wherein R⁷A group of one of the following formulae:

wherein:

R⁷¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷²is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁴is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁵is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁷is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group; and is

R⁷⁸Is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

79. A compound or pharmaceutically acceptable salt thereof according to claim 78, wherein R⁷A group of one of the following formulae:

80. the compound of any one of claims 1 to 63, 66 to 73, and 75 to 77, or a pharmaceutically acceptable salt thereof, wherein Cy is^7AUnsubstituted or substituted by 0, 1 or 2 Cy^7BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

81. A compound according to claim 80 or pharmaceutically acceptable thereofSalt of, wherein Cy^7AIs unsubstituted or substituted by 1 Cy^7BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

82. The compound of claim 81, or a pharmaceutically acceptable salt thereof, wherein Cy^7AIs unsubstituted or substituted by 1 Cy^7BSubstituted C_6-10Aryl radicals, for example phenyl.

83. The compound of any one of claims 1 to 63, 66 to 73, 75 to 77, and 80 to 82, or a pharmaceutically acceptable salt thereof, wherein each Cy is^7BIs C unsubstituted or substituted by 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

84. The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein each Cy is^7BIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl).

85. The compound of any one of claims 1 to 63, 66 to 73 and 75 to 77 and 80 to 84, or a pharmaceutically acceptable salt thereof, wherein Cy is^7AA group of one of the following formulae:

wherein:

R⁷¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷²is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN,OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁴is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁵is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical、C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁷is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group; and is

R⁷⁸Is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

86. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein Cy is^7AA group of one of the following formulae:

87. the compound of any one of claims 1 to 63, 66 to 73, and 75 to 77, or a pharmaceutically acceptable salt thereof, wherein Cy is^7AUnsubstituted or substituted by 0, 1 or 2 Cy^7BAnd C substituted with 0, 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

88. The compound according to any one of claims 75 to 87, or a pharmaceutically acceptable salt thereof, wherein:

R¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group; and is

89. A compound or pharmaceutically acceptable salt thereof according to claim 88, wherein a¹Is CR¹，A²Is CR²，A³Is CR³，A⁴Is CR⁴，A⁵Is CR⁵，A⁶Is CR⁶，A⁸Is CR⁸，A⁹Is CR⁹And A is¹⁰Is CR¹⁰。

90. A compound or pharmaceutically acceptable salt thereof according to claim 88, wherein a¹Is CR¹，A³Is CR³，A⁴Is CR⁴，A⁵Is N, A⁶Is CR⁶，A⁸Is CR⁸，A⁹Is CR⁹And A is¹⁰Is CR¹⁰。

91. The compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof, wherein A⁷Is N.

92. The compound of any one of claims 1 to 91, or a pharmaceutically acceptable salt thereof, wherein a⁸Is CR⁸。

93. A compound or pharmaceutically acceptable salt thereof according to claim 92, wherein R⁸Is H.

94. A compound or pharmaceutically acceptable salt thereof according to claim 92, wherein R⁸Is Cy^8A、OCy^8A、O(C_1-3Alkylene) Cy^8A、C(O)OCy^8A、C(O)O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^8A、C(O)NHCy^8A、C(O)NH(C_1-3Alkylene) Cy^8A、C(O)N(C_1-6Alkyl) Cy^8AOr C (O) N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8A。

95. A compound or pharmaceutically acceptable salt thereof according to claim 92, wherein R⁸Is Cy^8A、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8A。

96. A compound or pharmaceutically acceptable salt thereof according to claim 95, wherein R⁸Is NHCy^8A。

97. A compound or pharmaceutically acceptable salt thereof according to claim 96, wherein R⁸A group of one of the following formulae:

wherein:

R⁸¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr by 1,2 or 3 of eachSelected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸²is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁴is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁵is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁷is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group; and is

R⁸⁸Is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

98. A compound or pharmaceutically acceptable salt thereof according to claim 96, wherein R⁸A group of one of the following formulae:

99. the compound of any one of claims 1 to 63, 66 to 87, 91, 92, or 94 to 96, or a pharmaceutically acceptable salt thereof, wherein Cy is^8AUnsubstituted or substituted by 0, 1 or 2 Cy^8BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is 1,2 or3 are each independently selected from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

100. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein Cy is^8AIs unsubstituted or substituted by 1 Cy^8BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

101. The compound of claim 100, or a pharmaceutically acceptable salt thereof, wherein Cy is^8AIs unsubstituted or substituted by 1 Cy^8BSubstituted C_6-10Aryl radicals, for example phenyl.

102. The compound of any one of claims 1 to 63, 66 to 87, 91, 92, 94 to 96, or 99 to 101, or a pharmaceutically acceptable salt thereof, wherein each Cy is Cy^8BIs C unsubstituted or substituted by 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

103. The compound of claim 102, or a pharmaceutically acceptable salt thereof, wherein each Cy is^8BIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl).

104. The compound of any one of claims 1 to 63, 66 to 87, 91, 92, or 94 to 96, or a pharmaceutically acceptable salt thereof, wherein Cy is^8AA group of one of the following formulae:

wherein:

R⁸¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸²is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are each independentlySelected from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁵is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl group (C) ((C))C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

105. The compound of claim 104, or a pharmaceutically acceptable salt thereof, wherein Cy is^8AA group of one of the following formulae:

106. the compound of any one of claims 1 to 63, 66 to 87, 91, 92, or 94 to 96, or a pharmaceutically acceptable salt thereof, wherein Cy is^8AUnsubstituted or substituted by 0, 1 or 2 Cy^8BAnd C substituted with 0, 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

107. The compound according to any one of claims 90 to 100, or a pharmaceutically acceptable salt thereof, wherein:

R¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1Or by 1,2 or 3 eachIndependently selected from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group; and is

R⁷Is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1Or 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

108. A compound or pharmaceutically acceptable salt thereof according to claim 107, wherein a¹Is CR¹，A²Is CR²，A³Is CR³，A⁴Is CR⁴，A⁵Is CR⁵，A⁶Is CR⁶，A⁷Is CR⁷，A⁸Is CR⁸，A⁹Is CR⁹And A is¹⁰Is CR¹⁰。

109. A compound or pharmaceutically acceptable salt thereof according to claim 107, wherein a¹Is CR¹，A³Is CR³，A⁴Is CR⁴，A⁵Is N, A⁶Is CR⁶，A⁷Is CR⁷，A⁸Is CR⁸，A⁹Is CR⁹And A is¹⁰Is CR¹⁰。

110. The compound of any one of claims 1 to 91, or a pharmaceutically acceptable salt thereof, wherein a⁸Is N.

111. The compound according to any one of claims 1 to 109, or a pharmaceutically acceptable salt thereof, wherein a⁹Is CR⁹。

112. A compound or pharmaceutically acceptable salt thereof according to claim 110, wherein R⁹Is H, C_1-6Alkyl or C_1-6A haloalkyl group.

113. A compound or pharmaceutically acceptable salt thereof according to claim 110, wherein R⁹Is H, methyl or trifluoroethyl.

114. A compound or pharmaceutically acceptable salt thereof according to claim 110, wherein R⁹Is H.

115. The compound according to any one of claims 1 to 109, or a pharmaceutically acceptable salt thereof, wherein a⁹Is N.

116. The compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, wherein a¹⁰Is CR¹⁰。

117. A compound or pharmaceutically acceptable salt thereof according to claim 115, wherein R¹⁰Is H.

118. The compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, wherein a¹⁰Is N.

119. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of one of the following formulae (I-1) to (I-60):

wherein:

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R^N、A¹、A²、A³、A⁴、A⁵、A⁶、A⁷、A⁸、A⁹、A¹⁰、Cy^1A、Cy^1B、Cy^7A、Cy^7B、Cy^8A、Cy^8B、L¹and L²As defined in claim 1;

L⁷absent, O, NH or N (C)_1-6Alkyl groups);

L⁸absent, O, NH or N (C)_1-6Alkyl groups);

R¹³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹⁴is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 substituents independently selected from halogen,C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹⁸is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸²is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁴is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁵is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6An alkenyl group,C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁷is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group; and is

R⁸⁸Is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

120. A compound or pharmaceutically acceptable salt thereof according to claim 119, wherein R¹Is OH.

121. A compound or pharmaceutically acceptable salt thereof according to claim 119, wherein R¹Is OC_1-6Alkyl (e.g., OMe).

122. A compound or pharmaceutically acceptable salt thereof according to claim 119, wherein R¹Is C_2-6Alkenyl (e.g., vinyl).

123. The compound of any one of claims 119 to 122, or a pharmaceutically acceptable salt thereof, wherein L⁷Is NH.

124. The compound of any one of claims 119 to 122, or a pharmaceutically acceptable salt thereof, wherein L⁸Is NH.

125. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of one of the following formulae:

126. a compound or claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from any one of the following compounds:

127. a composition comprising a compound according to any one of claims 1 to 126, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

128. A method of inhibiting palmitoylation of a TEAD-transcription factor, the method comprising contacting the TEAD-transcription factor with a compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, or with a composition of claim 127.

129. A method of treating a disease or condition associated with the activity of TEAD-transcription factor comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-126 or a pharmaceutically acceptable salt thereof or a composition of claim 127.

130. A method of treating cancer, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1-126 or a pharmaceutically acceptable salt thereof, or a composition of claim 127.

131. The method of claim 130, wherein the cancer is a solid tumor or a hematologic cancer.

132. The method of claim 130 or 131, wherein the cancer is prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, lymphoma, leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, non-hodgkin's lymphoma, or multiple myeloma.

133. The method of claim 130 or 131, wherein the cancer is hepatocellular carcinoma, medulloblastoma, cutaneous squamous cell carcinoma, lung cancer, pancreatic cancer, esophageal cancer, liver cancer, colon cancer, melanoma, or uveal melanoma.

Technical Field

The present application relates to pharmaceutically acceptable compounds. The present disclosure provides novel compounds, as well as compositions and methods of use thereof. The compounds inhibit the self-palmitoylation of TEAD-transcription factors, and are therefore useful in the treatment of diseases associated with the activity of TEAD-transcription factors, including, for example, cancer and other diseases.

Background

Hippo signaling plays a key role in organ size control and tumor suppression. Signal transduction involves a core kinase cascade, comprising MST1/2 and Lats1/2 kinases, which cause YAP/TAZ phosphorylation, cytoplasmic retention and inhibition³. Physiological or pathological inactivation of these kinases leads to YAP/TAZ dephosphorylation and nuclear accumulation. Subsequently, the nucleus YAP/TAZ binds to TEA domain transcription factors (TEAD 1-4 in mammals and Scallopd in Drosophila) to mediate target gene expression. The TEAD-YAP complex regulates normal development of skin, muscle, lung and liver, and is also an amplified carcinogenic factor in many human cancers. TEAD also binds to Vgll4, which is thought to be a tumor suppressor by competing with YAP/TAZ for binding to TEAD. TEAD is therefore essential in regulating the transcriptional export of the Hippo pathway. Although targeting TEAD-YAP may be a promising therapeutic approach to Hippo pathway dysregulated diseases, direct inhibition of transcription factors with small molecules remains challenging. Therefore, understanding the regulation of TEAD may provide new therapeutic opportunities for drug discovery.

Post-translational S-palmitoylation links a palmitate ester of 16 carbons to a cysteine residue via a reversible thioester bond. A large number of palmitoylated proteins have been identified by proteomic studies. Dynamic S-palmitoylation plays a key role in regulating the transport, membrane localization, and function of many proteins, including Src family kinases, gtpases, and synaptic adhesion molecules. The Asp-His-His-Cys (DHHC) family of proteins is an evolutionarily conserved protein Palmitoyl Acyltransferase (PAT) that mediates enzymatic S-palmitoylation. In addition, some proteins can bind directly to palmitoyl-coenzyme a (coa) and undergo PAT-independent self-palmitoylation. However, self-palmitoylation was not fully characterized. Most reported examples of self-palmitoylation were observed at non-physiological, high concentrations (> 100. mu.M) of palmitoyl-CoA. To date, only a few proteins, including the yeast transporter Bet3, are self-palmitoylated at physiological concentrations of palmitoyl-CoA (1-10 μ M). Therefore, it is important to reveal additional self-palmitoylated proteins and understand their regulation and function.

Disclosure of Invention

The present disclosure provides, inter alia, compounds of formula (I):

or a pharmaceutically acceptable salt thereof; wherein the variables are as defined below.

The present disclosure also provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

The present disclosure also provides methods of treating cancer and other diseases comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.

Drawings

Figure 1 shows a schematic diagram of the structure of an example of a compound within the scope of the invention.

Figure 2 is a schematic diagram showing the structure of some reference compounds.

FIG. 3 is a graph showing the results of streptavidin and histidine blots, which shows the results of assays for the inhibition of TEAD2 from palmitoylation in vitro by compounds CP-1, flufenamic acid, CP-41, CP-42, CP-51, CP-52, CP-53, CP-54, CP-55, CP-56, CP-57, and CP-58.

Figure 4 is a graph showing the results of streptavidin and histidine blots, which shows the results of a determination of the inhibition of TEAD2 from palmitoylation in vitro at different concentrations of compound CP-55.

FIG. 5 is a graph showing the inhibition of cell proliferation of compound CP-55 at various concentrations on the 92.1 uveal melanoma cell line, the cellosaurus OCM1 cell line, the human hepatoma huh7 cell line, the SNU398 human hepatoma cell line, and the MDA-MB-453 human breast metastatic cell line.

FIG. 6 is a graph showing inhibition of gene expression of CYR61, CTGF, and ANKRD1 genes in huh7 human liver cancer cell line by compound CP-55 at various time points and concentrations.

Figure 7 is a graph showing the results of streptavidin and histidine blots, which shows the results of a determination of the inhibition of TEAD2 from palmitoylation in vitro at different concentrations of compound CP-58.

FIG. 8 is a graph showing the inhibition of cell proliferation in the 92.1 uveal melanoma cell line by compounds CP-1, CP-52, CP-55, and CP-58 at different concentrations.

Figure 9 is a graph showing the inhibition of cell proliferation in huh7 human liver cancer cell line by compound CP-57 at different concentrations.

Fig. 10 is a graph showing the inhibition of cell proliferation in huh7 human liver cancer cell line by compound CP-58 at different concentrations.

FIG. 11 is a pair of plots showing inhibition of gene expression of the genes CYR61 and CTGF and ANKRD1 by Compound CP-58 in huh7 human liver cancer cell line after 24 hours compared to control.

FIG. 12 is a graph showing the results of streptavidin and histidine blots, which shows the results of assays for the inhibition of TEAD2 from palmitoylation in vitro by compounds CP-1, CP-55, CP-58, CP-59, CP-60, CP-61, and CP-62.

FIG. 13 is a graph of the inhibition of cell proliferation in the huh7 human hepatoma cell line by compounds CP-58, CP-59, CP-60, CP-61, and CP-62 at different concentrations.

Detailed Description

The terms "for example" and "such as" and grammatical equivalents thereof, unless expressly stated otherwise, are to be understood as being followed by the phrase "and not limited to".

The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

The term "about" means "about" (e.g., +/-about 10% of the indicated value).

The expressions "ambient temperature" and "room temperature" (abbreviated as "r.t.") generally refer to a temperature (e.g., reaction temperature) that is about the temperature of the room in which the reaction is conducted, such as a temperature of about 20 ℃ to about 30 ℃, typically about 25 ℃.

Through proteomic and biochemical studies, TEAD transcription factors have been identified to be palmitoylated at evolutionarily conserved cysteine residues. It has been found that at physiological concentrations of palmitoyl-CoA, TEAD undergoes PAT-independent self-palmitoylation. The crystal structure of lipid-bound TEAD and reveals new ligand binding sites in TEAD. In addition, autopalmitoylation plays a key role in regulating TEAD-YAP association and its physiological function in vitro and in vivo. Thus, palmitoylation of TEAD plays an important role in the regulation of Hippo pathway transcription complexes.

The discovery of new ligand binding sites in TEAD has led to the discovery of small molecule inhibitors of TEAD self-palmitoylation. While not being bound by any theory, it is understood that the ligand binds to the palmitate binding pocket and inhibits TEAD-YAP interaction, cancer cell proliferation and migration. Thus, direct inhibition of TEAD self-palmitoylation activity may be useful in inhibiting these oncogenic transcription factors.

I. Compound (I)

The present disclosure provides, inter alia, compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

L¹is absent or of the formula N (R)^N) Or the group of C (O);

d is a group of formula (D1), (D2), (D3), (D4), (D5), (D6) or (D7):

m is 1,2 or 3;

A¹is C (O) R¹、S(O)₂R¹、NHC(O)R¹、(C_1-3Alkylene) -C (O) R¹、NH(C_1-3Alkylene) -C (O) R¹、CN、NO₂5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C)_1-3Alkylene) -5-to 10-membered heteroaryl or (C)_1-3Alkylene) -4-to 10-membered heterocycloalkyl, in which A is formed¹Is (C)_1-3Alkylene) -C (O) R¹Of group (C)_1-3Alkylene) group unsubstituted OR substituted with 1,2,3,4 OR 5 substituents each independently selected from halogen, OR^a1、NR^c1R^d1、NR^a1(CO)(C_1-6Alkyl) and NR^a1(CO)O(C_1-6Alkyl groups); and wherein form A¹5-to 10-membered heteroaryl, 4-to 10-membered heterocycloalkyl, (C)_1-3Alkylene) -5-to 10-membered heteroaryl or (C)_1-3Alkylene) -4-to 10-membered heterocycloalkyl unsubstituted or substituted by 1,2,34 OR 5 substituents each independently selected from halogen, OR^a1、SR^a1、C(O)OR^a1、NR^c1R^d1And C (O) NR^c1R^d1；

L²Is absent or of the formula N (R)^N) A group of O or C (O);

L³is absent or of the formula CH₂、C≡C、N(R^N) Or the group of C (O);

each R^NIndependently H, C_1-6Alkyl, C (O) C_1-6Alkyl or C (O) OC_1-6An alkyl group;

A²is CR²Or N;

A³is CR³Or N;

A⁴is CR⁴Or N;

A⁵is CR⁵Or N;

A⁶is CR⁶Or N;

A⁷is CR⁷Or N;

A⁸is CR⁸Or N;

A⁹is CR⁹Or N;

A¹⁰is CR¹⁰Or N;

A^D41is CH, C (C)_1-6Alkyl) or N;

A^D42is CH₂NH or NC_1-6An alkyl group;

each Cy^8BIs C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^8BC of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl is unsubstitutedSubstituted or substituted with 1,2,3,4 or 5 substituents each independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

With the following conditions:

when L is²When is C (O), L¹Is of the formula N (R)^N) A group of (a);

when L is²Is N (R)^N) When L is¹Is a group of formula C (O);

when L is¹When is C (O), L²Is absent or of the formula N (R)^N) A group of (a);

when L is¹Is N (R)^N) When L is²Absent or a group of formula C (O);

when A is^D42Is NH or NC_1-6When there is alkyl, A^D41Is CH, C (C)_1-6Alkyl groups);

when A is^D41Is NH or NC_1-6When there is alkyl, A^D42Is CH₂；

A²、A³、A⁴And A⁵No more than two of N;

A⁶、A⁷、A⁸、A⁹and A¹⁰No more than two of N; and is

R¹Is present and is Cy^1A、OCy^1A、O(C_1-3Alkylene) Cy^1A、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1A(ii) a Or

The present disclosure provides, inter alia, compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

L¹is absent or of the formula N (R)^N) Or the group of C (O);

d is a group of formula (D1), (D2), (D3), (D4), (D5), (D6) or (D7):

m is 1,2 or 3;

L²Is absent or of the formula N (R)^N) A group of O or C (O);

L³is absent or of the formula CH₂、C≡C、N(R^N) Or the group of C (O);

each R^NIndependently H, C_1-6Alkyl, C (O) C_1-6Alkyl or C (O) OC_1-6An alkyl group;

A²is CR²Or N;

A³is CR³Or N;

A⁴is CR⁴Or N;

A⁵is CR⁵Or N;

A⁶is CR⁶Or N;

A⁷is CR⁷Or N;

A⁸is CR⁸Or N;

A⁹is CR⁹Or N;

A¹⁰is CR¹⁰Or N;

A^D41is CH, C (C)_1-6Alkyl) or N;

A^D42is CH₂NH or NC_1-6An alkyl group;

R⁴is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1Or by 1,2 or 3Each independently selected from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

each Cy^8BIs C_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^8BC of (A)_6-10Aryl radical, C_3-15Each of cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1,2,3,4 or 5 substituents each independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

Cy^D71is C_6-10Aryl radical, C_3-15Cycloalkyl, 5-14 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy is formed^D71C of (A)_6-10Aryl radical, C_3-15Cycloalkyl radicals5-10 membered heteroaryl or 4-10 membered heterocycloalkyl each unsubstituted or substituted with 0, 1 or 2 members selected from Cy^D72、CH₂Cy^D72、OCy^D72、NHCy^D72、O-C_1-6alkylene-Cy^D72、N(C_1-6Alkyl) Cy^D72、N(C(O)C_1-6Alkyl) Cy^D72And C (O) NHCy^D72And 0, 1,2,3,4, or 5 substituents each independently selected from the group consisting of: unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、C(O)OR^a1And NR^c1R^d1C substituted by a substituent of_1-6Alkyl or C_2-6An alkenyl group;

R^a1、R^b1、R^c1And R^d1Each independently selected from H, C_1-6Alkyl, HO-C_1-6Alkylene radical, C_1-6alkoxy-C_1-6Alkylene radical, C_6-10Aryl radical, C_2-6Alkenyl and C_2-6An alkynyl group; or

R^c1And R^d1And the nitrogen atom to which they are both attached together form a 4-10 membered unsubstituted heterocycloalkyl ring;

in some embodiments:

when L is²When is C (O), L¹Is of the formula N (R)^N) A group of (a);

when L is²Is N (R)^N) When L is¹Is a group of formula C (O);

when L is¹When is C (O), L²Is absent or of the formula N (R)^N) A group of (a);

when L is¹Is N (R)^N) When L is²Absent or a group of formula C (O);

when A is^D42Is NH or NC_1-6When there is alkyl, A^D41Is CH, C (C)_1-6Alkyl groups);

when A is^D41Is NH or NC_1-6When there is alkyl, A^D42Is CH₂；

A²、A³、A⁴And A⁵No more than two of N;

A⁶、A⁷、A⁸、A⁹and A¹⁰No more than two of N; and is

R¹Is present and is Cy^1A、OCy^1A、O(C_1-3Alkylene) Cy^1A、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1A(ii) a Or

In some embodiments, L¹Is absent.

In some embodiments, L¹Is N (R)^N) For example NH or NMe.

In some embodiments, L¹Is C (O).

In some embodiments, D is a group of formula (D1).

In some embodiments, D is a group of formula (D2).

In some embodiments, D is a group of formula (D3).

In some embodiments, D is a group of formula (D4).

In some embodiments, D is a group of formula (D5).

In some embodiments, D is a group of formula (D6).

In some embodiments, D is a group of formula (D7).

In some embodiments, A¹Is C (O) R¹For example, C (O) OH.

In some embodiments, A¹Is S (O)₂R¹。

In some embodiments, A¹Is NHC (O) R¹。

In some embodiments, A¹Is NH (C)_1-3Alkylene) -C (O) R¹。

In some embodiments, wherein A¹Is (C)_1-3Alkylene) -C (O) R¹In which form A¹Is (C)_1-3Alkylene) -C (O) R¹Of group (C)_1-3Alkylene) group is unsubstituted OR substituted with 0, 1,2,3,4 OR 5 substituents each independently selected from halogen, OR^a1、NR^c1R^d1、NR^a1(CO)(C_1-6Alkyl) and NR^a1(CO)O(C_1-6Alkyl groups).

In some embodiments, A¹Is (C)_1-3Alkylene) -C (O) R¹In which form A¹Is (C)_1-3Alkylene) -C (O) R¹Of group (C)_1-3Alkylene) groups are substituted with: NR (nitrogen to noise ratio)^c1R^d1、NR^a1(CO)(C_1-6Alkyl) or NR^a1(CO)O(C_1-6Alkyl) such as CH₂CH(NH₂)C(O)OH。

In some embodiments, A¹Is CN.

In some embodiments, A¹Is NO₂。

In some embodiments, A¹Is a 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C) unsubstituted or substituted with 0, 1,2,3,4 or 5 substituents_1-3Alkylene) -5-to 10-membered heteroaryl or (C)_1-3Alkylene) -4-10 membered heterocycloalkyl, each of said substituents being independently selected from halogen, OR^a1、SR^a1、C(O)OR^a1、NR^c1R^d1And C (O) NR^c1R^d1；

In some embodiments, A¹Is unsubstituted or substituted by 1,2,3,4 or 5 substituents, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CH₂(5-10 membered heteroaryl) or CH₂(4-10 membered heterocycloalkyl), each of said substituents being independently selected from halogen, OR^a1、SR^a1、C(O)OR^a1、NR^c1R^d1And C (O) NR^c1R^d1；

In some embodiments, A²Is CR²。

In some embodiments, R²Is H.

In some embodiments, A²Is N.

In some embodiments, A³Is CR³。

In some embodiments, R³Is H, C_1-6Alkyl or C_1-6A haloalkyl group.

In some embodiments, R³Is H, methyl or trifluoroethyl.

In some embodiments, R³Is H.

In some embodiments, A³Is N.

In some embodiments, A⁴Is CR⁴。

In some embodiments, R⁴Is H.

In some embodiments, A⁴Is N.

In some embodiments, A⁵Is CR⁵。

In some embodiments, R⁵Is H.

In some embodiments, A⁵Is N.

In some embodiments, A²Is CR²，A³Is CR³，A⁴Is CR⁴And A is⁵Is CR⁵。

In some embodiments, A²Is CR²，A³Is CR³，A⁴Is CR⁴And A is⁵Is N.

In some embodiments, D is a group of formula (D4).

In some embodiments, A^D41Is CH.

In some embodiments, A^D41Is C (C)_1-6Alkyl groups).

In some embodiments, A^D41Is N.

In some embodiments, A^D42Is NH.

In some embodiments, A^D42Is NC_1-6Alkyl groups, such as NMe.

In some embodiments, A^D42Is CH₂。

In some embodiments, D is a group of formula (D4) and m is 1.

In some embodiments, D is a group of formula (D4) and m is 2.

In some embodiments, D is a group of formula (D4) and m is 3.

In some embodiments, D is a group of formula (D5).

In some embodiments, D is a group of formula (D5) and m is 1.

In some embodiments, D is a group of formula (D5) and m is 2.

In some embodiments, D is a group of formula (D5) and m is 3.

In some embodiments, D is a group of formula (D6).

In some embodiments, D is a group of formula (D6) and m is 1.

In some embodiments, D is a group of formula (D6) and m is 2.

In some embodiments, D is a group of formula (D6) and m is 3.

In some embodiments, D is a group of formula (D7).

In some embodiments, L²Is absent.

In some embodiments, L²Is a group of formula O.

In some embodiments, L²Is of the formula N (R)^N) A group of (1).

In some embodiments, L²Is a radical of the formula C (O).

In some embodiments, L³Is absent.

In some embodiments, L³Is a formula CH₂A group of (1).

In some embodiments, L³Is of the formula N (R)^N) A group of (1).

In some embodiments, L³Is a radical of the formula C (O).

At one endIn some embodiments, L³Is a group of formula C ≡ C.

In some embodiments, Cy^D71Is C_6-10Aryl (e.g., phenyl).

In some embodiments, Cy^D71Is C_3-15Cycloalkyl (e.g., cyclopropyl).

In some embodiments, Cy^D71Is a 5-to 10-membered heteroaryl group (e.g., triazole, pyridine, dihydropyrido [2,1-b ]]Pyrimidin-2-one, 3, 4-dihydroquinolin-2-one, benzo [ d]Isothiazole-1, 1-dioxide, 2H-indazole, pyrazole, dioxolane, pyrrole, indole, imidazole, benzimidazole).

In some embodiments, Cy^D71Is a 4-to 10-membered heterocycloalkyl group (e.g., piperidine, 1, 3-dioxolane, indoline, pyrrolidine).

In some embodiments, Cy is formed^D71C of (A)_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted.

In some embodiments, Cy is formed^D71C of (A)_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.

In some embodiments, Cy is formed^D71C of (A)_6-10Aryl radical, C_3-15The cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is substituted with 1,2,3,4 or 5 substituents each independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、C(O)OR^a1And NR^c1R^d1C substituted by a substituent of_1-6Alkyl or C_2-6An alkenyl group.

In some embodiments, Cy is formed^D71C of (A)_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl orThe 4-10 membered heterocycloalkyl group is substituted with 0, 1 or 2 substituents selected from Cy^D72、CH₂Cy^D72、OCy^D72、NHCy^D72、O-C_1-6alkylene-Cy^D72、N(C_1-6Alkyl) Cy^D72、N(C(O)C_1-6Alkyl) Cy^D72And C (O) NHCy^D72。

In some embodiments, Cy^D72Is C_6-10Aryl (e.g., phenyl).

In some embodiments, Cy^D72Is C_3-15Cycloalkyl (e.g., cyclopropyl).

In some embodiments, Cy^D72Is a 5-to 10-membered heteroaryl group (e.g., triazole, pyridine, dihydropyrido [2,1-b ]]Pyrimidin-2-one, 3, 4-dihydroquinolin-2-one, benzo [ d]Isothiazole-1, 1-dioxide, 2H-indazole, pyrazole, dioxolane, pyrrole, indole, imidazole, benzimidazole).

In some embodiments, Cy^D72Is a 4-to 10-membered heterocycloalkyl group (e.g., piperidine, 1, 3-dioxolane, indoline, pyrrolidine).

In some embodiments, Cy is formed^D72C of (A)_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted.

In some embodiments, Cy is formed^D72C of (A)_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.

In some embodiments, Cy is formed^D72C of (A)_6-10Aryl radical, C_3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is substituted with 0, 1 or 2 substituents selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-15Cycloalkyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、C(O)OR^a1、C(O)NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、C(O)OR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, R¹Is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, Cy^1A、OH、OC_1-6Alkyl radical OCy^1A、O(C_1-3Alkylene) Cy^1A、NH₂、NHC_1-6Alkyl, N (C)_1-6Alkyl radical)₂、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1A。

In some embodiments, R¹Is Cy^1A、OCy^1A、O(C_1-3Alkylene) Cy^1A、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1A。

In some embodiments, R¹Is NHCy^1A。

In some embodiments, R¹Is C_1-6Alkyl (e.g. methyl), C_2-6Alkenyl radical, C_2-6Alkynyl, Cy^1AOH or OC_1-6Alkyl (e.g., OMe).

In some embodiments, R¹Is OH.

In some embodiments, R¹A group of one of the following formulae:

wherein:

R¹³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

In some embodiments, R¹A group of one of the following formulae:

in some embodiments, Cy^1AUnsubstituted or substituted by 0, 1 or 2 Cy^1BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, Cy^1AIs unsubstituted or substituted by 1 Cy^1BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, Cy^1AIs unsubstituted or substituted by 1 Cy^1BSubstituted C_6-10Aryl radicals, for example phenyl.

In some embodiments, each Cy is^1BIs C unsubstituted or substituted by 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, each Cy is^1BIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl).

In some embodiments, Cy^1AA group of one of the following formulae:

wherein:

R¹³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R¹⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene oxideRadical) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

In some embodiments, Cy^1AA group of one of the following formulae:

in some embodiments, Cy^1AUnsubstituted or substituted by 0, 1 or 2 Cy^1BAnd C substituted with 0, 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group. In some embodiments, Cy^1AIs C unsubstituted or substituted by 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group. In some embodiments, Cy^1AIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl). In some embodiments, Cy^1AUnsubstituted or substituted adamantyl, such as adamant-1-yl. In some embodiments, Cy^1AIs unsubstituted adamantyl, e.g., adamant-1-yl.

In some embodiments:

In some embodiments, R⁷Is H, and R⁸Is H.

In some embodiments, L²Is absent.

In some embodiments, L²Is N (R)^N)。

In some embodiments, L²Is C (O).

In some embodiments, R^NIs H.

In some embodiments, A⁶Is CR⁶。

In some embodiments, R⁶Is H.

In some embodiments, A⁶Is N.

In some embodiments, A⁷Is CR⁷。

In some embodiments, R⁷Is H.

In some embodiments, R⁷Is Cy^7A、OCy^7A、O(C_1-3Alkylene) Cy^7A、C(O)OCy^7A、C(O)O(C_1-3Alkylene) Cy^7A、NHCy^7A、NH(C_1-3Alkylene) Cy^7A、N(C_1-6Alkyl) Cy^7A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^7A、C(O)NHCy^7A、C(O)NH(C_1-3Alkylene) Cy^7A、C(O)N(C_1-6Alkyl) Cy^7AOr C (O) N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7A。

In some embodiments, R⁷Is Cy^7A、OCy^7A、O(C_1-3Alkylene) Cy^7A、NHCy^7A、NH(C_1-3Alkylene) Cy^7A、N(C_1-6Alkyl) Cy^7AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7A。

In some embodiments, R⁷Is N (C (O) C_1-6Alkyl) Cy^7A。

In some embodiments, R⁷Is NHCy^7A。

In some embodiments, R⁷A group of one of the following formulae:

wherein:

R⁷²is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^7B、OH、OCy^7B、O(C_1-3Alkylene) Cy^7B、NHCy^7B、NH(C_1-3Alkylene) Cy^7B、N(C_1-6Alkyl) Cy^7BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^7BOr is 1,2 or3 are each independently selected from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

In some embodiments, R⁷A group of one of the following formulae:

in some embodiments, Cy^7AUnsubstituted or substituted by 0, 1 or 2 Cy^7BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, Cy^7AIs unsubstituted or substituted by 1 Cy^7BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, Cy^7AIs unsubstituted or substituted by 1 Cy^7BSubstituted C_6-10Aryl radicals, e.g.A phenyl group.

In some embodiments, each Cy is^7BIs C unsubstituted or substituted by 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, each Cy is^7BIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl).

In some embodiments, Cy^7AA group of one of the following formulae:

wherein:

R⁷³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁷⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

In some embodiments, Cy^7AA group of one of the following formulae:

in some embodiments, Cy^7AUnsubstituted or substituted by 0, 1 or 2 Cy^7BAnd C substituted with 0, 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group. In some embodiments, Cy^7AIs C which is unsubstituted or substituted by 01, 2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group. In some embodiments, Cy^7AIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl). In some embodiments, Cy^7AUnsubstituted or substituted adamantyl, such as adamant-1-yl. In some embodiments, Cy^7AIs unsubstituted adamantyl, e.g., adamant-1-yl.

In some embodiments:

In some embodiments, A¹Is CR¹，A²Is CR²，A³Is CR³，A⁴Is CR⁴，A⁵Is CR⁵，A⁶Is CR⁶，A⁸Is CR⁸，A⁹Is CR⁹And A is¹⁰Is CR¹⁰。

In some embodiments, A¹Is CR¹，A³Is CR³，A⁴Is CR⁴，A⁵Is N, A⁶Is CR⁶，A⁸Is CR⁸，A⁹Is CR⁹And A is¹⁰Is CR¹⁰。

In some embodiments, A⁷Is N.

In some embodiments, A⁸Is CR⁸。

In some embodiments, R⁸Is H.

In some embodiments, R⁸Is Cy^8A、OCy^8A、O(C_1-3Alkylene) Cy^8A、C(O)OCy^8A、C(O)O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8A、N(C_1-6Alkyl) (C_1-3Alkylene) Cy^8A、C(O)NHCy^8A、C(O)NH(C_1-3Alkylene) Cy^8A、C(O)N(C_1-6Alkyl) Cy^8AOr C (O) N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8A。

In some embodiments, R⁸Is Cy^8A、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8A。

In some embodiments, R⁸Is N (Cy)^8A)₂。

In some embodiments, R⁸Is N (C (O) C_1-6Alkyl) Cy^8A。

In some embodiments, R⁸Is SO₂NHCy^8A。

In some embodiments, R⁸Is C_1-3alkylene-C (O) NHCy^8A。

In some embodiments, R⁸Is NHCy^8A。

In some embodiments, R⁸A group of one of the following formulae:

wherein:

R⁸¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

In some embodiments, R⁸A group of one of the following formulae:

in some embodiments, Cy^8AUnsubstituted or substituted by 0, 1 or 2 Cy^8BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, Cy^8AIs unsubstituted or substituted by 1 Cy^8BAnd C substituted with 0, 1,2,3,4 or 5 substituents_6-10Aryl, e.g. phenyl, each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, Cy^8AIs unsubstituted or substituted by 1 Cy^8BSubstituted C_6-10Aryl radicals, for example phenyl.

In some embodiments, each Cy is^8BIs C unsubstituted or substituted by 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group.

In some embodiments, each Cy is^8BIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl).

In some embodiments, Cy^8AA group of one of the following formulae:

wherein:

R⁸¹is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁵is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8A、OH、OCy^8A、O(C_1-3Alkylene) Cy^8A、NHCy^8A、NH(C_1-3Alkylene) Cy^8A、N(C_1-6Alkyl) Cy^8AOr N (C)_1-6Alkyl) (C_1-3Alkylene oxideRadical) Cy^8AOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

In some embodiments, Cy^8AA group of one of the following formulae:

in some embodiments, Cy^8AUnsubstituted or substituted by 0, 1 or 2 Cy^8BAnd C substituted with 0, 1,2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group. In some embodiments, Cy^8AIs C which is unsubstituted or substituted by 01, 2,3,4 or 5 substituents_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl, e.g. adamantyl, e.g. adamantan-1-yl), each of said substituents being independently selected from unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1And is selected from 1,2 or 3 independently of one another from halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group. In some embodiments, Cy^8AIs unsubstituted C_3-15Cycloalkyl (e.g. C)_3-10Cycloalkyl groups, such as adamantyl, e.g., adamantan-1-yl). In some embodiments, Cy^8AUnsubstituted or substituted adamantyl, such as adamant-1-yl. In some embodiments, Cy^8AIs unsubstituted adamantyl, e.g., adamant-1-yl.

In some embodiments:

In some embodiments, A¹Is CR¹，A²Is CR²，A³Is CR³，A⁴Is CR⁴，A⁵Is CR⁵，A⁶Is CR⁶，A⁷Is CR⁷，A⁸Is CR⁸，A⁹Is CR⁹And A is¹⁰Is CR¹⁰。

In some embodiments, A¹Is CR¹，A³Is CR³，A⁴Is CR⁴，A⁵Is N, A⁶Is CR⁶，A⁷Is CR⁷，A⁸Is CR⁸，A⁹Is CR⁹And A is¹⁰Is CR¹⁰。

In some embodiments, A⁸Is N.

In some embodiments, A⁹Is CR⁹。

In some embodiments, R⁹Is H, C_1-6Alkyl or C_1-6A haloalkyl group.

In some embodiments, R⁹Is H, methyl or trifluoroethyl.

In some embodiments, R⁹Is H.

In some embodiments, A⁹Is N.

In some embodiments, A¹⁰Is CR¹⁰。

In some embodiments, R¹⁰Is H.

In some embodiments, A¹⁰Is N.

In some embodiments, the compound is a compound of one of the following formulas (I-1) to (I-60):

wherein:

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R^N、A¹、A²、A³、A⁴、A⁵、A⁶、A⁷、A⁸、A⁹、A¹⁰、Cy^1A、Cy^1B、Cy^7A、Cy^7B、Cy^8A、Cy^8B、L¹and L²As defined above for compounds of formula (I) or any embodiment thereof;

L⁷absent, O, NH or N (C)_1-6Alkyl groups);

L⁸absent, O, NH or N (C)_1-6Alkyl groups);

R¹³is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^1B、OH、OCy^1B、O(C_1-3Alkylene) Cy^1B、NHCy^1B、NH(C_1-3Alkylene) Cy^1B、N(C_1-6Alkyl) Cy^1BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

R⁸⁶is H, unsubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, C_1-6Haloalkyl, CN, OR^a1、SR^a1、NR^c1R^d1、Cy^8B、OH、OCy^8B、O(C_1-3Alkylene) Cy^8B、NHCy^8B、NH(C_1-3Alkylene) Cy^8B、N(C_1-6Alkyl) Cy^8BOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^8BOr 1,2 or 3 are independently selected from halogen and C_1-6Haloalkyl, CN, OR^a1、SR^a1And NR^c1R^d1C substituted by a substituent of_1-6An alkyl group;

In some embodiments, R¹Is OH.

In some embodiments, R¹Is OC_1-6Alkyl (e.g., OMe).

In some embodiments, R¹Is C_2-6Alkenyl (e.g., vinyl).

In some embodiments, L⁷Is NH.

In some embodiments, L⁸Is NH.

In some embodiments, R^a1、R^b1、R^c1And R^d1Each independently selected from H,C_1-6Alkyl, HO-C_1-6Alkylene radical, C_1-6alkoxy-C_1-6Alkylene radical, C_6-10Aryl radical, C_2-6Alkenyl and C_2-6Alkynyl.

In some embodiments, the compound is a compound of one of the following formulae:

in some embodiments, the compound is a compound of one of the following formulae:

the compound or any embodiment thereof may be provided in the form of a composition, such as a pharmaceutical composition, comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one additional agent, such as a pharmaceutically acceptable carrier.

It is further to be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (and that such embodiments are intended to be combined as if written in multiple dependent forms). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. Thus, it is contemplated that the features of the embodiments described as compounds of formula (I) may be combined in any suitable combination.

In various places throughout this specification, certain features of the compounds are disclosed in groups or ranges. It is specifically intended that this disclosure encompass each individual subcombination of the members of such groups and ranges. The term "C_1-6Alkyl "is specifically intended to disclose (but not limited to) methyl, ethyl, C individually₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

The term "n-membered" (where n is an integer) generally describes the number of ring-forming atoms in the moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3, 4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl ring. When the term is used to refer to carbocyclic rings (e.g., aryl or cycloalkyl), all ring atoms are carbon atoms. When the term is used to refer to a heterocyclic ring (e.g., heteroaryl or heterocycloalkyl), one or more ring atoms (e.g., 1,2,3, or 4) are heteroatoms (e.g., nitrogen, oxygen, or sulfur) and the remainder (e.g., n-1, n-2, n-3, or n-4) are carbon atoms.

In various places in the specification, variables are described that define divalent linking groups. It is specifically intended that each linking substituent comprises both the forward and reverse versions of the linking substituent. For example, -NR (CR' R ")_n-comprises NR (CR 'R')_n-and (CR 'R')_nNR-and is intended to disclose each form separately. In the structureWhere a linking group is required, the Markush variables listed for the group are understood to be linking groups. For example, if a structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl," it is understood that "alkyl" or "aryl" refers to a linking alkylene or arylene group, respectively.

The term "substituted" refers to an atom or group of atoms formally replacing a hydrogen as a "substituent" attached to another group. Unless otherwise indicated, the term "substituted" refers to any level of substitution, such as mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected and the substitution can be at any chemically accessible position. It is understood that substitution at a given atom is limited by valence. The term "optionally substituted" refers to unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced with a substituent. A single divalent substituent (e.g., oxo) may replace two hydrogen atoms.

The term "C_n-m"indicates ranges including endpoints, where n and m are integers and indicate the number of carbons. Examples include C_1-4、C_1-6And the like. Whenever the term is used to describe group C_nTo C_mAs if each member were explicitly listed. For example, the term C_1-6Intended to describe the member C₁、C₂、C₃、C₄、C₅And C₆Each of which.

The term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight or branched. The term "C_n-mAlkyl "refers to an alkyl group having n to m carbon atoms. Alkyl corresponds formally to an alkane in which one CH bond is replaced by the point of attachment of the alkyl to the rest of the compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butylA butyl group; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2, 2-trimethylpropyl and the like.

The term "alkenyl", used alone or in combination with other terms, refers to a straight or branched chain hydrocarbon radical corresponding to an alkyl radical having one or more carbon-carbon double bonds. Alkenyl formally corresponds to having an alkene in which one CH bond is replaced by the point of attachment of the alkenyl to the rest of the compound. The term "C_n-mAlkenyl "means alkenyl having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

The term "alkynyl", alone or in combination with other terms, refers to a straight or branched chain hydrocarbon radical corresponding to an alkyl radical having one or more carbon-carbon triple bonds. Alkyl formally corresponds to alkyne, wherein one CH bond is replaced by the point of attachment of the alkynyl to the rest of the compound. The term "C_n-mAlkynyl "refers to alkynyl groups having n to m carbons. Exemplary alkynyl groups include, but are not limited to, ethynyl, prop-1-yl, prop-2-yl, and the like. In some embodiments, an alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

The term "alkylene" used alone or in combination with other terms refers to a divalent alkyl linking group. The alkylene group corresponds formally to an alkane in which the two CH bonds are replaced by the point of attachment of the alkylene group to the rest of the compound. The term "C_n-mAlkylene "means an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethyl-1, 2-diyl, propyl-1, 3-diyl, propyl-1, 2-diyl, butyl-1, 4-diyl, butyl-1, 3-diyl, butyl-1, 2-diyl, 2-methyl-propyl-1, 3-diyl, and the like.

The term "alkoxy", used alone or in combination with other terms, refers to a group of the formula-O-alkyl, wherein alkyl is as defined above. The term "C_n-mAlkoxy "refers to an alkoxy group, the alkyl group of which has n to m carbons. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

The terms "halo" or "halogen," used alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodo.

The term "haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms have been replaced with a halogen atom. The term "C_n-mHaloalkyl "means a C having n to m carbon atoms and at least one up to {2(n to m) +1} halogen atoms_n-mAlkyl, the halogen atoms may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups comprise CF₃、C₂F₅、CHF₂、CCl₃、CHCl₂、C₂Cl₅And the like. In some embodiments, the haloalkyl is fluoroalkyl.

The term "haloalkoxy", used alone or in combination with other terms, refers to a group of the formula-O-haloalkyl, wherein haloalkyl is as defined above. The term "C_n-mHaloalkoxy "refers to haloalkoxy, the haloalkyl of which has n to m carbons. Exemplary haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

The term "amino" refers to the formula-NH₂A group of (1).

The term "carbamoyl" refers to a compound of formula-C (═ O) NH₂A group of (1).

The term "carbonyl", used alone or in combination with other terms, refers to a C (═ O) group, which can also be written as C (O).

The term "carbonyl" used alone or in combination with other terms refers to a C (═ O) group.

The term "carboxy" refers to a group of formula-C (═ O) OH.

The term "oxo" refers to oxygen as a divalent substituent to form a carbonyl group, or attached to a heteroatom to form a sulfoxide or sulfone group or an N-oxide group.

The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings with aromatic character (i.e., having (4n +2) delocalized pi (pi) electrons, where n is an integer).

The term "aryl", alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings). The term "C_n-mAryl "refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, indenyl, and the like. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, aryl is phenyl.

The term "arylalkylene," used alone or in combination with other terms, refers to an aryl group, as defined herein, attached to an alkylene group, as defined herein. The term "C_n-mAryl radical C_o-pAlkylene "refers to arylalkylene groups in which an aryl group having n to m ring carbon atoms is bonded to an alkylene group having o to p carbon atoms. Arylalkylene groups include, for example, benzyl, phenethyl, and the like.

The term "heteroaryl" or "heteroaromatic" used alone or in combination with other terms refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl is a 5-or 6-membered monocyclic heteroaryl ring. In some embodiments, heteroaryl is 5 to 10 membered C_1-9Heteroaryl, which is monocyclic or bicyclic and has 1,2,3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, heteroaryl has 5-10 ring atoms, including carbon atoms and 1,2,3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, heteroaryl has 5-6 ring atoms and 1,2,3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heteroaryl is a five or six membered heteroaryl ring. Exemplary heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, and derivatives thereof,Pyridazine, pyrrole, pyrazole, oxazolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo [1,2-b ]]Thiazole, imidazo [1,2-b ]]Pyridazines, purines, furopyridines (e.g. furan [3,2-b ]]Pyridine), thienopyridines (e.g. thieno [3, 2-b)]Pyridine), and the like.

A five-membered heteroaryl ring is a heteroaryl having five ring atoms, wherein one or more (e.g., 1,2,3, or 4) ring atoms are independently selected from N, O and S. Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2, 3-triazolyl, tetrazolyl, 1,2, 3-thiadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-triazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-triazolyl, 1,3, 4-thiadiazolyl, and 1,3, 4-oxadiazolyl.

A six membered heteroaryl ring is a heteroaryl group having six ring atoms, wherein one or more (e.g., 1,2, or 3) ring atoms are independently selected from N, O and S. Exemplary six-membered ring heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term "heteroarylalkylene," used alone or in combination with other terms, refers to a heteroaryl group, as defined herein, attached to an alkylene group, as defined herein. The term "n-m-membered heteroaryl C_o-pAlkylene "refers to a heteroaryl group having n to m ring atoms attached to an alkylene group having o to p carbon atoms. Heteroarylalkylene groups include, for example, pyridylmethyl, pyridylethyl and the like.

The term "cycloalkyl", used alone or in combination with other terms, refers to a non-aromatic, saturated, monocyclic, bicyclic, or polycyclic hydrocarbon ring system containing cyclized alkyl and alkenyl groups. The term "C_n-mCycloalkyl "refers to cycloalkyl groups having n to m ring member carbon atoms. Cycloalkyl groups may comprise monocyclic or polycyclic (e.g. having 2,3 or 4 fused rings) groups and spiro rings. Cycloalkyl groups may have, for example, 3,4, 5, 6, 7, 8, 9 or 10 ring-forming carbons (C)_3-10) Or 3,4, 5, 6 or 7 ring-forming carbons (C)_3-7). In some embodiments, the cycloalkyl group hasThere are 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, cycloalkyl is C_3-6Monocyclic cycloalkyl groups. The ring-forming carbon atoms of the cycloalkyl groups may be optionally substituted by oxo or thioxo. Cycloalkyl groups also contain cycloalkylene groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, norbornyl, norindenyl, bicyclo [2.1.1]Hexyl, bicyclo [1.1.1]Pentyl, adamantyl, and the like. In some embodiments cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings fused to (i.e., having a common bond with) a cycloalkyl ring (e.g., a benzo or thienyl derivative of cyclopentane, cyclohexane, or the like, such as indanyl or tetrahydronaphthalene). The cycloalkyl group containing a fused aromatic ring may be linked through any ring-forming atom including the ring-forming atoms of the fused aromatic ring.

The term "arylalkylene," used alone or in combination with other terms, refers to a cycloalkyl group, as defined herein, attached to an alkylene group, as defined herein. The term "C_n-mCycloalkyl radical C_o-pAlkylene "refers to cycloalkylalkylene in which a cycloalkyl group having n to m ring carbon atoms is linked to an alkylene group having o to p carbon atoms. Cycloalkylalkylene groups include, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclohexylmethyl, and the like.

The term "heterocycloalkyl", used alone or in combination with other terms, refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of a ring structure, independently having at least one heteroatom ring member selected from nitrogen, sulfur, oxygen, and phosphorus, and having 4-10 ring members, 4-7 ring members, or 4-6 ring members. Heterocycloalkyl includes monocyclic 4-, 5-, 6-and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can comprise a monocyclic or bicyclic (e.g., having two fused or bridged rings) ring system. In some embodiments, heterocycloalkyl is of 1,2, or 3A monocyclic group of heteroatoms independently selected from nitrogen, sulfur and oxygen. Examples of heterocycloalkyl groups include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, pyran, azepane, tetrahydropyran, tetrahydrofuran, dihydropyran, dihydrofuran, and the like. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally oxo or thioxo (e.g., C (═ O), S (═ O), C (S), or S (═ O)₂Etc.) or the nitrogen atom may be quaternized. The heterocycloalkyl group may be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., having a common bond with) a heterocycloalkyl ring (e.g., a benzo or thienyl derivative of piperidine, morpholine, azepine, etc.). The heterocycloalkyl group containing a fused aromatic ring may be linked through any ring-forming atom including the ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include 1,2,3, 4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane, diazepane (e.g., 1, 4-diazepane), pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, pyran, tetrahydrofuran, and dihydropyran and tetrahydropyran.

The term "heterocycloalkylalkylene," used alone or in combination with other terms, refers to a heterocycloalkyl group, as defined herein, attached to an alkylene group, as defined herein. The term "n-m membered heterocycloalkyl C_o-pAlkylene "refers to a heterocycloalkyl group having n to m ring atoms attached to an alkylene group having o to p carbon atoms. Heteroarylalkylene groups include, for example, tetrahydrofuryl.

In certain places, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise indicated, these rings may be attached to any ring member, provided that the valency of the atoms is not exceeded. For example, the azetidine ring may be attached at any position on the ring, while the azetidin-3-yl ring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., have one or more stereogenic centers). Unless otherwise indicated, all stereoisomers (such as enantiomers and diastereomers) are meant. The compounds of the invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C ═ N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the invention are described and may be separated as mixtures of isomers or as individual isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. One method involves fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for use in the fractional recrystallization process are, for example, optically active acids such as tartaric acids in the D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids (e.g.. beta. -camphorsulfonic acid). Other resolving agents suitable for the fractional crystallization process include stereoisomerically pure forms of methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine). One skilled in the art can determine a suitable elution solvent composition.

In some embodiments, the compounds of the present invention have the (R) -configuration. In other embodiments, the compound has the (S) -configuration. In compounds having more than one chiral center, each chiral center in the compound may independently be (R) or (S), unless otherwise specified.

The compounds of the present invention also include tautomeric forms. Tautomeric forms arise from the exchange of a single bond with an adjacent double bond along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Exemplary proton tautomers include keto-enol pairs, amide-imide pairs, lactam-lactam pairs, enamine-imine pairs, and cyclic forms in which a proton may occupy two or more positions of a heterocyclic ring system, such as 1H-and 3H-imidazole, 1H-, 2H-, and 4H-1,2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole. Tautomeric forms can be in equilibrium or, by appropriate substitution, sterically locked into one form.

The compounds of the invention may also contain isotopes of all atoms present in the intermediate or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The term "compound" is intended to encompass all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure.

All compounds and their pharmaceutically acceptable salts can be found (e.g., hydrates and solvates) with other materials such as water and solvents or can be isolated. When in the solid state, the compounds described herein and salts thereof may exist in various forms and may, for example, take the form of solvates, including hydrates. The compounds may be in any solid state form, such as polymorphs or solvates, and thus, unless expressly stated otherwise, references to compounds and salts thereof in the specification are to be understood as encompassing any solid state form of the compound.

In some embodiments, the compounds of the invention or salts thereof are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation may comprise, for example, a composition enriched in a compound of the invention. Substantially isolating may comprise a composition comprising at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound of the invention, or a salt thereof.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The expressions "ambient temperature" and "room temperature" are as understood in the art and generally refer to a temperature (e.g., reaction temperature) that is about the temperature of the room in which the reaction is conducted, such as a temperature from about 20 ℃ to about 30 ℃.

The invention also encompasses salts, in particular pharmaceutically acceptable salts, of the compounds described herein. The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by conversion of an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred. A list of suitable salts can be found below: remington's Pharmaceutical Sciences, 17 th edition, (Iston Mark Publishing Company (Mack Publishing Company, Easton),1985), p 1418; berge et al, journal of pharmaceutical sciences (j.pharm.sci.), 1977,66(1),1-19 and Stahl et al, handbook of pharmaceutical salts: properties, Selection, and Use (Handbook of Pharmaceutical Salts, Selection, and Use), (Wiley Press, 2002). In some embodiments, the compounds described herein comprise an N-oxide form.

The following abbreviations may be used herein: AcOH (acetic acid); ac of₂O (acetic anhydride); al (Al)₂O₃(alumina); (aqueous); atm. (atmospheric pressure); boc (tert-butoxycarbonyl); boc₂O (di-tert-butyl dicarbonate); BOP ((benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate); br (wide); c-Pr (cyclopropyl); cbz (carboxybenzyl); calc (calculated); CeCl₃·7H₂O (cerium (III) chloride heptahydrate); cs₂CO₃(cesium carbonate); CuI (copper (I) iodide); d (doublet); dd (doublet of doublets); DCM (dichloromethane); DIPEA (N, N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (N, N-dimethylformamide); DMSO (dimethyl sulfoxide); et (ethyl); EtOAc (ethyl acetate); EtOH (ethanol); fmoc (9-fluorenylmethylmethoxycarbonyl); g (grams); h (hours); h₂(hydrogen gas); h₂O₂(hydrogen peroxide); HATU (N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate); HBr (hydrogen bromide); HCl (hydrochloric acid or hydrogen chloride); HPLC (high performance liquid chromatography); hz (hertz); i-Pr (isopropyl); i-PrOH (isopropanol); j (coupling constant); KOAc (potassium acetate); k₃PO₄(potassium phosphate); k₃PO₄·H₂O (tripotassium phosphate hydrate); LCMS (liquid chromatography-mass spectrometry); LiAlH₄(lithium tetrahydroaluminate); LiBH₄(lithium tetrahydroborate); LiOH (lithium hydroxide); LiOH · H2O (lithium hydroxide monohydrate); m (multiplet); m (mole); mCPBA (m-chloroperoxybenzoic acid); me (methyl); MeCN (acetonitrile); MeOH (methanol); MgSO4 (magnesium sulfate); MS (mass spectrometry); mg (milligrams); min. (min) mL (mL); mmol (millimole); n (normal); n is a radical of₂(nitrogen); NaHCO 2₃(sodium bicarbonate); NaIO₄(sodium metaperiodate); NaN₃(sodium azide); NaOH (sodium hydroxide); na (Na)₂SO₄(sodium sulfate); n-Bu (n-butyl); n-BuLi (n-butyl lithium); NH (NH)₄Cl (ammonium chloride); NH (NH)₄OH (ammonium hydroxide); nM (nanomolar);NMR (nuclear magnetic resonance spectrum); pd (palladium); pd (dppf) Cl₂([1,1' -bis (diphenylphosphino) ferrocene)]Palladium (II) dichloride); pd (OAc)₂(palladium acetate); pd (tBu)₃P)₂(bis (tri-tert-butylphosphino) palladium); pM (picomolar); pd (PPh)₃)₄(tetrakis (triphenylphosphine) palladium (0)); PPh₃(triphenylphosphine); psi (pounds per square inch); PTFE (polytetrafluoroethylene); RP-HPLC (reverse phase high performance liquid chromatography); r.t. (room temperature); s (singlet); t (triplet or tertiary); tert (tertiary); tt (triple triplet); TBAF (tetra-n-butylammonium fluoride); t-Bu (tert-butyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μ g (μ g); μ L (microliters); μ m (micromolar); wt% (weight percent).

Synthesis of

The compounds of the invention (including salts thereof) may be prepared using known organic synthesis techniques and may be synthesized according to any of a number of possible synthetic routes, as shown in the following schemes.

The reactions used to prepare the compounds of the present invention may be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reaction is carried out (e.g., temperatures that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for the particular reaction step may be selected by the skilled person.

The preparation of the compounds of the invention may involve the protection and deprotection of different chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of the protecting groups is described, for example, in the following: kocienski, "Protecting Groups (Protecting Groups), (Thieme, 2007); robertson, "protective Group Chemistry" (Oxford University Press), 2000); smith et al, advanced organic chemistry, Machi: reactions, Mechanisms and structures (March's Advanced Organic Chemistry: Reactions, mechanics, and Structure), 6 th edition (Willi Press, 2007); petursion et al, "protective Groups in Carbohydrate Chemistry" (journal of chemical education (j.chem.educ.), "1997, 74(11), 1297; and Wuts et al, Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), 4 th edition (Willi Press, 2006).

The reaction may be monitored according to any suitable method known in the art. For example, the light may be detected by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g.,¹h or¹³C) Infrared spectroscopy, spectrophotometry (e.g., visible UV), mass spectrometry, or monitoring product formation by chromatographic methods such as High Performance Liquid Chromatography (HPLC) or Thin Layer Chromatography (TLC).

The following schemes provide general guidance for the preparation of the compounds of the present invention. One skilled in the art will appreciate that the general knowledge of organic chemistry can be used to modify or optimize the preparations shown in the schemes to prepare the various compounds of the invention.

Compounds of formula (I) may be prepared as shown in scheme 1 by coupling an aniline of formula (II) with a compound of formula III, wherein L is a suitable leaving group which may comprise a halogen, such as bromine or iodine, or a sulfonate group (an alkyl or aryl sulfonate, e.g. mesylate, triflate, besylate, p-toluenesulfonate or naphthalenesulfonate). The reaction may be carried out in the presence of a base such as potassium carbonate and a copper salt such as copper (I) iodide or copper (I) oxide. The reaction may also be carried out in the presence of a suitable organometallic catalyst, for example using Buchwald-Hartwig cross-coupling conditions. Suitable solvents for the reaction include tetrahydrofuran, 1, 4-dioxane, toluene or 1, 2-dichlorobenzene. The preferred solvent is 1, 2-dichlorobenzene. The reaction may generally be carried out at a temperature of from 0 to 200 deg.C, for example at a temperature of 100-150 deg.C.

The present disclosure provides, inter alia, methods for preparing certain compounds of formula (I) according to formula (Ia) by the routes shown in scheme 1:

scheme 1

The compounds of formula (II) and compounds of formula (III) are commercially available, known in the literature, or can be prepared by methods known to those skilled in the art.

Certain compounds of formula (I) may be useful as intermediates in the synthesis of other compounds of formula (I). For example, wherein R¹Is OC_1-6Alkyl radical OCy^1A、O(C_1-3Alkylene) Cy^1A、NHCy^1A、NH(C_1-3Alkylene) Cy^1A、N(C_1-6Alkyl) Cy^1AOr N (C)_1-6Alkyl) (C_1-3Alkylene) Cy^1AThe compounds of formula (I) can be used for the synthesis of compounds wherein R is an ester or amide group by hydrolysis¹A compound of formula (I) which is OH.

It will be appreciated by those skilled in the art that the methods described are not the only means by which the compounds of the invention can be synthesized, and that a wide range of synthetic organic reactions are potentially useful for synthesizing the compounds of the invention. The skilled person knows how to select and implement an appropriate synthetic route. Suitable synthetic methods for starting materials, intermediates and products can be determined by reference, which includes reference sources such as: advanced in Heterocyclic Chemistry, volumes 1-107 (Elsevier, 1963-; journal of Heterocyclic Chemistry, volumes 1-49 (Journal of Heterocyclic Chemistry, 1964-; carreira et al (eds.) Science of Synthesis, volumes 1-48 (2001-2010) and Knowledge Updates (Knowledge Updates) KU 2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); katritzky et al (eds.) Integrated Organic Functional Group Transformations (Comprehensive Organic Functional groups Transformations) (Pergamman Press, 1996); katritzky et al (editors); comprehensive Organic Functional Group transformation II (comprehensive Organic Functional groups Transformations II) (Elsevier, 2 nd edition, 2004); katritzky et al (eds.), (Comprehensive Heterocyclic Chemistry) (Pegman Press, 1984); katritzky et al, "synthetic Heterocyclic Chemistry II" (Pergemman Press, 1996); smith et al, advanced organic chemistry, Machi: reactions, Mechanisms and structures (March's Advanced Organic Chemistry: Reactions, mechanics, and Structure), 6 th edition (Willi Press, 2007); trost et al (ed.), Comprehensive Organic Synthesis (Pergeman publishers, 1991).

Use of compounds

The compounds of the invention may inhibit the self-palmitoylation of TEAD-transcription factor and are therefore useful in the treatment of diseases and disorders associated with the activity of TEAD-transcription factor. For the uses described herein, any of the compounds of the present invention, including any of its embodiments, may be used.

Accordingly, the present disclosure provides methods of treating a TEAD-transcription factor-associated disease or disorder in an individual (e.g., patient) in need of such treatment by administering to the individual a therapeutically effective amount or a therapeutically effective dose of a compound of formula (I) or any embodiment thereof or a pharmaceutical composition thereof. The present disclosure also provides a compound of formula (I) or any embodiment thereof or a pharmaceutical composition thereof for use in treating a TEAD-transcription factor associated disease or disorder. Also provided is the use of a compound of formula (I) or any embodiment thereof or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of a TEAD-transcription factor associated disease or disorder. The disease or disorder may be a disease or disorder associated with TEAD1, TEAD2, TEAD3, or TEAD 4.

A TEAD-transcription factor-associated disease may comprise any disease, disorder or condition associated directly or indirectly with expression or activity of a TEAD-transcription factor, including overexpression and/or abnormal activity levels. Abnormal activity levels can be determined by comparing the activity level in normal, healthy tissue or cells to the activity level in diseased cells. A TEAD-transcription factor-associated disease may also comprise any disease, disorder or condition that can be prevented, ameliorated, inhibited or cured by modulation of TEAD-transcription factor activity. In some embodiments, the disease is characterized by aberrant activity or expression (e.g., overexpression) of a TEAD-transcription factor. A TEAD-transcription factor-associated disease may also refer to any disease, disorder or condition in which modulating the expression or activity of TEAD-transcription factor is beneficial.

TEAD-transcription factor related diseases that can be treated using the compounds of the present invention include cancer. The cancer includes solid tumors such as prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, and the like. Other TEAD-transcription factor related diseases include hepatocellular carcinoma, medulloblastoma, cutaneous squamous cell carcinoma, lung carcinoma, pancreatic carcinoma, esophageal carcinoma, liver carcinoma, colon carcinoma, melanoma or uveal melanoma. TEAD-transcription factor related diseases also comprise hematological cancers, e.g. lymphomas, leukemias such as Acute Lymphocytic Leukemia (ALL), Acute Myelocytic Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myelocytic Leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-hodgkin's lymphoma (including recurrent non-hodgkin's lymphoma, refractory non-hodgkin's lymphoma and recurrent follicular non-hodgkin's lymphoma), hodgkin's lymphoma and multiple myeloma.

The cancer may be a cancer in which the aberrantly proliferating cancer cells express one or more TEADs, for example a cancer that expresses one or more of TEAD1, TEAD2, TEAD3, and/or TEAD 4. The methods may comprise testing cancer cells of the individual for expression of one or more TEADs, for example expression of one or more of TEAD1, TEAD2, TEAD3, and/or TEAD4, and determining to treat the cancer according to the methods described herein based on: the cancer expresses TEAD1, TEAD2, TEAD3, and/or TEAD 4.

The terms "individual" or "patient" are used interchangeably to refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

The phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, subject, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

The term "treating" or "treatment" refers to one or more of the following: (1) inhibiting the disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting a pathology or symptomatology of the disease, condition, or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition, or disorder (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder, such as reducing the severity of the disease. In one embodiment, treating comprises preventing or reducing the risk of developing a disease; for example, preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder, but does not yet experience or display the pathology or symptomology of the disease.

Combination therapy

The growth and survival of cancer cells can be affected by a variety of signaling pathways. Thus, it is useful to combine different chemotherapeutic agents to treat such conditions. The use of combination therapy may reduce the likelihood of drug resistance in the cell population, and/or reduce the toxicity of the treatment.

The compounds may be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Exemplary chemotherapeutic agents include any of the following: abarelix (abarelix), aldesleukin (aldesleukin), alemtuzumab (alemtuzumab), alditeno (aletretinoin), allopurinol (allopurinol), altretamine (altretamine), anastrozole (anastrozole), arsenic trioxide, asparaginase, azacitidine (azacitidine), bevacizumab (bevacizumab), bexarotene (bexarotene), bleomycin (bleomycin), bortezomib (bortezomib), intravenous busulfan (busufacinous), oral busulfan (busufan oratal), carboplatin (calsterone), capecitabine (capecitabine), carboplatin (carboplatin), carboplatin (carbaactinomycin), cartilaginine (carbapenem), cytarabine (clavine), chlorambucil (sulfadiazine), chlorambucil (sulfadoxylamine (clofibrate), chlorambucil (sulfabendazole), cisplatin (sulfabendazole (e), sulfabendazole (e (sulfabendazole), cisplatin (e), sulfabendazole (e (sulfabendazole (e), sulfadiazine (e), clofibrate (sulfadiazine (e), clofibrate (clofibrate), clofibrate (clofibrate), clofibrate (clofibrate), clofibrate), clofibrate (clofibrate), clofibrate (clofibrate, clofibrate, Daunorubicin (daunorubicin), decitabine (decitabine), dinil interleukin (denileukin), denil interleukin (denilin difitox), dexrazoxane (dexrazoxane), docetaxel (docetaxel), doxorubicin (doxorubicin), dromostanolone propionate (dromostanolone propionate), eculizumab (eculizumab), epirubicin (epirubicin), erlotinib (erlotinib), estramustine (estramustine), etoposide phosphate (etoposide phosphate), etoposide (etoposide), exemestane (exemestane), fentanyl citrate (fentanoate), filgrastim (fluuridine), fludarabine (fludarabine), fluorouracil (fluraciridine), gemcitabine (flutamicidine), flutamicidine (flutamicidine), flutamide (flutamide), gemcitabine (flutamicidin), flutamicidine (flutamicid), flutamicid (lutetinib), docetaxel (docetaxel), docetaxel (docetaxel), doxastin), doxicin (doxicin), flunomin (flunomine), flunomib (flunomib), flunomib (flunomiben (flunomib), flunomiben (flunomiben), flunomiben (flunomiben), flunomib), flunomiben (fluben), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (flunixin), flunixin (, Imatinib mesylate (imatinib mesylate), interferon alpha 2a (interferon alfa 2a), irinotecan (irinotecan), lapatinib ditosylate xylenesulfonate (lapatinib ditosylate), lenalidomide (lenalidomide), letrozole (letrozole), leucovorin (leucovorin), leuprolide acetate (leuprolide acetate), levamisole (levamisole), lomustine hydrochloride (lomustine), megestrol acetate (megestrol acetate), melphalan (melphalan), mercaptopurine (mertepurine), methotrexate (methotrexate), methoxsalene (methoxsate), mitomycin C (mitomycin C), mitotane (mitoxantrone), mitoxantrone (mitoxantrone), phenylphosphonic acid (matrine), paclitaxel (oxaliplatin), paclitaxel), nonpalmitin (paclitaxel), nonpalmitone (paclitaxel), pemetrexendine (oxaliplatin), pemetrexendine (paclitaxel), pemetrexendin (paclitaxel), pemirostrin (paclitaxel), pemetrexendin (paclitaxel), pemetrexendine (paclitaxel), pemetrexendin (matrine), pemetrexendine (matrine), pemetrexendin (matrine), pemetrexelate), pemetrexendin (matrine), pemetrexelate), pemetrexendin (matrine), pemetrexendin (matrine), pemetrexelate), pemetrexelate, pemetrexendin (matrine, pemetrexelate), pemetrexelate (matrine, pemetrexelate), pemetrexelate, pemetrexed (pemetrexelate, pemetrexed (pemetrexelate), pemetrexed (pemetrexelate), pemetrexelate), pemetrexed (pemetrexelate), pemetrexed, Pentostatin (pentostatin), pipobromane (piproman), plicamycin (plicamycin), procarbazine (procarbazine), quinacrine (quinacrine), labyrine (rasburicase), rituximab (rituximab), ruxotinib (ruxolitinib), sorafenib (sorafenib), streptozotocin (streptozocin), sunitinib (sunitinib), sunitinib maleate (sunitinib maloate), tamoxifen (tamoxifen), temozolomide (temozolomide), teniposide (teniposide), testolactone (testolactone), thalidomide (thalidomide), thioguanine (thioguanine), thiotepa (thiotepa), topotecan (topotecan), toremifene (toremifene), tositumomab (tositumomab), trastuzumab (trastuzumab), tretinoin (tretinoin), uramustine (uracil musard), valrubicin (valrubicin), vinblastine (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), ritotal (vorinostat), and zoledronate (zoledronate).

When more than one agent is administered to a patient, the agents may be administered simultaneously, sequentially, or in combination (e.g., for more than two agents).

Formulation, dosage form and administration

When used as a medicament, the compounds of the invention may be administered in the form of a pharmaceutical composition. Accordingly, the present disclosure provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any embodiment thereof, and at least one pharmaceutically acceptable carrier. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered by a variety of routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and to mucosal membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial (e.g., intrathecal or intracerebroventricular) administration. Parenteral administration may be in the form of a single bolus dose, or may be performed, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may comprise transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

The invention also encompasses pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for oral administration. In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient or encapsulated within such a carrier, e.g., in the form of a capsule, sachet (sachet), paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing the formulation, the active compound may be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it may be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

The compounds of the invention may be milled using known milling procedures (e.g., wet milling) to obtain a particle size suitable for tablet formation as well as for other formulation types. Finely divided (nanoparticulate) formulations of the compounds of the invention can be prepared by methods known in the art, see, for example, WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulation may additionally comprise: lubricants, such as talc, magnesium stearate, mineral oil; a wetting agent; emulsifying and suspending agents; preservatives, such as methyl and propylhydroxybenzoates; a sweetener; and a flavoring agent. The compositions of the present invention may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one component selected from the group consisting of microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, lactose monohydrate, and hydroxypropylmethylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102^TM. In some embodiments, the lactose monohydrate is Fast-flo 316^TM. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208K4M (e.g., Methocel K4M Premier)^TM) And/or hydroxypropyl methylcellulose 2208K100LV (e.g., Methocel K00 LV)^TM). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105)^TM)。

In some embodiments, the composition is produced using a wet granulation process. In some embodiments, the composition is produced using a dry granulation process.

The compositions may be formulated in unit dosage forms, each dosage containing from about 5 to about 1,000mg (1g) of the active ingredient, more typically from about 100mg to about 500mg of the active ingredient. In some embodiments, each dose contains about 10mg of the active ingredient. In some embodiments, each dose contains about 50mg of the active ingredient. In some embodiments, each dose contains about 25mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical composition are of high purity and are substantially free of potentially harmful contaminants (e.g., at least national food grade, typically at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the compositions are preferably manufactured or formulated according to the high quality production specification standards defined in the applicable regulations of the U.S. food and drug administration. For example, suitable formulations may be sterile and/or substantially isotonic and/or fully compliant with all quality manufacturing code regulations of the U.S. food and drug administration.

The active compounds can be effective over a wide dosage range and are generally administered in therapeutically effective amounts. It will be understood, however, that the amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

The therapeutic dosage of the compounds of the invention may vary depending, for example, on the particular use being treated, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention may be provided in an aqueous physiological buffer solution for parenteral administration comprising from about 0.1 to about 10% w/v of the compound. Some typical dosages range from about 1 μ g/kg body weight/day to about 1g/kg body weight/day. In some embodiments, the dosage ranges from about 0.01mg/kg body weight/day to about 100mg/kg body weight/day. The dosage may depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

For preparing solid compositions (e.g., tablets), the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of a compound of the present invention. When referring to these pre-formulated compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from about 0.1mg to about 1000mg of the active ingredient of the invention.

The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill can include an inner dosage component and an outer dosage component, the latter being in the form of a film coating over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, such materials including polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

Liquid forms that may be incorporated into the compounds and compositions of the present invention for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, these compositions are administered via the oral or nasal respiratory route for obtaining a local or systemic effect. The composition may be atomized by using an inert gas. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask plug or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

Topical formulations may contain one or more conventional carriers. In some embodiments, the ointment may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier composition of the cream may be based on water in combination with glycerin and one or more other components (e.g., glyceryl monostearate, PEG-glyceryl monostearate, and cetyl stearyl alcohol). The gelling agent may be formulated using isopropanol and water, suitably in combination with other components (such as, for example, glycerol, hydroxyethylcellulose, and the like). In some embodiments, a topical formulation contains at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt% of a compound of the present invention. The topical formulation may be suitably packaged in, for example, 100g tubes, optionally with instructions for treating a selected indication (e.g., psoriasis or other skin condition).

The amount of the compound or composition administered to a patient will vary depending on the drug being administered, the purpose of the administration (e.g., prevention or treatment), the condition of the patient, the mode of administration, and the like. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially inhibit the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated and, at the discretion of the attending clinician, on factors such as the severity of the disease, the age, weight and general condition of the patient, etc.

The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized formulation being combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation is typically between 3 and 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of certain of the aforementioned excipients, carriers or stabilizers should result in the formation of pharmaceutically acceptable salts.

Labeled compounds and assays

The compounds of the invention may further be used to study biological processes in normal and abnormal tissues. Thus, another aspect of the invention relates to labeled compounds (radiolabeled, fluorescently labeled, etc.) of the invention that are useful not only in imaging techniques, but also in vitro and in vivo assays for locating and quantifying TEAD transcription factors in tissue samples, including humans, and identifying TEAD transcription factor ligands by inhibiting the binding of labeled compounds. Thus, the invention encompasses assays for compounds containing such labels.

The invention further comprises isotopically-labelled compounds of the invention. An "isotopically labeled" or "radiolabeled" compound is a compound of the invention in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the present invention include, but are not limited to³H (tritium also written as T),¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、¹⁸F、³⁵S、³⁶Cl、⁸²Br、⁷⁵Br、⁷⁶Br、⁷⁷Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹I. the radionuclide that is incorporated into the radiolabeled compounds of the present invention will depend on the particular application for which the radiolabeled compound is used. For example, for in vitro labeling and competition assays, incorporation³H、¹⁴C、⁸²Br、¹²⁵I、¹³¹I、³⁵Compounds of S will generally be the most useful. For the application of radiological imaging,¹¹C、¹⁸F、¹²⁵I、¹²³I、¹²⁴I、¹³¹I、⁷⁵Br、⁷⁶br or⁷⁷Br will generally be the most useful.

It will be understood that a "radiolabeled" or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of:³H、¹⁴C、¹²⁵I、³⁵s and⁸²br is added. In some embodiments, the compound incorporates 1,2, or 3 deuterium atoms. Synthetic methods for incorporating radioisotopes into organic compounds are known in the art.

In particular, the labeled compounds of the invention can be used in screening assays to identify and/or evaluate compounds. For example, a newly synthesized or identified labeled compound (i.e., test compound) can be evaluated for its ability to bind to a TEAD transcription factor by monitoring its concentration change upon contact with the TEAD transcription factor by means of a tracking label. For example, the ability of a test compound (labeled) to reduce the binding of another compound known to bind to a TEAD transcription factor (i.e., a standard compound) can be assessed. Thus, the ability of a test compound to compete with a standard compound for binding to TEAD transcription factor is directly related to its binding affinity. In contrast, in some other screening assays, the standard compound is labeled and the test compound is unlabeled. Thus, the concentration of the labeled standard compound is monitored in order to assess competition between the standard compound and the test compound, thereby determining the relative binding affinity of the test compound.

V. kit

The present disclosure also encompasses pharmaceutical kits useful, for example, in the treatment or prevention of a TEAD transcription factor-associated disease or disorder, such as cancer, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any embodiment thereof. Such kits may further comprise one or more conventional pharmaceutical kit components, such as a container with one or more pharmaceutically acceptable carriers, additional containers, and the like, as will be apparent to those skilled in the art. Instructions indicating the amount of the components to be administered (as an insert or as a label), directions for administration, and/or directions for mixing the components may also be included in the kit.

The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a number of non-critical parameters that may be altered or modified to produce substantially the same result.

Examples of the invention

Synthesis of compounds

Experiment:

the MS (mass spectrometry) data provided in the examples were obtained using the following equipment: API 2000 LC/MS/MS/triple quadrupole; agilent (1260 definition) LCMS-SQD 6120/single quadrupole and Shimadzu (Shimadzu) LCMS-2020/single quadrupole.

NMR data provided in the examples is using equipment —¹HNMR：¹HNMR: varian-400 MHz, JEOL-400 MHz.

Abbreviations used throughout the specification may be summarized below in their specific meaning.

deg.C (degrees Celsius); δ (delta); percent (percent); (BOC)₂O (Boc anhydride); bs (broad singlet); CDCl₃(deuterated chloroform); DCM (dichloromethane); DMF (dimethylformamide); DIPEA (N, N-diisopropylethylamine); DMAP (dimethylaminopyridine); (DMSO-d6 (deuterated DMSO); d (doublet), dd (doublet), Fe (iron powder); g or gm (g) HATU (1- [ bis (dimethylamino) methylene)]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide hexafluorophosphate); h or H₂(hydrogen); h₂O (water); HCl (hydrochloric acid); h or hr (hours); hz (hertz); HPLC (high performance liquid chromatography); j (coupling constant); LiOH (lithium hydroxide); MeOH (methanol); mmol (millimole); m (mole); mL (milliliters); mg (milligrams); m (multiplet); mm (millimeters); MHz (megahertz); min (minutes); NaH (sodium hydride); NaHCO 2₃(sodium bicarbonate); na (Na)₂SO₄(sodium sulfate); n is a radical of₂(nitrogen); NMR (nuclear magnetic resonance spectrum); Pd/C (palladium on carbon); RT (room temperature); s (singlet); TEA (triethylamine); TFA (trifluoroacetic acid); TLC (thin layer chromatography); THF (tetrahydrofuran); t (triplet); binap ((±) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthalene); pd₂dba₃(tris (dibenzylideneacetone) dipalladium (0)); XPhos (2-dicyclohexylphosphine-2 ', 4', 6 ' -triisopropylbiphenyl); in vacuo (under vacuum); eq. (eq); ppt (precipitation); NA (not applicable).

The general procedure for synthesizing certain exemplified compounds is shown in scheme II below:

scheme 2

To a solution of iodide (1mmol) and amine (1mmol) in 1, 2-dichlorobenzene under nitrogen was added potassium carbonate (1.5mmol) followed by copper iodide (0.05 mmol). The resulting mixture was stirred at room temperature for 1 hour, and then heated at 180 ℃ for 2 days. After completion of the reaction, the resulting mixture was diluted with dichloromethane (50mL) and filtered through a celite bed. The organic solution was washed with MgSO₄Dried, concentrated under vacuum and purified by flash column chromatography using hexane/ethyl acetate (gradient of pure hexane to 20/1 hexane/ethyl acetate) as eluent in 40-69% yield.

Compound 2a was confirmed by proton NMR and mass spectrometry (ESI) and (Rf 0.3 with pure hexane as eluent, TLC).

In the case of the compound 2a,¹H NMR(500MHz,CDCl₃) δ 9.46(s,1H),7.98-7.94(m,1H),7.40(s,1H),7.35(m,1H),7.28(d,1H),7.19-7.13(m,3H),6.79(m,1H),3.90(s,3H) ppm. Mass (M + H,307.1), yield 56%.

Compounds 2b (M + H306.1), 2c (M + H375.1), 2d (M + H325.1), 2e (M + H443.1) were confirmed by mass spectrometry (LC-MS/ESI) and were also consistent with retention factor (Rf 0.3 with pure hexane as eluent) on TLC.

The general procedure for the synthesis of the starting materials for compounds CP-59 and CP-65 is shown in scheme 3 below:

scheme 3

The desired amine (1mmol) and chloronicotinate (1mmol) were dissolved in ethylene glycol and then heated at 140 ℃ for 24 hours. After completion of the reaction, the resulting mixture was diluted with ethyl acetate (50mL) and washed three times with 20mL of water. Will haveMgSO (MgSO) for organic solution₄Dried, concentrated under vacuum and purified by flash column chromatography using hexane/ethyl acetate (gradient of pure hexane to 15/1 hexane/ethyl acetate) as eluent. The yield was 55-59%.

Compound 2f (M + H,376.1) and 2g (M + H,322.1) were confirmed by spectroscopy (ESI) and (Rf 0.1 with pure hexane as eluent, TLC).

The cross-coupling procedure for preparing several exemplary compounds is shown below in scheme 4.

Scheme 4

To an oven dried Schlenk tube were added amine (1mmol) and bromide (1mmol) and toluene (3 mL). To the above homogeneous solution was added t-BuONa (1.5 mmol). After stirring for 5 minutes, Pd was added under nitrogen atmosphere₂(dba)₃(0.05mmol) and Bu₃P (0.075 mmol). The mixture was stirred at 110 ℃ for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50mL) and filtered through a celite bed. The organic solution was washed with MgSO₄Dried, concentrated under vacuum and purified by flash column chromatography using hexane/ethyl acetate (gradient of pure hexane to 10/1 hexane/ethyl acetate) as eluent to give the desired product. The yield thereof was found to be 42 to 55%.

In the case of the compound 3a,¹H NMR(500MHz,CDCl₃):δ9.45(s,1H),8.01(s,1H),7.5-7.7.30(m,2H),7.2-7.1(m,2H),6.98(s,1H),6.8(s,1H)6.78-6,26(m,4H),5.99(s,1H)3.90(s,3H),2.23-1.97(m,15H)ppm

in the case of the compound 3c,¹H NMR(500MHz,CDCl₃):δ9.45(s,1H),8.01(s,1H),7.45-7.23.(d,2H),7.23-7.01(m,6H),6.98-7.01(d,2H),6.94(s,1H),3.93(s,3H),5.99(s,1H)2.21-1.98(m,15H)ppm

in the case of the compound 3d,¹H NMR(500MHz,CDCl₃):δ9.45(s,1H),8.01(s,1H),7.45-7.01(m,4H),6.94(s,1H),6.63(s,1H)6.65-6,20(m,4H),5.98(s,1H)3.92(s,3H),2.21-1.98(m,15H)ppm

the cross-coupling procedure for preparing several exemplary compounds is shown below in scheme 5.

Scheme 5

In the case of the compound 3f,¹H NMR(500MHz,CDCl₃):δ9.45(s,1H),8.01(s,1H),7.49-7.33.(d,2H),7.23-7.01(m,5H),6.91-7.04(d,2H),6.94(s,1H),3.93(s,3H),5.99(s,1H)2.21-1.98(m,15H)ppm

compound 3g was confirmed using LC-MS/ESI (M + H468.57).

The cross-coupling procedure for preparing several exemplary compounds is shown below in scheme 6.

Scheme 6

To an oven dried Schlenk tube were added amine (1mmol) and bromide (1mmol) and toluene (3 mL). To the above homogeneous solution was added t-BuONa (1.5 mmol). After stirring for 5 minutes, Pd was added under nitrogen atmosphere₂(dba)₃(0.05mmol) and Bu₃P (0.075 mmol). The mixture was stirred at 110 ℃ for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50mL) and filtered through a celite bed. Will haveMgSO (MgSO) for organic solution₄Dried, concentrated under vacuum and purified by flash column chromatography using hexane/ethyl acetate (gradient of pure hexane to 10/1 hexane/ethyl acetate) as eluent to give the desired product (39-55% yield).

In the case of the compound 3b,¹H NMR(500MHz,CDCl₃):δ9.45(s,1H),8.01(s,1H),7.67-7.56(d,2H),7.2-7.1(m,2H),6.98(s,1H),6.82(s,1H)6.78-6,26(m,2H),5.99(s,1H)3.92(s,3H),2.23-1.97(m,15H)ppm

in the case of the compound 3e,¹H NMR(500MHz,CDCl₃):δ9.46(s,1H),8.05(s,1H),7.79-7.56(m,4H),7.2-6.99(m,4H),6.98(s,1H,5.99(s,1H)3.94(s,3H),2.23-1.97(m,15H)ppm

the carboxylic acid compounds were prepared by hydrolysis reactions as shown in schemes 7, 8, 9 and 10 and following experimental procedures.

Scheme 7

To a solution of the ester (1mmol) in ethanol (10mL) was added a 2N NaOH solution of 2mmol and heated at 40 ℃ for 24-48 h. After completion of the reaction, the reaction was cooled on ice and acidified with 2N hydrochloride solution and extracted three times with 10mL of ethyl acetate. The organic solution was washed with MgSO₄Dried, concentrated under vacuum and purified by flash column chromatography using hexane/ethyl acetate (gradient of pure hexane to 5/1 hexane/ethyl acetate) as eluent to give the desired product. The yield was 70-79%.

CP-52 was confirmed by LC-MS (ESI, M + H439.1).

CP-57 was confirmed by LC-MS (ESI M + H521.1).

CP-62 was confirmed by LC-MS (ESI M + H457.1).

Scheme 8

To a solution of the ester (1mmol) in ethanol (10mL) was added 2mmol of 2N NaOH solution and heating at 40 deg.c for 24-48 hr. After completion of the reaction, the reaction was cooled on ice and acidified with 2N hydrochloride solution and extracted three times with 10mL of ethyl acetate. The organic solution was washed with MgSO₄Dried, concentrated under vacuum and purified by flash column chromatography using hexane/ethyl acetate (gradient of pure hexane to 5/1 hexane/ethyl acetate) as eluent to give the desired product. The yield thereof was found to be 80-83%.

CP-59 was confirmed by LC-MS (ESI, M + H509.1).

CP-65 was confirmed by LC-MS (ESI, M + H454.1).

Scheme 9

CP-55 was confirmed by LC-MS (ESI, M + H439.12).

CP-64 was confirmed by LC-MS (ESI, M + H474.1).

Scheme 10

CP-55 was confirmed by LC-MS (ESI, M + H521.1).

CP-64 was confirmed by LC-MS (ESI, M + H575.1).

The carboxylic acid compounds are converted to vinyl ketone compounds as shown in scheme 11 and the experimental procedures described below.

Scheme 11

The acid is converted to the Weinreb amide. To a solution of the acid (0.1mmol) in dichloromethane (1mL) was added triethylamine (0.25mmol), followed by Weinreb amine salt (0.2mmol), HATU (0.2mmol) and stirring at room temperature for 16 h. After the reaction was complete, water was added and extracted three times with 10mL of ethyl acetate. The organic solution was washed with MgSO₄Dried, concentrated under vacuum and purified by flash column chromatography using hexane/ethyl acetate (gradient of pure hexane to 5/1 hexane/ethyl acetate) as eluent to give the desired product.

To an ice-cooled solution of Weinreb amide (1mmol) in anhydrous THF (10mL) was added 4mL of a 1M solution of vinylmagnesium bromide in THF and warmed to room temperature, and after completion of the reaction, stirred for 4 hours, quenched with 1N hydrochloric acid solution at 0 ℃, and extracted three times with 10mL of ethyl acetate. The organic solution was washed with MgSO₄Dried, concentrated under vacuum and purified by flash column chromatography using hexane/ethyl acetate (gradient of pure hexane to 5/1 hexane/ethyl acetate) as eluent to give the desired product. The yield thereof was found to be 42-57%.

CP-55 was confirmed by LC-MS (ESI, M + H449.14).

CP-64 was confirmed by LC-MS (ESI, M + H449.16).

Certain exemplary compounds can be synthesized and characterized as discussed below.

intermediate-I

Step-a: synthesis of N- (4- ((3r,5r,7r) -adamantan-1-yl) phenyl) acetamide (Ia)

To a solution of acetanilide (50g, 369mmol, 1.0eq.) in 1,1,2, 2-tetrachloroethane (300mL) was added 1-bromoadamantane (87.5g, 406mmol, 1.1eq.) and stirred for 5 minutes. Anhydrous zinc chloride (25.1g, 184mmol, 0.5eq.) was added and stirred at 100 ℃ for 36 hours. The reaction mixture was cooled to room temperature and excess tetrachloroethane was removed by concentration under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, adsorbed by silica and purified by flash column chromatography to give the title product as a white solid (58g, 58%).

¹H NMR(400MHz,DMSO-d6)δ9.81(s,1H),7.47(d,J＝8.8Hz,2H),7.25(d,J＝8.8Hz,2H),2.04(bs,2H),2.00(s,3H),1.82(s,6H),1.72(s,6H)；LC-MS:m/z 270.1(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-Ia using the appropriate reactants and reagents in the presence of the appropriate solvent and appropriate reaction conditions.

Step-b: synthesis of N- (4- ((3r,5r,7r) -adamantan-1-yl) -2-chlorophenyl) acetamide (Ib)

To a solution of N- (4- ((3r,5r,7r) -adamantan-1-yl) phenyl) acetamide (25g, 92.8mmol, 1.0eq.) in DMF (500mL) was added N-chlorosuccinimide (13.6g, 101mmol, 1.1eq.) at 0 ℃. The reaction mixture was allowed to reach room temperature and stirred for 16 hours. Excess DMF was removed by concentration under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude solid obtained (22g, 78%) was used in the next step without further purification.

¹H NMR(400MHz,DMSO-d6)δ9.42(s,1H),7.58(d,J＝8.3Hz,1H),7.37(d,J＝2.5Hz,1H),7.29(dd,J₁＝2.85Hz,J₂＝8.8Hz,1H),2.06(bs,6H),1.75(s,6H),1.69(s,6H)；LC-MS:m/z 304.10(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-Ib using the appropriate reactants and reagents in the presence of the appropriate solvents and appropriate reaction conditions.

Step-c: synthesis of 4- ((3r,5r,7r) -adamantan-1-yl) -2-chloroaniline (intermediate-I)

To a solution of N- (4- ((3r,5r,7r) -adamantan-1-yl) -2-chlorophenyl) acetamide (17g, 56mmol, 1.0eq.) in methanol (150mL) was added concentrated HCl (150mL) and refluxed at 100 ℃ for 8 hours. Excess methanol was removed under vacuum. The white precipitate obtained is filtered off. The filtered solid was washed successively with sodium bicarbonate solution and water and dried under vacuum. The desired product was obtained as a white solid (13g, 88%).

¹H NMR(400MHz,DMSO-d6)δ7.08(d,J＝2.4Hz,1H),7.02(dd,J₁＝1.9Hz,J₂＝8.3Hz,1H),6.73(d,J＝8.3Hz,1H),5.09(bs,2H),2.01(s,3H),1.76(s,6H),1.66(s,6H)；LC-MS:m/z 262.2(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-I using the appropriate reactants and reagents in the presence of the appropriate solvents and appropriate reaction conditions.

The following intermediates were prepared by procedures analogous to those described in the literature using the appropriate reactants and reagents in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-II:

step-a: synthesis of methyl 2- ((4-bromophenyl) amino) benzoate (intermediate-II)

To a solution of methyl 2-iodobenzoate (30g, 114.5mmol, 1.0eq.) and 4-bromoaniline (19.3g, 114.5mmol, 1.0eq.) in toluene (500mL) was added cesium carbonate (49g, 150mmol, 1.3eq.) and N was used₂The gas was degassed for 15 minutes. Palladium acetate (1.28g, 5.7mmol, 0.05eq.) and rac. binap (3.56g, 5.7mmol, 0.05eq.) were added and degassed for 5 minutes. The reaction mass was heated at 110 ℃ for 16 hours. The reaction mass was filtered through celite (celite), concentrated under vacuum and purified by combi-flash to give the title product as a light brown liquid (33g, 94%).

¹H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.89(dd,J₁＝2.0Hz,J₂＝8.3Hz,1H),7.51(d,J＝2.9Hz,2H),7.48(t,J＝1.9Hz,1H),7.26(d,J＝7.8Hz,1H),7.21(d,J＝4.9Hz,2H),6.87(t,J＝1.0Hz,1H),3.84(s,3H)；LC-MS:m/z 307.9(M+H)²⁺

The following intermediates were prepared by a procedure similar to intermediate-II, using the appropriate reactants and reagents, with the appropriate Pd and Fe catalysts and ligands and in the presence of the appropriate solvents and appropriate reaction conditions.

Intermediate-ii.28:

step-a: synthesis of methyl 2- ((5-bromopyrimidin-2-yl) (tert-butoxycarbonyl) amino) benzoate (II.28)

To a solution of intermediate-ii.3 (1.3g, 4.3mmol, 1eq.) in THF (30mL) was added DMAP (0.1g, 0.84mmol, 0.2eq.), pyridine (0.67g, 8.7mmol, 2eq.), Boc anhydride (1.38g, 6.3mmol, 1.5eq.) and heated at 60 ℃ overnight. The reaction mass was concentrated in vacuo and purified by combi-flash to give the title product as an off-white solid (1.4g, 82%). LC-MS M/z 408.2(M + H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-ii.28 using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

The following intermediates were prepared by a procedure analogous to intermediate-II, using the appropriate reactants and reagents, with the appropriate Pd catalyst and ligand, and in the presence of the appropriate solvent and appropriate reaction conditions.

intermediates-IIIa and IIIb:

step-a: ethyl 2- (5-bromo-1H-indazol-1-yl) acetate and ethyl 2- (5-bromo-2H-indazol-2-yl) acetate Synthesis of (IIIa and IIIb)

To a solution of 5-bromo-1H-indazole (1g, 5.1mmol, 1.0eq.) in acetonitrile (25mL) was added potassium carbonate (1.8g, 12.8mmol, 2.5eq.) with stirring. Ethyl bromoacetate (0.7mL, 6.1mmol, 1.2eq.) was added dropwise and the reaction mass was heated to reflux overnight. The reaction mass was concentrated in vacuo, washed with water, adsorbed on silica and purified by combi-flash to give the title products IIIa (400mg, 28%, white solid) and IIIb (180mg, 13%, yellow solid).

intermediate-IIIa:¹H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.05(s,1H),7.68-7.65(m,1H),7.53-7.51(m,1H),5.40(s,2H),4.18-4.12(m,2H),1.19(t,J＝6.8Hz,3H)；LC-MS:m/z283.0(M+H)⁺

intermediate-IIIb:¹H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.02(s,1H),7.60-7.58(m,1H),7.35-7.32(m,1H),5.42(s,2H),4.20-4.15(m,2H),1.18(t,J＝6.4Hz,3H)；LC-MS:m/z283.0(M+H)⁺

the following intermediates were prepared by a procedure similar to intermediates-IIIa and IIIb using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-IV:

step-a: synthesis of methyl 2- (4-bromobenzoylamino) benzoate (intermediate-IV)

To a solution of methyl 2-aminobenzoate (5g, 33.1mmol, 1.0eq.) in DCM (50mL) was added triethylamine (11g, 108mmol, 3eq.) followed by 4-bromobenzoyl chloride (7.2g, 33.1mmol, 1.0eq.) and stirred at room temperature overnight. The reaction mixture was extracted from water with ethyl acetate and concentrated under vacuum. The crude was washed with n-pentane and dried to give the title product (9g, 85%).

¹H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.47(d,J＝8.3Hz,1H),8.04(d,J＝8.4Hz,1H),7.89(d,J＝8.8Hz,2H),7.83(d,J＝8.8Hz,2H),7.67(t,J＝7.3Hz,1H),7.24(t,J＝7.3Hz,1H),3.87(s,3H).

The following intermediates were prepared by a procedure analogous to intermediate-IV using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-V:

step-a: synthesis of methyl 2- ((4-bromophenyl) (methyl) amino) nicotinate (intermediate-V):

to a solution of intermediate-ii.10 (0.4g, 1.3mmol, 1.0eq.) in DMF (3mL) was added sodium hydride (50%, 0.16g, 3.9mmol, 3eq.) and stirred for 10 min. Methyl iodide (0.25mL, 3.9mmol, 3eq.) was added dropwise and stirred in a sealed tube at room temperature overnight. The reaction mass was poured into water, extracted with ethyl acetate and concentrated in vacuo. The crude was purified by combi-flash to give the title product as a colorless liquid (0.21g, 50%).

¹H NMR(400MHz,DMSO-d6)δ8.46(dd,J₁＝2.0Hz,J₂＝4.0Hz,1H),7.85(dd,J₁＝2.0Hz,J₂＝7.6Hz,1H),7.44-7.40(m,2H),7.05(dd,J₁＝3.6Hz,J₂＝7.2Hz,1H),6.94-6.90(m,2H),3.44(s,3H),3.29(s,3H)；LC-MS:m/z 321.0(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-V using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-VI:

step-a: methyl 2- ((4- ((4- ((3R,5R) -adamantan-1-yl) phenyl) amino) benzoate (intermediate-VI) Synthesis:

a solution of intermediate-II (0.5g, 1.63mmol, 1.0eq.) and intermediate-I.1 (0.37g, 1.63mmol, 1.0eq.) in toluene (10mL) was treated with N₂The gas was degassed for 15 minutes. Addition of Pd₂dba₃(0.12g, 0.13mmol, 0.08eq.) and XPhos (0.16g, 0.326mmol, 0.2eq.) and degassed for 5 minutes. The reaction mass was heated at 110 ℃ for 16 hours. The reaction mass was filtered through celite, concentrated under vacuum and purified by combi-flash to give the title product as a pale yellow solid (0.26g, 35%).

¹H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.02(s,1H),7.86(dd,J₁＝1.4Hz,J₂＝7.8Hz,1H),7.35(t,J＝1.4Hz,1H),7.21(d,J＝8.8Hz,2H),7.12-6.96(m,7H),6.69(t,J＝6.8Hz,1H),3.85(s,3H),2.04(s,3H),1.83(s,6H),1.72(s,6H)；LC-MS:m/z 452.4(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-VI, using the appropriate reactants and reagents, with the appropriate Pd catalyst and ligand, and in the presence of the appropriate solvent and appropriate reaction conditions.

intermediate-VII:

step-d: process for preparation of 4- ((3R,5R) -adamantan-1-yl) -2-chloro-N- (4-nitrophenyl) aniline (intermediate-VII) Synthesis of

A solution of intermediate-I (8.5g, 32.5mmol, 1eq.) and 4-bromonitrobenzene (6.57g, 32.5mmol, 1eq.) in toluene (100mL) was degassed by bubbling nitrogen for 5 minutes. Cesium carbonate (16g, 48.9mmol, 1.5eq.) was added followed by palladium acetate (0.72g, 3.25mmol, 0.1eq.) and XPhos (2.32g, 4.88mmol, 0.15eq.) and degassing again for 5 minutes. The reaction mixture was heated at 110 ℃ for 16 hours with stirring. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The organic layer was adsorbed by silica and purified by flash column chromatography. The desired product was eluted in 5% to 10% ethyl acetate in hexane. Concentrate under vacuum to give a dark yellow oil (7g, 57%).

¹H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.09-8.07(m,2H),7.44(s,1H),7.38(s,2H),6.83-6.79(m,2H),2.06(s,3H),1.88(s,6H),1.74(s,6H)；LC-MS:m/z 383.2(M+H)⁺

The following intermediates were prepared by a procedure similar to intermediate-VII, using the appropriate reactants and reagents, with the appropriate Pd catalyst and ligand, and in the presence of the appropriate solvent and appropriate reaction conditions.

The following intermediates were prepared by a procedure analogous to intermediate-V, using the appropriate reactants and reagents, with the appropriate Pd catalyst and ligand, and in the presence of the appropriate solvent and appropriate reaction conditions.

intermediate-VIII:

step-a: process for preparation of N- (4- ((3R,5R) -adamantan-1-yl) phenyl) -3-nitrobenzamide (intermediate-VIII) Synthesis of

The title compound (1.6g, 96%) was synthesized from intermediate-i.1 (1g, 4.4mmol, 1eq.) and 3-nitrobenzoyl chloride (0.82g, 4.4mmol, 1eq.) using a procedure similar to intermediate-IV. LC-MS M/z 377.2(M + H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-VIII using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-IX:

step-a: synthesis of (3R,5R) -1- (3-chloro-4- (4-nitrophenoxy) phenyl) adamantane (intermediate-IX)

To a solution of 4-fluoronitrobenzene (0.6mL, 5.7mmol) and intermediate-i.25 (1.5g, 6.84mmol, 1.2eq.) in DMSO (10mL) was added potassium carbonate (1.57g, 11.4mmol, 2eq.) and stirred at room temperature overnight. The reaction mass was poured into cold water and the resulting solid was filtered and dried to give the title compound as an off-white solid (2g, 91%).

¹H NMR(400MHz,DMSO-d6)δ8.26(d,J＝9.3Hz,2H),7.58(s,1H),7.47(d,J＝2.0Hz,1H),7.32(d,J＝8.8Hz,1H),7.1(d,J＝8.3Hz,2H),2.07(bs,2H),1.89(s,6H),1.7(s,6H).LC-MS:m/z 382.0(M-H)^-

The following intermediates were prepared by a procedure analogous to intermediate-IX using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-X:

step-a: synthesis of (3r,5r,7r) -1- (3-chloro-4-methylphenyl) adamantane (Xa)

To a solution of (3r,5r,7r) -1- (p-tolyl) adamantane (2g, 8.8mmol) in acetic acid was added N-chlorosuccinimide in portions over a period of 30 minutes. The reaction mass was heated at 75 ℃ overnight. The reaction mass was poured into cold water and the solid obtained was filtered off and dried under vacuum. The title compound was obtained as a white solid (2.2g, 96%).¹H NMR(400MHz,DMSO-d6)δ7.31(d,J＝1.9Hz,1H),7.26-7.22(m,2H),2.27(s,3H),2.04(s,3H),1.83(s,6H),1.72(s,6H).

Step-b: synthesis of (3r,5r,7r) -1- (4- (bromomethyl) -3-chlorophenyl) adamantane (Xb)

To a solution of compound Xa (1g, 3.8mmol) in carbon tetrachloride (40mL) was added dropwise bromine (0.61g, 3.8mmol) and benzoyl peroxide (catalytic). The reaction mass was heated to reflux overnight. Concentrated under vacuum and the crude was purified by column chromatography to give an ashThe title product as a white solid (0.5g, 38%).¹H NMR(400MHz,DMSO-d6)δ7.38(d,J＝8.0Hz,2H),7.24(m,1H),4.58(s,2H),2.10(s,3H),1.81(s,6H),1.72(s,6H).

Step-c: 1- (4- ((3R,5R) -adamantan-1-yl) -2-chlorobenzyl) -4-nitro-1H-pyrazole (intermediate-X) Synthesis of (2)

This intermediate was prepared according to a similar procedure described for intermediate-III by using intermediate-Xb (0.3g, 0.88mmol, 1eq.) and 4-nitropyrazole (0.12g, 1.06mmol, 1.2eq.) to give the title product as an off-white solid (0.3g, 91%).¹H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.28(s,1H),7.41(d,J＝2.0Hz,1H),7.35(dd,J₁＝1.9Hz,J₂＝8.3Hz,1H),7.21(d,J＝8.3Hz,1H),5.47(s,2H),2.04(s,3H),1.83(s,6H),1.72(s,6H).

The following intermediates were prepared by a procedure analogous to intermediate-X using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-XI:

step-a: process for preparation of N1- (4- ((3R,5R) -adamantan-1-yl) -2-chlorophenyl) benzene-1, 4-diamine (intermediate-XI) Synthesis of

To a solution of intermediate-VII (7g, 18.3mmol, 1eq.) in THF: water (50mL +50mL) was added ammonium chloride (19.42g, 36.6mmol, 20eq.) followed by zinc dust (11.91g, 183mmol, 10eq.) and stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and brine in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude was washed with n-pentane and dried under vacuum to give the desired product as a yellow gum (5.9g, 91%). It was used in the next step without further purification.

¹H NMR(400MHz,DMSO-d6)δ7.20(d,J＝1.9Hz,1H)7.04(dd,J₁＝2.0Hz,J₂＝8.3Hz,1H),6.84(d,J＝8.8Hz,2H),6.78(s,1H),6.72(d,J＝8.8Hz,1H),6.54(d,J＝8.8Hz,2H),4.85(s,2H),2.02(s,3H),1.78(s,6H),1.70(s,6H)；LC-MS:m/z 353.1(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-XI using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-XII:

step-a: 2- ((4- ((4- ((3r,5r,7r) -adamantan-1-yl) -2-chlorophenyl) amino) phenyl) amino) nicotine Synthesis of methyl ester of acid (intermediate-XII)

A solution of intermediate-XI (8g, 22.72mmol, 1eq.) and methyl 2-chloronicotinate (4.27g, 25mmol, 1.1eq.) in toluene (100mL) was degassed by bubbling nitrogen for 5 minutes. Cesium carbonate (11.1g, 34.1mmol, 1.5eq.) was added followed by palladium acetate (0.5g, 2.27mmol, 0.1eq.) and rac. binap (2.12g, 3.41mmol, 0.15eq.) and degassed again for 5 minutes. The reaction mixture was heated at 110 ℃ for 16 hours with stirring. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The organic layer was adsorbed by silica and purified by flash column chromatography. The desired product was eluted in 10% ethyl acetate in hexane. Concentrate under vacuum to give a yellow solid (5.4g, 49%).

¹H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.37(dd,J₁＝2.0Hz,J₂＝4.4Hz,1H),8.22(dd,J₁＝2.0Hz,J₂＝7.6Hz,1H),7.55(d,J＝8.8Hz,2H),7.41(s,1H),7.31(d,J＝1.6Hz,1H),7.19-7.12(m,2H),7.04(d,J＝8.8Hz,2H),6.84-6.81(m,1H),3.89(s,3H),2.04(s,3H),1.83(s,6H),1.72(s,6H)；LC-MS:m/z 488.1(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-XII, using the appropriate reactants and reagents, with the appropriate Pd catalyst and ligand, and in the presence of the appropriate solvent and appropriate reaction conditions.

intermediate-XIII:

step-a: 2- ((1, 4-dioxaspiro [4.5 ]]Synthesis of decan-8-yl) amino) benzoic acid methyl ester (XIIIa)

To a solution of methyl anthranilate (3g, 20mmol, 1eq.) and 1, 4-cyclohexanedione monoacetal (4.6g, 30mmol, 1.5eq.) in dichloroethane (50mL) was added acetic acid (20mL) and stirred at room temperature for 2 hours. The reaction mass was cooled to 0 ℃ and sodium triacetoxyborohydride (6.3g, 30mmol, 1.5eq.) was added and stirred at room temperature for 36 h. To the reaction mass was added a saturated bicarbonate solution and extracted with dichloromethane, purified by combi-flash to give the title product (1.01g, 17%).

¹H NMR(400MHz,DMSO-d6)δ7.77(d,J＝7.6Hz,1H),7.71(d,J＝7.6Hz,1H),7.39-7.35(m,1H),6.83(d,J＝8.8Hz,1H),6.57-6.53(m,1H),3.87(s,4H),3.78(s,3H),3.60-3.58(m,1H),1.95-1.90(m,2H),1.70-1.61(m,4H),1.60-1.48(m,2H)；LC-MS:m/z292.0(M+H)⁺

Step-b: synthesis of methyl 2- ((4-oxocyclohexyl) amino) benzoate (XIIIb)

To a solution of compound XIIIa (1.01g, 3.4mmol, 1eq.) in acetone (30mL) was added 2N HCl (10mL) and stirred at room temperature overnight. The reaction mass was extracted from water with ethyl acetate and concentrated under vacuum. The crude product was further used without purification.

¹H NMR(400MHz,DMSO-d6)δ7.81(dd,J₁＝0.8Hz,J₂＝7.6Hz,1H),7.75(d,J＝7.6Hz,1H),6.94(d,J＝8.8Hz,1H),6.59(t,J＝7.6Hz,1H),3.97-3.95(m,1H),3.79(s,3H),2.57-2.53(m,2H),2.29-2.19(m,4H),1.77-1.72(m,2H)；LC-MS:m/z 248.2(M+H)⁺

Step-c: 2- ((4- ((4- ((3r,5r,7r) -adamantan-1-yl) -2-chlorophenyl) amino) cyclohexyl) amino) Synthesis of methyl benzoate (intermediate-XIII)

To a solution of compound XIIIb (0.5g, 2.02mmol, 1eq.) and intermediate-I (0.53g, 2.02mmol, 1eq.) in acetic acid (10mL) was added sodium triacetoxyborohydride (1.28g, 6.06mmol, 3eq.) and heated at 80 ℃ for 16 hours. The reaction mass was extracted from saturated bicarbonate and brine with ethyl acetate and concentrated under vacuum. The crude was purified by combi-flash to give the title compound as a pale pink liquid (0.67g, 67%). LC-MS M/z 493.3(M + H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-XIII using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-XIV:

step-a: synthesis of 4- ((2- (methoxycarbonyl) phenyl) amino) benzoic acid (intermediate-XIV)

A solution of intermediate-ii.20 (3g, 9.1mmol, 1eq.) in DCM (30mL) was cooled in ice for 10 min. TFA (3mL) was added dropwise and stirred at room temperature for 16 hours. The reaction mass was concentrated under vacuum. The crude was triturated with n-pentane and dried under vacuum to give the title product as a pale green solid (2.0g, 80%).

¹H NMR(400MHz,DMSO-d6)δ12.58(s,1H),9.40(s,1H),7.93(dd,J₁＝1.6Hz,J₂＝8.0Hz,1H),7.87(dd,J₁＝2.0Hz,J₂＝6.8Hz,2H),7.52-7.46(m,2H),7.26(d,J＝8.8Hz,2H),7.01-6.97(m,1H),3.84(s,3H)；LC-MS:m/z 272.1(M+H)⁺

Alternative or general procedure for the synthesis of the corresponding carboxylic acid compounds with methyl and ethyl esters:

to the ester (1mmol) in THF: MeOH: H₂To a solution of O (4+4+2mL), LiOH. H was added₂O (5mmol) and stirred at room temperature for 16 h. The reaction mass was concentrated in vacuo, diluted with water and acidified to pH 5 with 2N HCl. The precipitate obtained was filtered and dried under vacuum. The solid was washed with a 10% diethyl ether in hexane mixture and dried to give the desired acid.

The following intermediates were prepared by a procedure similar to intermediate-XIV using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-XV:

step-a: 2- ((4- ((4- ((3R,5S) -adamantan-1-yl) phenyl) carbamoyl) phenyl) amino) benzyl Synthesis of methyl ester of acid (intermediate-XV)

A solution of compound-XIV (0.2g, 0.74mmol, 1eq.) and intermediate-i.1 (0.185g, 0.81mmol, 1.1eq.) was cooled in ice. HATU (0.34g, 0.89mmol, 1.2eq.) was added followed by DIPEA (0.39mL, 2.22mmol, 3eq.) and stirred at room temperature for 16 h. The reaction mass was slowly added to ice water with stirring. The resulting precipitate was filtered, washed twice with cold water, then twice with n-pentane and dried under vacuum to give the title compound as a cream solid (0.35g, 98%).

¹H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.43(s,1H),7.96-7.91(m,3H),7.69(d,J＝8.4Hz,2H),7.54-7.49(m,1H),7.45(d,J＝8.0Hz,1H),7.34-7.31(m,4H),6.95(t,J＝6.8Hz,1H),3.86(s,3H),2.06(s,3H),1.87(s,6H),1.74(s,6H)；LC-MS:m/z 481.1(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-XV using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-XVI:

step-a: n- (4- (N- (4- ((3r,5r,7r) -adamantan-1-yl) phenyl) sulfamoyl) phenyl) acetamide Synthesis of (intermediate-XVI)

A solution of intermediate-i.1 (0.5g, 2.2mmol) in dichloromethane (10mL) was cooled to 0 ℃ and triethylamine (0.66g, 6.6mmol, 3eq.) was added, followed by 4-acetamidobenzenesulfonyl chloride (0.51g, 2.2mmol) and stirred at room temperature for 3 hours. The reaction mass was concentrated under vacuum and cold water was added. The solid obtained was filtered and dried under vacuum to give the title product (0.88g, 94%). LC-MS M/z 425.1(M + H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-XVI using the appropriate reactants and reagents and in the presence of the appropriate solvent and appropriate reaction conditions.

intermediate-XVII:

step-a: n- (4- ((3r,5r,7r) -adamantan-1-yl) phenyl) -4-aminobenzenesulfonamide (intermediate-XVII) Synthesis of (2)

This compound was prepared from intermediate-XVI (0.85g, 2mmol, 1eq.) by a procedure similar to that described for intermediate-I from Ib to give the title product as a white solid (0.75g, 98%).

¹H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.38(d,J＝8.8Hz,2H),7.17(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),6.52(d,J＝8.8Hz,2H),5.93(s,2H),2.01(s,3H),1.77(s,6H),1.69(s,6H)；LC-MS:m/z 383.0(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-XVII using the appropriate reactants and reagents and in the presence of the appropriate solvent and appropriate reaction conditions.

intermediate-XVIII:

step-a: 2- ((4- (N- (4- ((3R,5R) -adamantan-1-yl) phenyl) sulfamoyl) phenyl) amino) benzyl Synthesis of methyl ester of acid (intermediate-XVIII)

intermediate-XVIII was prepared from intermediate-XVII and methyl 2-bromobenzoate by a procedure analogous to that described for intermediate-II.

¹H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.31(s,1H),7.89(d,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,2H),7.50(t,J＝7.6Hz,1H),7.42(d,J＝8.0Hz,1H),7.24-7.19(m,4H),7.03-6.99(m,3H),3.77(s,3H),2.00(s,3H),1.76(s,6H),1.69(s,6H)；LC-MS:m/z 517.1(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-XVIII, using the appropriate reactants and reagents, with the appropriate Pd catalyst and ligand, and in the presence of the appropriate solvent and appropriate reaction conditions.

intermediate-XIX:

step-a: synthesis of phenyl (4- ((3r,5r,7r) -adamantan-1-yl) phenyl) carbamate (XIXa)

To a solution of intermediate-i.1 (0.5g, 2.2mmol, 1eq.) and phenyl chloroformate (0.42g, 2.64mmol, 1.2eq.) in DCM was added triethylamine (0.44g, 4.4mmol, 2eq.) and stirred at room temperature for 2 hours. The reaction mixture was washed with water, concentrated under vacuum and purified by combi-flash to give the title compound as a white solid (0.48g, 63%).

¹H NMR(400MHz,DMSO-d6)δ10.10(s,1H),7.44-7.39(m,4H),7.31-7.19(m,5H),2.05(s,3H),1.84(s,6H),1.73(s,6H)；LC-MS:m/z 348.1(M+H)⁺

Step-b: methyl 2- ((4- (3- (4- ((3R,5R) -adamantan-1-yl) phenyl) ureido) phenyl) amino) nicotinate Synthesis of (intermediate-XIX)

intermediate-XIXa (0.285g, 0.82mmol, 1eq.) and methyl 2- ((4-aminophenyl) amino) nicotinate (0.2g, 0.82mmol, 1eq.) were added to THF (20mL) and triethylamine (0.8mL) was added and refluxed overnight. The reaction mass was concentrated in vacuo, and the crude obtained was washed twice with n-hexane and dried in vacuo. The crude product was further used without purification.

¹H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.52(d,J＝14.0Hz,2H),8.38-8.37(m,1H),7.76(d,J＝8.4Hz,2H),7.41-7.35(m,4H),7.25(d,J＝8.4Hz,2H),6.84(dd,J₁＝4.4Hz,J₂＝8.0Hz,1H),3.87(s,3H),2.05(s,3H),1.84(s,6H),1.73(s,6H)；LC-MS:m/z 497.2(M+H)⁺

The following intermediates were prepared by a procedure similar to intermediate-XIX using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

Intermediate-xix.4:

step-a: ((4- ((4- ((3R,5S) -adamantan-1-yl) -2-chlorophenyl) amino) phenyl) carbamoyl) prolyl Synthesis of methyl ester of amino acid (XIX.4)

To a solution of intermediate-XI (0.1g, 0.283mmol, 1eq.) in DCM (10mL) was added triphosgene (0.084g, 0.283mmol, 1eq.) dropwise at 0 ℃ and stirred at 0 ℃ for 1 hour. This solution was added to a solution of proline methyl ester (0.056g, 0.32mmol, 1.2eq.) in DCM (10mL) and stirred at 0 ℃ for 1 hour. Quenched with saturated bicarbonate solution and extracted with DCM and purified by column chromatography to give the title product as a light brown solid (0.13g, 90%).

¹H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.34(d,J＝8.8Hz,2H),7.28(d,J＝2.0Hz,1H),7.26(s,1H),7.14(dd,J₁＝2.0Hz,J₂＝8.0Hz,1H),7.04(d,J＝8.8Hz,1H),6.96(d,J＝9.6Hz,2H),4.37-4.34(m,1H),3.62(s,3H),3.56-3.46(m,2H),2.21-2.14(m,1H),2.03(s,3H),1.98-1.84(m,3H),1.81(d,J＝2.4Hz,6H),1.71(s,6H)；LC-MS:m/z 508.4(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-xix.4 using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

intermediate-XX:

step-a: 2- ((4- ((4- ((3R,5R) -adamantan-1-yl) phenyl) (methyl) amino) phenyl) (methyl) ammonia Yl) Synthesis of methyl benzoate (intermediate-XX)

A solution of intermediate-VI (4g, 8.85mmol, 1eq.) in DMF (80mL) was cooled to 0 ℃ and sodium hydride (1.06g, 44.2mmol, 5eq.) was added portionwise and stirred for 15 min. Methyl iodide (6.3g, 44.2mmol, 5eq.) was added dropwise and the reaction mass was heated in a sealed tube at 80 ℃ for 16 hours. The reaction mass was cooled to room temperature and poured into cold water. The precipitated solid was filtered and dried. This crude was absorbed through silica and purified by combi-flash to give the title product as a pale yellow solid (3g, 70.7%).

¹H NMR(400MHz,DMSO-d6)δ7.65(dd,J₁＝2.0Hz,J₂＝8.0Hz,1H),7.60(t,J＝7.6Hz,1H),7.33(d,J＝7.6Hz,1H),7.26(t,J＝7.2Hz,1H),7.13(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),6.67(d,J＝8.8Hz,2H),6.59(d,J＝8.8Hz,2H),3.55(s,3H),3.20(s,3H),3.13(s,3H),2.02(s,3H),1.80(s,6H),1.71(s,6H)；LC-MS:m/z 480.25(M+H)⁺

The following intermediates were prepared by a procedure analogous to intermediate-XX using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

The following compounds are prepared by a procedure analogous to intermediate-VI, using the appropriate reactants and reagents, with the appropriate Pd catalyst and ligand, and in the presence of the appropriate solvent and appropriate reaction conditions.

The following compounds are prepared by a procedure analogous to intermediate-XIII using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

The following compounds are prepared by a procedure analogous to intermediate-XI using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

The following compounds are prepared by a procedure analogous to intermediate-XIX using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

2- ((4- ((4- ((3R,5R) -adamantan-1-yl) phenyl) amino) benzoic acid (Compound 24) (CP-55)) Synthesis

To intermediate-VI (8.5g, 16.5mmol, 1eq.) in THF MeOH H₂LiOH XH was added to a solution of O (40+40+20mL)₂O (3.3g, 82.4mmol, 5eq.) and stirred at room temperature for 16 h. The reaction mass was concentrated in vacuo, diluted with water and acidified to pH 5 with 2N HCl. The precipitate obtained was filtered and dried under vacuum. The solid was washed with 10% diethyl ether in hexanes and dried to give the title product as an off-white solid (5.5g, 67%).

¹H NMR(400MHz,DMSO-d6)δ12.99(s,1H),9.42(s,1H),8.00(s,1H),7.85(d,J＝6.8Hz,1H),7.32(t,1H),7.21(d,J＝8.8Hz,2H),7.11-6.96(m,7H),6.67(t,J＝3.4Hz,1H),2.08(s,3H),1.83(s,6H),1.72(s,6H)；LC-MS:m/z 438.4(M+H)⁺

The following compounds were prepared by a procedure similar to that described in compound-24, under the appropriate reaction conditions, in the presence of the appropriate solvent, by using the appropriate reagents. The physicochemical properties of the compounds are also summarized.

The following compounds are prepared by a procedure analogous to intermediate-XV using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

The following compounds are prepared by a procedure analogous to intermediate-XIV using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

2- ((4- ((4- ((3r,5r,7r) -adamantan-1-yl) -2-chlorophenyl) amino) phenyl) carbamoyl) benzoic acid Synthesis of acid (Compound 293) (CP-119):

step (i): a solution of intermediate-XI (0.05g, 0.16mmol, 1eq.) and phthalic anhydride (0.024g, 0.16mmol, 1eq.) in DCM was stirred at room temperature for 2 hours. The obtained precipitate was filtered and dried under vacuum to give the title product as a pale yellow solid (0.01g, 12.5%).

¹H NMR(400MHz,DMSO-d6)δ12.98(s,1H),10.17(s,1H),7.86(d,J＝7.8Hz,1H),7.63(d,J＝7.3Hz,1H),7.57-7.52(m,4H),7.41(s,1H),7.31(d,J＝1.6Hz,1H),7.17-7.12(m,2H),7.04(d,J＝8.8Hz,2H),2.05(s,3H),1.83(s,6H),1.72(s,6H).LC-MS:m/z 501.1(M+H)⁺²

The following compounds are prepared by procedures analogous to those for compound 293 using the appropriate reactants and reagents and in the presence of the appropriate solvents and appropriate reaction conditions.

Experimental procedure and physicochemical Properties of Compound CP-453

Intermediate:

the above intermediate was prepared by a procedure similar to intermediate-XII and by using intermediate-xi.16 (0.145g, 0.43mmol, 1eq.) and methyl 2-bromo-5-isobutoxybenzoate (0.125g, 0.43mmol, 1eq.) to give the title product (0.05g, 22%) as a brown solid.¹H NMR(400MHz,DMSO-d₆):δ8.79(s,1H),7.54-7.52(m,1H),7.44-7.42(m,1H),7.28-6.98(m,9H),3.85(s,3H),3.80(d,J＝2.4Hz,2H),3.37(s,3H),2.04(s,3H),2.00-1.96(m,1H),1.83(s,6H),1.72(s,6H),0.97(d,J＝6.4Hz,6H).

Final compound:

the above compounds are prepared by a procedure similar to that described in compound-24, under appropriate reaction conditions, in the presence of an appropriate solvent, by using appropriate reagents. The physicochemical properties of the compounds are also summarized.

¹H NMR(400MHz,DMSO-d₆):δ13.10(s,1H),9.12(s,1H),7.37(d,J＝2.0Hz,1H),7.23(d,J＝8.4Hz,2H),7.10(d,J＝9.2Hz,2H),7.05(dd,J₁＝2.8Hz,J₂＝9.2Hz,2H),6.97(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),3.68(d,J＝6.4Hz,2H),3.21(s,3H),2.04(s,3H),2.01-1.98(m,1H),1.83(d,J＝2.6Hz,6H),1.72(s,6H),0.97(d,J＝6.8Hz,6H).LC-MS:525.3(M+H)⁺

Biological assay

In vitro palmitoylation

Recombinant GST-TEAD2 or His6TEAD2(500ng) proteins were preincubated with the indicated concentrations of compounds for 15 minutes and then either with 1. mu.M alkyne palmitoyl-5 CoA (cayman chemical) for 30 minutes or with 50mM MES, pH 6.4, followed by click reactions with biotin-azides as described previously (Zheng, B, et al, J.Am.Chem.Soc., 2013,135, 7082-7085). The click reaction was performed with 100. mu.M biotin-azide, 1mM tris (2-carboxyethyl) phosphine hydrochloride (TCEP), 100. mu.M tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) and 1mM CuSO4 for 1 hour at room temperature.

The reaction was stopped by adding 12. mu.L of 6 XSDS sample loading buffer (50mM Tris-HCl, pH 6.8, 6% SDS, 48% glycerol, 0.03% bromophenol blue, 30mM EDTA, 9% MeSH). Samples were analyzed by SDS-PAGE and western blots were performed by independent probing with streptavidin HRP and histidine HRP antibodies. The intensity of the bands obtained from the streptavidin blot was quantified using the BIORAD, Gel doc system, and the percentage inhibition of Tead2 from palmitoylation was determined by comparison with DMSO control treated samples.

The activity of these compounds to inhibit TEAD2 palmitoylation was tested in the above assay. Data for compounds are provided in the table below as the percent inhibition of TEAD2 palmitoylation by compounds at a concentration of 10 μ M.

Cell proliferation

HuH7 cells (or other cells) were cultured in DMEM supplemented with 10% FBS. Cells were seeded at a density of 5000 cells/well in 96 wells. After cells attach to wells, compound-containing DMSO solutions (1% DMSO concentration) were added to the cells, serially diluted to the final concentrations indicated. Cells were further incubated for 3 days. Cell viability was then determined using CellTiter Glo, MTT or crystal violet staining. Inhibition curves were plotted using GraphPad.

qRT-PCR

YAP target gene expression was analyzed using LightCycler480 (Roche). Total RNA was isolated from cells using TRIzol (Life Technologies), and then used to generate cDNA using a transcript first strand cDNA synthesis kit (roche). The resulting cDNA was then used to react with LightCycler480SYBR Green I Master mix (Roche) where the probe detects CTGF or CYR61 and GAPDH.

CMP assay

7-diethylamino-3- (4' -maleimidophenyl) -4-methylcoumarin (CPM) reacts with the thiol of CoA released in the enzymatic reaction and generates a fluorescence signal (excitation 350-. The assay detects a product produced by palmitoyl-CoA (free CoA) as a method for detecting enzyme activity. Thus, test compounds that inhibit TEAD activity are able to block CMP fluorescence signals.

TEAD2/4 protein (10. mu.L of 50 ng/. mu.L solution) and test compound solution (0.5. mu.L, different concentrations) were preincubated at room temperature for 30 minutes. A mixture prepared from MES pH 6.4 buffer (6.5. mu.L of 50mM solution), EDTA (1. mu.L of 20mM solution), palmitoyl-CoA (1. mu.L of 20. mu.M solution), and 7-diethylamino-3- (4' -maleimidophenyl) -4-methylcoumarin (1. mu.L of 10. mu.M solution) was added and the resulting mixture was mixed well using a pipette. The solution was then incubated in the dark at room temperature for 30-120 minutes and fluorescence was detected at 350nm every 30 minutes until the fluorescence signal was saturated. From the results, IC was calculated for the ability of the compound to inhibit fluorescence₅₀。

The results of the bioassay are shown in fig. 3-12 and tables 1 and 2.

Compounds having TEAD palmitoylation inhibitor activity

The exemplary compounds were tested for activity in inhibiting TEAD2 palmitoylation in the above assay and CMP assay. The data for the compounds provided in table 1 are as percent inhibition of TEAD2 palmitoylation by the compound at a concentration of 10 μ M or IC50 in the CMP assay.

TABLE 1 Activity of Compounds as TEAD palmitoylation inhibitors

TABLE 2 Activity of Compounds as TEAD2 palmitoylation inhibitors

TABLE 3 Activity of Compounds as TEAD2 palmitoylation inhibitors

Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including but not limited to all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

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