CN117203202A

CN117203202A - Quinoxaline derivative and use thereof

Info

Publication number: CN117203202A
Application number: CN202280025749.4A
Authority: CN
Inventors: 马修·C·卢卡斯; 费尔南多·帕迪拉
Original assignee: Black Diamond Treatment Co
Current assignee: Black Diamond Treatment Co
Priority date: 2021-02-05
Filing date: 2022-02-04
Publication date: 2023-12-08

Abstract

The present disclosure relates to compounds of formula (I'): and pharmaceutically acceptable salts and stereoisomers thereof. The disclosure also relates to methods of making the compounds, compositions comprising the compounds, and methods of using the compounds, e.g., to treat cancer.

Description

Quinoxaline derivative and use thereof

Cross reference to related applications

The present application claims priority and benefit from U.S. provisional application number 63/146,312 filed on 5 of 2021, U.S. provisional application number 63/223,255 filed on 19 of 2021, and U.S. provisional application number 63/242,260 filed on 9 of 2021, the contents of each of which are incorporated herein by reference in their entirety.

Background

Specific mutations in human genes FGFR2 and FGFR3, encoding proteins FGFR2 and FGFR3, respectively, have been associated with several different types of cancer. Various FGFR2 and/or FGFR3 inhibitors have been developed for the treatment of cancer, including FDA approved drugs, such as erdasatinib (erdafitinib) and pemigatinib (pemigatinib). However, existing inhibitors exhibit various drawbacks that limit their clinical effectiveness. First, some existing inhibitors target FGFR2 only and fail to inhibit FGFR3, which limits their ability to treat certain types of cancers. In addition, several existing inhibitors also target FGFR1, resulting in dose-limiting toxicities such as hyperphosphatemia. Finally, after administration of some existing inhibitors, many patients develop additional mutations in FGFR2 and/or FGFR3, known as gatekeeper mutations, which result in resistance to the existing inhibitors. Thus, there is a long felt need in the art for new therapies specifically directed to FGFR2 and FGFR 3. The present disclosure provides compositions and methods for preventing or treating cancer in FGFR2 and/or FGFR3 and patients with over-expression and/or oncogenic mutations in FGFR2 and/or FGFR 3.

Disclosure of Invention

In some aspects, the present disclosure provides a compound of formula (I'):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ¹ when attached to a double bond and a single bond is C (R ^W1 ) When connected to two single bonds, is N (R ^W1 ) Or N when attached to a double bond and a single bond;

R ^W1 h, C of a shape of H, C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ An alkyl group);

W ² when attached to a double bond and a single bond is C (R ^W2 ) When connected to two single bonds, is N (R ^W2 ) Or O, or N when attached to a double bond and a single bond;

R ^W2 h, C of a shape of H, C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ An alkyl group);

W ³ is C or N;

W ⁴ is C (R) ^W4 ) Or N;

R ^W4 is H, halogen, cyano, C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ An alkyl group);

W ⁵ is C (R) ^W5 ) Or N;

R ^W5 is H, halogen, cyano, C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ An alkyl group);

W ⁶ when attached to a double bond and a single bond is C (R ^W6 ) When connected to two single bonds, is N (R ^W6 ) Or N when attached to a double bond and a single bond;

R ^W6 is H, halogen, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl or-S (=o) ₂ -(C ₁ -C ₆ An alkyl group);

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein-NH (C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl, optionally substituted with one or more R ^3a Substitution;

each R ^3a Independently halogen, cyano, oxo, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein NHC (=o) O (C ₁ -C ₆ Alkyl) optionally substituted with one or more halogens;

R ⁵ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁶ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

y is absent and is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ Alkoxy optionally substituted with one or more halogen, oxo, cyano, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl) -OH, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, optionally interrupted by- (C) ₁ -C ₆ Alkyl) (C) ₆ -C ₁₀ Aryl) substituted C ₁ -C ₆ Alkoxy or C ₃ -C ₁₂ Cycloalkyl substitution;

z is absent, H, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^Z Substitution;

each R ^Z Independently and separatelyIs oxo, halogen, cyano, -OH, =nr ^Za 、NH ₂ 、NHR ^Za 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) (3-to 12-membered heterocycloalkyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl optionally substituted with one or more R ^Za Substitution;

each R ^Za Independently H, oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl optionally substituted with one or more R ^Zb Substitution; and is also provided with

Each R ^Zb Independently oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ An alkoxy group.

In some aspects, the present disclosure provides a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ² when connected to aWith a double bond and a single bond being C (R ^W2 ) When connected to two single bonds, is N (R ^W2 ) Or N when attached to a double bond and a single bond;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

y is absent or C optionally substituted by one or more oxo or-OH groups ₁ -C ₆ An alkyl group;

z is H, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Z Substitution;

each R ^Z Independently oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Za Substitution;

each R ^Za Independently oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Zb Substitution; and is also provided with

In some aspects, the present disclosure provides an isotopic derivative of a compound described herein.

In some aspects, the present disclosure provides a method of preparing a compound described herein.

In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein.

In some aspects, the present disclosure provides compounds described herein for use in treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of a compound described herein in the manufacture of a medicament for treating or preventing cancer in a subject.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure is subject to.

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

Detailed Description

Compounds of the present disclosure

In some aspects, the present disclosure provides a compound of formula (I'):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

W ⁴ is C (R) ^W4 ) Or N;

W ⁵ is C (R) ^W5 ) Or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein-NH (C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^3a Substitution;

R ⁵ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁶ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

each R ^Z Independently oxo, halogen, cyano, -OH, =nr ^Za 、NH ₂ 、NHR ^Za 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) (3-to 12-membered heterocycloalkyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl optionally substituted with one or more R ^Za Substitution;

In some aspects, the present disclosure provides a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ² when attached to a double bond and a single bond is C (R ^W2 ) When connected to two single bonds, is N (R ^W2 ) Or N when attached to a double bond and a single bond;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

In some aspects, the present disclosure provides a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0;

R ^W1 is H;

R ^W2 is H;

W ³ is N;

W ⁴ is C (R) ^W4 )；

R ^W4 Is H or halogen;

W ⁵ is C (R) ^W5 )；

R ^W5 Is H or halogen;

R ^W6 is H or C ₁ -C ₆ An alkyl group;

X ¹ is N;

X ² is C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ is C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano, NH ₂ 、NHC(＝O)O(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl or 5-to 10-membered heteroaryl, wherein NHC (=o) O (C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkenyl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^3a Substitution;

each R ^3a Independently halogen, oxo, NHC (=o) O (C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl, wherein-NHC (=o) O (C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups are optionally substituted with one or more halogens;

R ⁵ is H or C ₁ -C ₆ An alkyl group;

R ⁶ is H or halogen;

y is absent and is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ Alkoxy optionally substituted with one or more halogen, oxo, cyano, -OH, NH ₂ 、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, optionally interrupted by- (C) ₁ -C ₆ Alkyl) (C) ₆ -C ₁₀ Aryl) substituted C ₁ -C ₆ Alkoxy or C ₃ -C ₁₂ Cycloalkyl substitution;

z is absent and is C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^Z Substitution;

each R ^Z Independently oxo, halogen, -OH, =nr ^Za 、NH ₂ 、NHR ^Za 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl optionally substituted with one or more R ^Za Substitution;

each R ^Za Independently H, oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl optionally substituted with one or more R ^Zb Substitution; and is also provided with

Each R ^Zb Independently oxo, halogen, -OH.

In some aspects, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ¹ when attached to two single bonds is C (R ^W1 ) Or N (R) ^W1 ) Or C or N when attached to a double bond and a single bond;

W ² when attached to two single bonds is C (R ^W2 ) Or N (R) ^W2 ) Or C or N when attached to a double bond and a single bond;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

z is C ₃ -C ₈ Cycloalkyl or 3To 8 membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Z Substitution;

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

y is C optionally substituted by one or more oxo or-OH groups ₁ -C ₆ An alkyl group;

z is C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Z Substitution;

each R ^Z Independently oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkylOptionally by one or more R ^Za Substitution;

Variable n, W ¹ 、R ^W1 、W ² 、R ^W2 、W ³ 、W ⁴ 、R ^W4 、W ⁵ 、R ^W5 、W ⁶ And R is ^W6

In some embodiments, eachIndependently represents a single bond or a double bond.

In some embodiments, eachIndependently represents a single bond. In some embodiments, each +.>Independently represents a double bond.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, W ¹ When attached to a double bond and a single bond is C (R ^W1 ) When connected to two single bonds, is N (R ^W1 ) Or N when attached to a double bond and a single bond.

In some embodiments, W ¹ When attached to a double bond and a single bond is C (R ^W1 )。

In some embodiments, W ¹ When connected to two single bonds is N (R ^W1 )。

In some embodiments, W ¹ And N when attached to a double bond and a single bond.

In some embodiments, W ¹ Is C (R) ^W1 ) Or N (R) ^W1 )。

In some embodiments, W ¹ Is C (R) ^W1 ). In some embodiments, W ¹ CH.

In some embodiments, W ¹ Is N (R) ^W1 ). In some embodiments, W ¹ Is NH.

In some embodiments, W ¹ Is N (-S (=O) ₂ -(C ₁ -C ₆ Alkyl)). In some embodiments, W ¹ Is N (-S (=O) ₂ -CH ₃ )。

In some embodiments, W ¹ Is N.

In some embodiments, R ^W1 H.

In some embodiments, R ^W1 Is C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, R ^W1 Is C ₁ -C ₆ An alkyl group.

In some embodiments, R ^W1 is-S (=O) ₂ -(C ₁ -C ₆ Alkyl). In some embodiments, R ^W1 is-S (=O) ₂ -CH ₃ 。

In some embodiments, W ² When attached to a double bond and a single bond is C (R ^W2 ) When connected to two single bonds, is N (R ^W2 ) Or N when attached to a double bond and a single bond.

In some embodiments, W ² When attached to a double bond and a single bond is C (R ^W2 )。

In some embodiments, W ² When connected to two single bonds is N (R ^W2 )。

In some embodiments, W ² And N when attached to a double bond and a single bond.

In some embodiments, W ² Is C (R) ^W2 ) Or N (R) ^W2 )。

In some embodiments, W ² Is C (R) ^W2 ). In some embodiments, W ² CH.

In some embodiments, W ² Is N (R) ^W2 ). In some embodiments, W ² Is NH.

In some embodiments, W ² Is N (-S (=O) ₂ -(C ₁ -C ₆ Alkyl)). In some embodiments, W ² Is N (-S (=O) ₂ -CH ₃ )。

In some embodiments, W ² Is N.

In some embodiments, R ^W2 H.

In some embodiments, R ^W2 Is C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, R ^W2 Is C ₁ -C ₆ An alkyl group.

In some embodiments, R ^W2 is-S (=O) ₂ -(C ₁ -C ₆ Alkyl). In some embodiments, R ^W2 is-S (=O) ₂ -CH ₃ 。

In some embodiments, W ³ Is C. In some embodiments, W ³ Is N.

In some embodiments, W ⁴ Is C (R) ^W4 ). In some embodiments, W ⁴ CH. In some embodiments, W ⁴ C (halogen).

In some embodiments, W ⁴ Is N.

In some embodiments, R ^W4 H.

In some embodiments, R ^W4 Is halogen, cyano, C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, R ^W4 Is halogen or cyano.

In some embodiments, R ^W4 Is halogen. In some embodiments, R ^W4 Is F, cl, br or I. In some embodiments, R ^W4 F. In some embodiments, R ^W4 Is Cl. In some embodiments, R ^W4 Is Br. In some embodiments, R ^W4 Is I.

In some embodiments, R ^W4 Is cyano.

In some embodiments, R ^W4 Is C ₁ -C ₆ An alkyl group.

In some embodiments, R ^W4 is-S (=O) ₂ -(C ₁ -C ₆ Alkyl). In some embodiments, R ^W4 is-S (=O) ₂ -CH ₃ 。

In some embodiments, W ⁵ Is C (R) ^W5 ). In some implementationsIn embodiments, W ⁵ CH. In some embodiments, W ⁵ C (halogen).

In some embodiments, W ⁵ Is N.

In some embodiments, R ^W5 H.

In some embodiments, R ^W5 Is halogen, cyano, C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, R ^W5 Is halogen or cyano.

In some embodiments, R ^W5 Is halogen. In some embodiments, R ^W5 Is F, cl, br or I. In some embodiments, R ^W5 F. In some embodiments, R ^W5 Is Cl. In some embodiments, R ^W5 Is Br. In some embodiments, R ^W5 Is I.

In some embodiments, R ^W5 Is cyano.

In some embodiments, R ^W5 Is C ₁ -C ₆ An alkyl group.

In some embodiments, R ^W5 is-S (=O) ₂ -(C ₁ -C ₆ Alkyl). In some embodiments, R ^W5 is-S (=O) ₂ -CH ₃ 。

In some embodiments, W ⁶ When attached to a double bond and a single bond is C (R ^W6 ) When connected to two single bonds, is N (R ^W6 ) Or N when attached to a double bond and a single bond.

In some embodiments, W ⁶ When attached to a double bond and a single bond is C (R ^W6 )。

In some embodiments, W ⁶ When connected to two single bonds is N (R ^W6 )。

In some embodiments, W ⁶ And N when attached to a double bond and a single bond.

In some embodiments, W ⁶ Is C (R) ^W6 ) Or N (R) ^W6 )。

In some embodiments, W ⁶ Is C (R) ^W6 ). In some embodiments, W ⁶ CH.

In some embodiments, W ⁶ Is N (R) ^W6 ). In some embodiments, W ⁶ Is NH.

In some embodiments, W ⁶ Is N (-S (=O) ₂ -(C ₁ -C ₆ Alkyl)). In some embodiments, W ⁶ Is N (-S (=O) ₂ -CH ₃ )。

In some embodiments, W ⁶ Is N.

In some embodiments, R ^W6 H.

In some embodiments, R ^W6 Is halogen, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl or-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, R ^W6 Is halogen or cyano.

In some embodiments, R ^W6 Is halogen. In some embodiments, R ^W6 Is F, cl, br or I. In some embodiments, R ^W6 F. In some embodiments, R ^W6 Is Cl. In some embodiments, R ^W6 Is Br. In some embodiments, R ^W6 Is I.

In some embodiments, R ^W6 Is cyano.

In some embodiments, R ^W6 Is C ₁ -C ₆ An alkyl group.

In some embodiments, R ^W6 Is C ₁ -C ₆ An alkoxy group.

In some embodiments, R ^W6 Is C ₁ -C ₆ A haloalkyl group.

In some embodiments, R ^W6 is-S (=O) ₂ -(C ₁ -C ₆ Alkyl). In some embodiments, R ^W1 is-S (=O) ₂ -CH ₃ 。

In some embodiments of the present invention, in some embodiments,is->In some embodiments, the->Is->In some embodiments of the present invention, in some embodiments,is->In some embodiments, the->Is thatIn some embodiments, the->Is->In some embodiments, the->Is->In some embodiments, the->Is->In some embodiments, the->Is->In some embodiments, the->Is that

Variable X ¹ 、X ² 、R ^X2 、X ³ And R is ^X3

In some embodiments, X ¹ Is C. In some embodiments, X ¹ Is N.

In some embodiments, X ² Is N. In some embodiments, X ² Is O.

In some embodiments, X ² Is C (R) ^X2 ). In some embodiments, X ² CH. In some embodiments, X ² Is C (C) ₁ -C ₆ Alkyl). In some embodiments, X ² Is C (CH) ₃ )。

In some embodiments, R ^X2 H.

In some embodiments, R ^X2 Is C ₁ -C ₆ An alkyl group. In some embodiments, R ^X2 Is CH ₃ 。

In some embodiments, X ³ Is N. In some embodiments, X ³ Is O.

In some embodiments, X ³ Is C (R) ^X3 ). In some embodiments, X ³ CH. In some embodiments, X ³ Is C (C) ₁ -C ₆ Alkyl). In some embodiments, X ³ Is C (CH) ₃ )。

In some embodiments, R ^X3 H.

In some embodiments, R ^X3 Is C ₁ -C ₆ An alkyl group. In some embodiments, R ^X3 Is CH ₃ . In some embodiments, X ¹ N, X of a shape of N, X ² Is C (R) ^X2 ) And X is ³ Is C (R) ^X3 )。

In some embodiments, X ¹ C, X of a shape of C, X ² Is C (R) ^X2 ) And X is ³ Is O.

In some embodiments of the present invention, in some embodiments,is->In some embodiments of the present invention, in some embodiments,is->In some embodiments, the->Is thatIn some embodiments, the->Is->In some embodiments, the->Is->In some embodiments, the->Is->Variable R ¹ 、R ² 、R ³ 、R ^3a 、R ⁴ 、R ⁵ And R is ⁶

In some embodiments, R ¹ H.

In some embodiments, R ¹ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

In some embodiments, R ¹ Is halogen. In some embodiments, R ¹ F or Cl.

In some embodiments, R ¹ F. In some embodiments, R ¹ Is Cl.

In some embodiments, R ¹ Is cyano.

In some embodiments, R ¹ Is C ₁ -C ₆ An alkyl group. In some embodiments, R ¹ Is CH ₃ 。

In some embodiments, R ² H.

In some embodiments, R ² Is halogen, cyano or C ₁ -C ₆ An alkyl group.

In some embodiments, R ² Is halogen. In some embodiments, R ² F or Cl.

In some embodiments, R ² F. In some embodiments, R ² Is Cl.

In some embodiments, R ² Is cyano.

In some embodiments, R ² Is C ₁ -C ₆ An alkyl group. In some embodiments, R ² Is CH ₃ 。

In some embodiments, R ³ Is H, halogen, cyano, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein-NH (C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^3a And (3) substitution.

In some embodiments, R ³ Is H, halogen, cyano, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl group,C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl.

In some embodiments, R ³ H.

In some embodiments, R ³ Is halogen, cyano or NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein-NH (C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl, optionally substituted with one or more R ^3a And (3) substitution.

In some embodiments, R ³ Is halogen, cyano or NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl.

In some embodiments, R ³ Is halogen, cyano or NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl group), wherein-NH (C) ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl) optionally substituted with one or more R ^3a And (3) substitution.

In some embodiments, R ³ Is halogen, cyano or NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl group。

In some embodiments, R ³ Is NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl group), wherein-NH (C) ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl) optionally substituted with one or more R ^3a And (3) substitution.

In some embodiments, R ³ Is NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl).

In some embodiments, R ³ Is NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ wherein-NH (C) ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Optionally by one or more R ^3a And (3) substitution.

In some embodiments, R ³ Is NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ HaloalkanesRadical), -NHC (=o) O (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ 。

In some embodiments, R ³ Is NH ₂ 。

In some embodiments, R ³ To optionally be covered by one or more R ^3a substituted-NH (C) ₁ -C ₆ Alkyl).

In some embodiments, R ³ is-NH (C) ₁ -C ₆ Alkyl).

In some embodiments, R ³ To optionally be covered by one or more R ^3a substituted-NHC (=o) (C ₁ -C ₆ Haloalkyl).

In some embodiments, R ³ is-NHC (=O) (C ₁ -C ₆ Haloalkyl).

In some embodiments, R ³ To optionally be covered by one or more R ^3a substituted-NHC (=O) O (C) ₁ -C ₆ Alkyl).

In some embodiments, R ³ is-NHC (=O) O (C) ₁ -C ₆ Alkyl).

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted N (C) ₁ -C ₆ Alkyl group ₂ 。

In some embodiments, R ³ Is N (C) ₁ -C ₆ Alkyl group ₂ 。

In some embodiments, R ³ is-S (=O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl), wherein-S (=o) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl) optionally substituted with one or more R ^3a And (3) substitution.

In some embodiments, R ³ is-S (=O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl).

In some embodiments, R ³ To optionally be covered by one or more R ^3a substituted-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, R ³ is-S (=O) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, R ³ is-C (=o) H.

In some embodiments, R ³ To optionally be covered by one or more R ^3a substituted-C (=o) (C ₁ -C ₆ Alkyl).

In some embodiments, R ³ is-C (=O) (C ₁ -C ₆ Alkyl).

In some embodiments, R ³ To optionally be covered by one or more R ^3a substituted-C (=O) O (C) ₁ -C ₆ Alkyl).

In some embodiments, R ³ is-C (=O) O (C) ₁ -C ₆ Alkyl).

In some embodiments, R ³ Is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^3a And (3) substitution.

In some embodiments, R ³ Is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl group,C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl.

In some embodiments, R ³ Is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy is optionally substituted with one or more R ^3a And (3) substitution.

In some embodiments, R ³ Is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ An alkoxy group.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted C ₁ -C ₆ An alkyl group.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted C ₂ -C ₆ Alkenyl groups.

In some embodiments, R ³ Is C ₂ -C ₆ Alkenyl groups.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted C ₂ -C ₆ Alkynyl groups.

In some embodiments, R ³ Is C ₂ -C ₆ Alkynyl groups.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted C ₁ -C ₆ An alkoxy group.

In some embodiments, R ³ Is C ₁ -C ₆ An alkoxy group.

In some embodiments, R ³ Is C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^3a And (3) substitution.

In some embodiments, R ³ Is C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, R ³ Is C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted C ₃ -C ₁₂ A cycloalkenyl group.

In some embodiments, R ³ Is C ₃ -C ₁₂ A cycloalkenyl group.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted 3-to 12-membered heterocycloalkyl.

In some embodiments, R ³ Is a 3 to 12 membered heterocycloalkyl.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted 3-to 12-membered heterocycloalkenyl.

In some embodiments, R ³ Is a 3-to 12-membered heterocycloalkenyl group.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl groups.

In some embodiments, R ³ Is C ₆ -C ₁₀ Aryl groups.

In some embodiments, R ³ To optionally be covered by one or more R ^3a Substituted 5-to 10-membered heteroaryl.

In some embodiments, R ³ Is a 5 to 10 membered heteroaryl.

In some embodiments, R ³ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

In some embodiments, R ³ Is halogen. In some embodiments, R ³ F or Cl.

In some embodiments, R ³ F. In some embodiments, R ³ Is Cl.

In some embodiments, R ³ Is cyano.

In some embodiments, R ³ Is C ₁ -C ₆ An alkyl group. In some embodiments, R ³ Is CH ₃ 。

In some embodiments, each R ^3a Independently halogen, cyano, oxo, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein-NH (C ₁ -C ₆ Alkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl optionally substituted with one or more halogens.

In some embodiments, each R ^3a Independently halogen, cyano, oxo, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein NHC (=o) O (C ₁ -C ₆ Alkyl) optionally substituted with one or more halogens.

In some embodiments, each R ^3a Independently halogen, cyano, oxo, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl), wherein NHC (=O) O (C ₁ -C ₆ Alkyl) optionally substituted with one or more halogens.

In some embodiments, each R ^3a Independently halogen, cyano, oxo or-OH.

In some embodiments, each R ^3a Independently a halogen. In some embodiments, each R ^3a Independently cyano. In some embodiments, each R ^3a Independently oxo. In some embodiments, each R ^3a independently-OH.

In some embodiments, each R ^3a Independently NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl) or-C (=O) O (C) ₁ -C ₆ Alkyl), wherein NHC (=O) O (C ₁ -C ₆ Alkyl) optionally substituted with one or more halogens.

In some embodiments, each R ^3a Independently NH ₂ 。

In some embodiments, each R ^3a independently-NH (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^3a Independently is-NHC (=o) O (C) optionally substituted with one or more halogens ₁ -C ₆ Alkyl).

In some embodiments, each R ^3a independently-NHC (=O) O (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^3a Independently N (C) ₁ -C ₆ Alkyl group ₂ 。

In some embodiments, each R ^3a Independently is-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^3a Independently is-C (=o) (C ₁ -C ₆ Alkyl).

In some embodiments, each R ^3a Independently is-C (=o) O (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^3a Independently C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^3a Independently C ₁ -C ₆ An alkyl group.

In some embodiments, each R ^3a Independently C ₂ -C ₆ Alkenyl groups.

In some embodiments, each R ^3a Independently C ₂ -C ₆ Alkynyl groups.

In some embodiments, each R ^3a Independently C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^3a Independently C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl.

In some embodiments, each R ^3a Independently C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, each R ^3a Independently a 3 to 12 membered heterocycloalkyl.

In some embodiments, each R ^3a Independently C ₆ -C ₁₀ Aryl groups.

In some embodiments, each R ^3a Independently a 5 to 10 membered heteroaryl.

In some embodiments, R ⁴ H.

In some embodiments, R ⁴ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

In some embodiments, R ⁴ Is halogen. In some embodiments, R ⁴ F or Cl.

In some embodiments, R ⁴ F. In some embodiments, R ⁴ Is Cl.

In some embodiments, R ⁴ Is cyano.

In some embodiments, R ⁴ Is C ₁ -C ₆ An alkyl group. In some embodiments, R ⁴ Is CH ₃ 。

In some embodiments, R ⁵ H.

In some embodiments, R ⁵ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

In some embodiments, R ⁵ Is halogen. In some embodiments, R ⁵ F or Cl.

In some embodiments, R ⁵ F. In some embodiments, R ⁵ Is Cl.

In some embodiments, R ⁵ Is cyano.

In some embodiments, R ⁵ Is C ₁ -C ₆ An alkyl group. In some embodiments, R ⁵ Is CH ₃ 。

In some embodiments, R ⁶ H.

In some embodiments, R ⁶ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

In some embodiments, R ⁶ Is halogen. In some embodiments, R ⁶ F or Cl.

In some embodiments, R ⁶ F. In some embodiments, R ⁶ Is Cl.

In some embodiments, R ⁶ Is cyano.

In some embodiments, R ⁶ Is C ₁ -C ₆ An alkyl group. In some embodiments, R ⁶ Is CH ₃ 。

Variable Y, Z, R ^Z 、R ^Za And R is ^Zb

In some embodiments, Y is absent and is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ Alkoxy optionally one or more halogen, oxo, cyano, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl) -OH, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, optionally interrupted by- (C) ₁ -C ₆ Alkyl) (C) ₆ -C ₁₀ Aryl) substituted C ₁ -C ₆ Alkoxy or C ₃ -C ₁₂ Cycloalkyl substitution.

In some embodiments, Y is absent.

In one placeIn some embodiments, Y is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ Alkoxy optionally substituted with one or more halogen, oxo, cyano, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl) -OH, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, optionally interrupted by- (C) ₁ -C ₆ Alkyl) (C) ₆ -C ₁₀ Aryl) substituted C ₁ -C ₆ Alkoxy or C ₃ -C ₁₂ Cycloalkyl substitution.

In some embodiments, Y is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₁ -C ₆ An alkoxy group.

In some embodiments, Y is C ₁ -C ₆ Alkyl optionally substituted with one or more halogen, oxo, cyano, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl) -OH, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy substitution.

In some embodiments, Y is C ₁ -C ₆ An alkyl group. In some embodiments, Y is-CH ₂ -。

In some embodiments, Y is C optionally substituted with one or more oxo, cyano or-OH ₁ -C ₆ An alkyl group.

In some embodiments, Y is C optionally substituted with one or more oxo groups ₁ -C ₆ An alkyl group.

In some embodiments, Y is C substituted with one or more oxo groups ₁ -C ₆ An alkyl group.

In some embodiments, Y is methyl optionally substituted with one or more oxo.

In some embodiments, Y is methyl substituted with oxo, i.e., Y is-C (=o) -.

In some embodiments, Y is optionallyC substituted by one or more cyano groups ₁ -C ₆ An alkyl group.

In some embodiments, Y is C substituted with one or more cyano groups ₁ -C ₆ An alkyl group.

In some embodiments, Y is methyl substituted with one or more cyano groups.

In some embodiments, Y is C optionally substituted with one or more-OH groups ₁ -C ₆ An alkyl group.

In some embodiments, Y is C substituted with one or more-OH groups ₁ -C ₆ An alkyl group.

In some embodiments, Z is H.

In some embodiments, Z is C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^Z And (3) substitution.

In some embodiments, Z is C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, Z is C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted C ₃ -C ₁₂ A cycloalkenyl group.

In some embodiments, Z is C ₃ -C ₁₂ A cycloalkenyl group.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted 3 toA 12 membered heterocycloalkyl; and is also provided with

In some embodiments, Z is a 3-to 12-membered heterocycloalkyl.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted 3-to 12-membered heterocycloalkenyl; and is also provided with

In some embodiments, Z is a 3-to 12-membered heterocycloalkenyl.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted C ₆ -C ₁₀ Aryl groups.

In some embodiments, Z is C ₆ -C ₁₀ Aryl groups.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted 5-to 10-membered heteroaryl.

In some embodiments, Z is a 5 to 10 membered heteroaryl.

In some embodiments, Z is C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Z And (3) substitution.

In some embodiments, Z is C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl.

In some embodiments, Z is C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl is substituted by one or more R ^Z And (3) substitution.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, Z is C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, Z is substituted with one or more R ^Z Substituted C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted cyclopropyl.

In some embodiments, Z isOptionally by one or more R ^Z Substituted cyclobutyl.

In some embodiments, Z is optionally substituted with one or more R ^Z A substituted cyclohexyl group.

In some embodiments, Z is optionally substituted with one or more R ^Z Substituted 3-to 8-membered heterocycloalkyl.

In some embodiments, Z is 3 to 8 membered heterocycloalkyl.

In some embodiments, Z is substituted with one or more R ^Z Substituted 3-to 8-membered heterocycloalkyl.

In some embodiments, Z is azetidinyl or oxetanyl, wherein azetidinyl or oxetanyl is optionally substituted with one or more R ^Z And (3) substitution.

In some embodiments, Z is azetidinyl or oxetanyl.

In some embodiments, Z is azetidinyl or oxetanyl, wherein azetidinyl or oxetanyl is substituted with one or more R ^Z And (3) substitution.

In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl, wherein the pyrrolidinyl or tetrahydrofuranyl is optionally substituted with one or more R ^Z And (3) substitution.

In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl.

In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl, wherein pyrrolidinyl or tetrahydrofuranyl is substituted with one or more R ^Z And (3) substitution.

In some embodiments, Z is piperidinyl or tetrahydropyranyl, wherein the piperidinyl or tetrahydropyranyl is optionally substituted with one or more R ^Z And (3) substitution.

In some embodiments, Z is piperidinyl or tetrahydropyranyl.

In some embodiments, Z is piperidinyl or tetrahydropyranyl, wherein the piperidinyl or tetrahydropyranyl is substituted with one or more R ^Z And (3) substitution.

In some embodiments, eachR ^Z Independently oxo, halogen, cyano, -OH, =nr ^Za 、NH ₂ 、NHR ^Za 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) (3-to 12-membered heterocycloalkyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl optionally substituted with one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently oxo, halogen, cyano, -OH, =nr ^Za 、NH ₂ 、NHR ^Za 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) (3-to 12-membered heterocycloalkyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3 to 12 membered heterocycloalkyl or 5 to 10 membered heteroaryl.

In some embodiments, each R ^Z Independently oxo, halogen, cyano, -OH.

In some embodiments, each R ^Z Independently R is ^Z Is oxo.

In some embodiments, each R ^Z Independently R is ^Z Is halogen. In some embodiments, each R ^Z Independently F or Cl.

In some embodiments, each R ^Z Independently F. In some embodiments, each R ^Z Independently Cl.

In some embodiments, each R ^Z Independently cyano. In some embodiments, each R ^Z independently-OH.

In some embodiments, each R ^Z Independently is =nr ^Za . In some embodiments, each R ^Z Is independently NHR ^Za 。

In some embodiments, each R ^Z Independently NH ₂ 、NH(C ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Wherein NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Optionally by one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently NH ₂ 。

In some embodiments, each R ^Z Independently NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Wherein NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group) ₂ Optionally by one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ 。

In some embodiments, each R ^Z Independently NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Wherein NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Is/are R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently is-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently is-S (=o) ₂ -CH ₃ 。

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-S (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently is one or more R ^Za substituted-S (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Is independently-S (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-S (=nr ^Za )-(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently is one or more R ^Za substituted-S (=nr ^Za )-(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently is-S (=NR ^Za )-(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-S (C) ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Z Independently is one or more R ^Za substituted-S (C) ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Z Is independently-S (C) ₂ -C ₆ Alkenyl).

In some embodiments, at least one R ^Z is-C (=O) - (C) ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl), wherein-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl) optionally substituted with one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently is-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Z Independently is-C (=o) - (C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z independently-C (=o) -ch=ch ₂ 。

In some embodiments, each R ^Z Independently is-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl), wherein-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl) is substituted with one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently is-S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) (3-to 12-membered heterocycloalkyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl) or-C (=o) - (C ₁ -C ₆ Alkoxy), wherein-S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) (3-to 12-membered heterocycloalkyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl) or-C (=o) - (C ₁ -C ₆ Alkoxy) optionally substituted with one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently is-S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) (3-to 12-membered heterocycloalkyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl) or-C (=o) - (C ₁ -C ₆ An alkoxy group).

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-S (=o) ₂ -(C ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Z Independently is-S (=o) ₂ -(C ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-C (=o) (3 to 12 membered heterocycloalkyl).

In some embodiments, each R ^Z Independently is-C (=o) (3 to 12 membered heterocycloalkyl).

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-C (=o) NH (C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z independently-C (=O) NH (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently is-C (=O) NR ^Za 。

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-C (=o) - (C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently C (=O) - (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-C (=o) - (C ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Z Independently is-C (=o) - (C ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za substituted-C (=o) - (C ₁ -C ₆ An alkoxy group).

In some embodiments, each R ^Z Independently is-C (=o) - (C ₁ -C ₆ An alkoxy group).

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted 5-to 10-membered heteroaryl.

In some embodiments, each R ^Z Independently a 5 to 10 membered heteroaryl.

In some embodiments, each R ^Z Independently C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy is optionally substituted with one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted C ₁ -C ₆ An alkyl group.

In some embodiments, each R ^Z Independently C ₁ -C ₆ An alkyl group.

In some embodiments, each R ^Z Independently is one or more R ^Za Substituted C ₁ -C ₆ An alkyl group.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted C ₂ -C ₆ Alkenyl groups.

In some embodiments, each R ^Z Independently C ₂ -C ₆ Alkenyl groups.

In some embodiments, each R ^Z Independently is one or more R ^Za Substituted C ₂ -C ₆ Alkenyl groups.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted C ₂ -C ₆ Alkynyl groups.

In some embodiments, each R ^Z Independently C ₂ -C ₆ Alkynyl groups.

In some embodiments, each R ^Z Independently is one or more R ^Za Substituted C ₂ -C ₆ Alkynyl groups.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^Z Independently C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^Z Independently is one or more R ^Za Substituted C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^Z Independently C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl, wherein C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl optionally substituted with one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Za And (3) substitution.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, each R ^Z Independently C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, each R ^Z Independently is one or more R ^Za Substituted C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, each R ^Z Independently C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, each R ^Z Independently is one or more R ^Za Substituted C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted 3-to 12-membered heterocycloalkyl.

In some embodiments, each R ^Z Independently a 3 to 12 membered heterocycloalkyl.

In some embodiments, each R ^Z Independently is one or more R ^Za Substituted 3-to 12-membered heterocycloalkyl.

In some embodiments, each R ^Z Independently are optionally substituted with one or more R ^Za Substituted 3-to 8-membered heterocycloalkyl.

In some embodiments, each R ^Z Independently a 3 to 8 membered heterocycloalkyl.

In some embodiments, each R ^Z Independently is one or more R ^Za Substituted 3-to 8-membered heterocycloalkyl.

In some embodiments, each R ^Za Independently H, oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl optionally substituted with one or more R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently H, oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl.

In some embodiments, each R ^Za Independently H.

In some embodiments, each R ^Za Independently oxo, halogen, cyano, -OH.

In some embodiments, each R ^Za Independently oxo.

In some embodiments, each R ^Za Independently a halogen. In some embodiments, each R ^Za Independently F or Cl.

In some embodiments, each R ^Za Independently F. In some embodiments, each R ^Za Independently Cl.

In some embodiments, each R ^Za Independently cyano.

In some embodiments, each R ^Za independently-OH.

In some embodiments, each R ^Za Independently NH ₂ 、NH(C ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Wherein NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Optionally by one or more R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently NH ₂ 。

In some embodiments, each R ^Za Independently NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Wherein NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Optionally by one or more R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ 。

In some embodiments, each R ^Za Independently NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Wherein NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Is/are R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently are optionally substituted with one or more R ^Zb substituted-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Za Independent and independentGround is-S (=O) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Za Independently is-S (=o) ₂ -CH ₃ 。

In some embodiments, each R ^Za Independently is one or more R ^Zb substituted-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Za Independently is-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl), wherein-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl) optionally substituted with one or more R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently is-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Za Independently is-C (=o) - (C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Za independently-C (=o) -ch=ch ₂ 。

In some embodiments, each R ^Za Independently is-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl), wherein-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl) is substituted with one or more R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy radicalOptionally by one or more R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently are optionally substituted with one or more R ^Zb Substituted C ₁ -C ₆ An alkyl group.

In some embodiments, each R ^Za Independently C ₁ -C ₆ An alkyl group.

In some embodiments, each R ^Za Independently is one or more R ^Zb Substituted C ₁ -C ₆ An alkyl group.

In some embodiments, each R ^Za Independently are optionally substituted with one or more R ^Zb Substituted C ₂ -C ₆ Alkenyl groups.

In some embodiments, each R ^Za Independently C ₂ -C ₆ Alkenyl groups.

In some embodiments, each R ^Za Independently is one or more R ^Zb Substituted C ₂ -C ₆ Alkenyl groups.

In some embodiments, each R ^Za Independently optionally substituted with one or more R ^Zb Substituted C ₂ -C ₆ Alkynyl groups.

In some embodiments, each R ^Za Independently C ₂ -C ₆ Alkynyl groups.

In some embodiments, each R ^Za Independently is one or more R ^Zb Substituted C ₂ -C ₆ Alkynyl groups.

In some embodiments, each R ^Za Independently are optionally substituted with one or more R ^Zb Substituted C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^Za Independently C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^Za Independently is one or more R ^Zb Substituted C ₁ -C ₆ An alkoxy group.

In some embodimentsEach R is ^Za Independently C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl, wherein C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl optionally substituted with one or more R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently are optionally substituted with one or more R ^Zb Substituted C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, each R ^Za Independently C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, each R ^Za Independently is one or more R ^Zb Substituted C ₃ -C ₁₂ Cycloalkyl groups.

In some embodiments, each R ^Za Independently are optionally substituted with one or more R ^Zb Substituted 3-to 12-membered heterocycloalkyl.

In some embodiments, each R ^Za Independently a 3 to 12 membered heterocycloalkyl.

In some embodiments, each R ^Za Independently is one or more R ^Zb Substituted 3-to 12-membered heterocycloalkyl.

In some embodiments, each R ^Za Independently C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Zb And (3) substitution.

In some embodiments, each R ^Za Independently are optionally substituted with one or more R ^Zb Substituted C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, each R ^Za Independently C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, each R ^Za Independently is one or more R ^Zb Substituted C ₃ -C ₈ Cycloalkyl groups.

In some embodiments, each R ^Za Independently are optionally substituted with one or more R ^Zb Substituted 3-to 8-membered heterocycloalkyl.

In some embodiments, each R ^Za Independently a 3 to 8 membered heterocycloalkyl.

In some embodiments, each R ^Za Independently is one or more R ^Zb Substituted 3-to 8-membered heterocycloalkyl.

In some embodiments, each R ^Zb Independently oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^Zb Independently oxo, halogen, cyano or-OH.

In some embodiments, each R ^Zb Independently oxo.

In some embodiments, each R ^Zb Independently halogen. In some embodiments, each R ^Zb Independently F or Cl.

In some embodiments, each R ^Zb Independently F. In some embodiments, each R ^Zb Independently Cl.

In some embodiments, each R ^Zb Independently cyano. In some embodiments, each R ^Zb independently-OH.

In some embodiments, each R ^Zb Independently NH ₂ 、NH(C ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ 。

In some embodiments, each R ^Zb Independently NH ₂ 。

In some embodiments, each R ^Zb Independently NH (C) ₁ -C ₆ Alkyl).

In some embodiments, each R ^Zb Independently N (C) ₁ -C ₆ Alkyl group ₂ 。

In some embodiments, each R ^Zb Independently is-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Zb Independently is-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Zb Independently is-C (=o) - (C ₁ -C ₆ Alkyl).

In some embodiments, each R ^Zb Independently is-C (=o) - (C ₂ -C ₆ Alkenyl).

In some embodiments, each R ^Zb independently-C (=o) -ch=ch ₂ 。

In some embodiments, each R ^Zb Independently C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^Zb Independently C ₁ -C ₆ An alkyl group.

In some embodiments, each R ^Zb Independently C ₂ -C ₆ Alkenyl groups.

In some embodiments, each R ^Zb Independently C ₂ -C ₆ Alkynyl groups.

In some embodiments, each R ^Zb Independently C ₁ -C ₆ An alkoxy group.

Exemplary embodiments of the Compounds

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

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has formula (I-a), (I-b), (I-c), or (I-d):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has formula (II):

/>

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound has the formula (II-a), (II-b), (II-c), or (II-d):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound described in tables I and II, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound described in tables I and II, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are those described in tables I and II.

In some embodiments, the compound is a compound described in table II, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound described in table II or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound described in table II.

In some embodiments, the compound is a compound described in table I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound described in table I or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound described in table I

TABLE I

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In some aspects, the present disclosure provides a compound that is an isotopic derivative of any of the compounds disclosed herein (e.g., isotopically-labeled compounds).

In some embodiments, the compound is an isotopic derivative of any one of the compounds described in table I and table II, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is an isotopic derivative of any one of the compounds described in tables I and II.

In some embodiments, the compound is an isotopic derivative of any one of the compounds described in table I, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is an isotopic derivative of any one of the compounds described in table I.

In some embodiments, the compound is an isotopic derivative of any one of the compounds described in table II, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is an isotopic derivative of any one of the compounds described in table II.

It will be appreciated that the isotopic derivatives may be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by carrying out the protocols and/or procedures disclosed in the examples described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

In some embodiments, the isotopic derivative is a deuterium-labeled compound.

In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of formula disclosed herein.

In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in table I and table II, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in table I and table II.

In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in table I, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in table I

In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in table II, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in table II.

It is understood that the deuterium-labeled compound includes deuterium atoms having deuterium abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

In some embodiments, the deuterium-labeled compound has a deuterium enrichment coefficient for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" means the ratio between deuterium abundance and natural abundance of deuterium.

It should be appreciated that any of a variety of art-recognized techniques may be used to prepare deuterium-labeled compounds. For example, deuterium-labeled compounds can generally be prepared by substituting a deuterium-labeled reagent for a non-deuterium-labeled reagent to carry out the procedures disclosed in the schemes and/or examples described herein.

Compounds of the present disclosure containing a deuterium atom as described above, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. Further, the formation of the metal oxide layer with deuterium (i.e., ² h) Substitution may provide for greater metabolic stability Certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements.

For the avoidance of doubt, it is to be understood that where a group is defined in this specification by "herein" the first occurrence and broadest definition of that group and each and all specific definitions of that group are covered.

Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of the compounds of the present disclosure which are sufficiently basic, for example, with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methane sulfonate or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the present disclosure which are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts or salts with organic bases providing a pharmaceutically acceptable cation, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine.

It is to be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of the compounds.

As used herein, the term "isomerism" means a compound having the same molecular formula but a different order of atomic bonding or a different arrangement of atoms in space. The isomers of different atomic spatial arrangements are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers" or sometimes as optical isomers. Mixtures containing equal amounts of individual enantiomeric forms with opposite chirality are referred to as "racemic mixtures".

As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

As used herein, "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as mixtures of diastereomers (referred to as "diastereomeric mixtures"). When one chiral center is present, stereoisomers may be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to chiral centers are considered ordered according to Cahn, ingold and Prelog's sequential Rule (Cahn et al, (Angew. Chem. Inter. Edit.) 1966,5,385, (Angew. Chem.) (1966, 78,413; cahn and Ingold, society of chemical (J. Chem. Soc.)) 1951 (London), 612; cahn et al, (Expientia) 1956,12,81; cahn, (J. Chem. Educ.)) 1964,41,116.

As used herein, the term "geometric isomer" means that there is a diastereomer that is blocked due to rotation about a double bond or cycloalkyl linker (e.g., 1, 3-cyclobutyl). The names of these configurations are distinguished by the prefix cis and trans, or Z and E, which indicates that the groups are on the same or opposite sides of the double bond in the molecule, according to Cahn-Ingold-Prelog rules.

It is to be understood that the compounds of the present disclosure may be described as different chiral isomers or geometric isomers. It is also to be understood that when a compound has chiral isomers or geometric isomer forms, all isomer forms are intended to be included within the scope of the present disclosure, and that naming of the compound does not exclude any isomer forms, it being understood that not all isomers may have the same level of activity.

It is to be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It is also understood that not all atropisomers may have the same level of activity.

As used herein, the term "atropisomer" is a stereoisomer in which the atoms of the two isomers are spatially arranged differently. Atropisomers exist due to limited rotation caused by the rotation of the large group about the central bond being blocked. Such atropisomers are usually present in the form of mixtures, however, due to recent advances in chromatographic techniques, it is possible in selected cases to separate mixtures of the two atropisomers.

As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in a formal shift of the hydrogen atom, accompanied by a conversion of the adjacent conjugated double bonds. Tautomers exist in solution as a mixture of tautomeric groups. In solutions where tautomerization may occur, chemical equilibrium of the tautomer will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers interconverted by tautomerization is called tautomerism. Of the various types of tautomerism that are possible, two are generally observed. In keto-enol tautomerism, both electrons and hydrogen atoms move simultaneously. The ring chain tautomerism is caused by the reaction of an aldehyde group (-CHO) in a sugar chain molecule with a hydroxyl group (-OH) in the same molecule, making it in a cyclic (ring) form, as presented by glucose.

It is to be understood that the compounds of the present disclosure may be described as different tautomers. It is also to be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the disclosure, and that the naming of the compound does not exclude any tautomeric forms. It is understood that certain tautomers may have higher levels of activity than other tautomers.

Compounds having the same molecular formula but different bonding properties or sequences of atoms or arrangements of atoms in space are referred to as "isomers". The isomers in which atoms are arranged differently in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and stereoisomers that are not superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, when it is bound to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described by the R and S order rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and are designated as either dextrorotatory or levorotatory (i.e., designated as (+) or (-) isomers, respectively). The chiral compounds may exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".

The compounds of the present disclosure may have one or more asymmetric centers; thus, such compounds may be produced as the (R) or (S) stereoisomers alone or as mixtures thereof. Unless otherwise indicated, descriptions or designations of particular compounds in the specification and claims are intended to include individual enantiomers, mixtures, racemates or other forms thereof. Methods for determining stereochemistry and isolating stereoisomers are well known in the art (see "advanced organic chemistry (Advanced Organic Chemistry)", 4 th edition, discussion in chapter 4 of j.march, john wili parent, new york city, 2001), for example, by synthesis from optically active starting materials or by resolution of the racemic form. Some compounds of the present disclosure may have geometric isomerism centers (E-isomer and Z-isomer). It is to be understood that the present disclosure encompasses all optical diastereomers and geometric isomers, as well as mixtures thereof, that have inflammatory body inhibitory activity.

The present disclosure also encompasses compounds of the present disclosure as defined herein, comprising one or more isotopic substitutions.

It is to be understood that any of the compounds of formula (la) described herein include the compounds themselves, as well as their salts and their solvates, if applicable. For example, salts can be formed between anions and positively charged groups (e.g., amino groups) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, salts may also be formed between the cations on the substituted compounds disclosed herein and negatively charged groups (e.g., carboxylate groups). Suitable cations include sodium, potassium, magnesium, calcium and ammonium cations such as tetramethylammonium or diethylamine. Substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

It is to be understood that the compounds of the present disclosure, e.g., salts of the compounds, may exist in hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

As used herein, the term "solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, forming solvates. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alkoxide. The hydrate is formed by the combination of one or more water molecules and one molecule of the substance, wherein the water maintains its molecular state as H ₂ O。

As used herein, the term "analog" refers to a compound that is similar in structure to another compound but slightly different in composition (e.g., one atom is replaced by an atom of a different element, or in the presence of a particular functional group, or one functional group is replaced by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound, but differs in structure or origin from the reference compound.

As used herein, the term "derivative" refers to a compound having a common core structure and substituted with various groups as described herein.

As used herein, the term "bioisostere" refers to a compound produced by the exchange of one atom or group of atoms with another, substantially similar atom or group of atoms. The purpose of bioisosteric substitution is to create new compounds with similar biological properties as the parent compound. Bioisosteric substitution may be physicochemical or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g., patani and LaVoie, chemical review (chem. Rev.) 96,3147-3176,1996.

It is also understood that certain compounds of the present disclosure may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrate, monohydrate, dihydrate or trihydrate. It is to be understood that the present disclosure includes all such solvated forms which possess inflammatory body inhibiting activity.

It is also understood that certain compounds of the present disclosure may exhibit polymorphism, and that the present disclosure includes all such forms or mixtures thereof, which have inflammatory body inhibitory activity. It is well known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse Reflection Infrared Fourier Transform (DRIFT) spectroscopy, near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

The compounds of the present disclosure may exist in many different tautomeric forms, and reference to a compound of the present disclosure includes all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all other compounds are still encompassed by formula (I). Examples of tautomeric forms include ketone forms, enol forms, and enol salt forms, such as, for example, the following tautomeric pairs: ketone/enol (shown below), imine/enamine, amide/iminoalcohol, amidine/amidine, nitroso/oxime, thioketone/enamine, and nitro/acid-nitro.

The compounds of the present disclosure that include amine functionality may also form N-oxides. Reference herein to compounds containing amine functionality disclosed herein also includes N-oxides. In the case of compounds containing several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. Specific examples of the N-oxide are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. The N-oxide may be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, jerry March, advanced organic chemistry, 4 th edition, wiley Interscience, pages. More specifically, the N-oxide may be prepared by the procedure of l.w. ready (synchronous communication (syn. Comm.)), 1977,7,509-514, wherein an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in, for example, an inert solvent such as methylene chloride.

The compounds of the present disclosure may be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to alter the physical and/or pharmacokinetic properties of the compounds of the present disclosure. When a compound of the present disclosure contains a suitable group or substituent, a prodrug may be formed, and the property-altering group may be attached to the suitable group or substituent. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents on the sulfonylurea group of a compound of any one of the formulae disclosed herein.

Thus, the present disclosure includes those compounds of the present disclosure as defined above, when available through organic synthesis, and when available in the human or animal body through cleavage of a prodrug thereof. Thus, the present disclosure includes those compounds of the present disclosure produced by organic synthetic means, as well as such compounds produced in the human or animal body by metabolism of the precursor compounds, i.e., the compounds of the present disclosure may be synthetically produced compounds or metabolically produced compounds.

Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure are prodrugs based on sound medical judgment, which are suitable for administration to the human or animal body without undesired pharmacological activity and without undue toxicity. Various forms of prodrugs have been described, for example, in the following documents: a) Widder et al, methods of enzymology (Methods in Enzymology), vol.42, pages 309-396 (academic Press 1985); b) H. Design of prodrugs (Design of Pro-drugs) edited by Bundgaard, (Elsevier, 1985); c) Textbooks on drug design and development (ATextbook of Drug Design and Development) by Krogsgaard-Larsen and H.Bundgaard, chapter 5, H.Bundgaard, prodrug design and application (Design and Application of Pro-drugs) ", pages 113-191 (1991); d) Bundegaard, advanced drug delivery comment (Advanced Drug Delivery Reviews), 8,1-38 (1992); e) H.Bundgaard et al, journal of pharmaceutical science (Journal of Pharmaceutical Sciences) 77,285 (1988); f) N. Kakeya et al, chemical and pharmaceutical bulletins (chem. Pharm. Bull.), 32,692 (1984); g) Higuchi and v.stilla, "Pro-drug as novel delivery system (Pro-Drugs as Novel Delivery Systems)", a.c. s.symposium Series, volume 14. And h) E.Roche (eds.), "bioreversible vehicle in drug design (Bioreversible Carriers in Drug Design)", pegamon Press (Pergamon Press), 1987.

Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a hydroxyl group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable ester or ether of the compounds of the present disclosure containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to yield the parent hydroxyl compound. Suitable pharmaceutically acceptable ester forming groups for the hydroxyl groups include inorganic esters such as phosphate esters (including cyclic phosphoramidates). Additional suitable pharmaceutically acceptable ester forming groups for the hydroxyl groups include C ₁ -C ₁₀ Alkanoyl groups, e.g. acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenethylAcyl, C ₁ -C ₁₀ Alkoxycarbonyl (e.g. ethoxycarbonyl), N- (C) ₁ -C ₆ Alkyl group ₂ Carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4- (C) ₁ -C ₄ Alkyl) piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for the hydroxyl groups include α -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a carboxyl group are, for example, in vivo cleavable amides, for example with amines such as ammonia, C _1-4 Alkylamines such as methylamine, (C) ₁ -C ₄ Alkyl group(s) ₂ Amines, e.g. dimethylamine, N-ethyl-N-methylamine or diethylamine, C ₁ -C ₄ alkoxy-C ₂ -C ₄ Alkylamines such as 2-methoxyethylamine, phenyl-C ₁ -C ₄ Amides of alkylamines such as benzylamine and amino acids such as glycine or esters thereof.

Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from amino groups include, for example, with C ₁ -C ₁₀ Alkanoyl groups such as acetyl, benzoyl, phenylacetyl and amides of substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4- (C) ₁ -C ₄ Alkyl) piperazin-1-ylmethyl.

The in vivo effects of the compounds of the present disclosure may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compounds of the present disclosure. As described above, the in vivo effects of the compounds of the present disclosure may also be exerted by metabolism of the precursor compounds (prodrugs).

Synthesis method

In some aspects, the present disclosure provides a method of preparing a compound disclosed herein.

In some aspects, the present disclosure provides a method of preparing a compound comprising one or more steps as described herein.

In some aspects, the present disclosure provides a compound obtainable by, or obtained directly by, a process for preparing a compound described herein.

In some aspects, the present disclosure provides an intermediate useful in a process for preparing a compound described herein.

The compounds of the present disclosure may be prepared by any suitable technique known in the art. Specific processes for preparing these compounds are further described in the appended examples.

In the description of the synthetic methods described herein and any reference synthetic methods for preparing the starting materials, it is understood that all of the proposed reaction conditions, including selection of solvents, reaction atmospheres, reaction temperatures, experimental durations, and treatment procedures, may be selected by one of skill in the art.

Those skilled in the art of organic synthesis will appreciate that the functional groups present on each part of the molecule must be compatible with the reagents and reaction conditions used.

It will be appreciated that during the synthesis of the compounds of the present disclosure in the methods defined herein or during the synthesis of certain starting materials, certain substituents may need to be protected from their undesirable reactants. The skilled chemist will know when such protection is needed and how such protecting groups can be placed in place and subsequently removed. For examples of protecting groups, see one of many general textbooks on the subject, e.g., protecting group in organic Synthesis (Protective Groups in Organic Synthesis), theodora GreeN (publishers: john Wiley & Sons). The protecting groups may be removed as desired by any convenient method described in the literature or known to the skilled chemist for removing the protecting groups in question, such methods being selected to effect removal of the protecting groups with minimal interference with groups elsewhere in the molecule. Thus, if a reactant includes a group such as an amino, carboxyl, or hydroxyl group, it may be desirable to protect the group in some of the reactions mentioned herein.

By way of example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, for example alkanoyl groups such as acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, arylmethoxycarbonyl groups, for example benzyloxycarbonyl or aroyl groups, for example benzoyl. The deprotection conditions for the protecting groups described above must vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed by hydrolysis, for example with a suitable base such as an alkali metal hydroxide, e.g. lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as benzyloxycarbonyl may be removed, in particular, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a lewis acid such as boron tris (trifluoroacetate). Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines, for example dimethylaminopropylamine, or with hydrazine.

Suitable protecting groups for hydroxy groups are, for example, acyl groups, for example alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the protecting groups described above will necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide or ammonia. Alternatively, arylmethyl groups such as benzyl groups may be removed, for example by hydrogenation over a catalyst such as palladium on carbon.

Suitable protecting groups for the carboxyl groups are, for example, esterified groups, e.g. methyl or ethyl groups which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or tert-butyl groups which can be removed, for example, by treatment with an acid such as an organic acid such as trifluoroacetic acid, or benzyl groups which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

Once the compounds of the present disclosure are synthesized by any of the processes defined herein, the process may then further comprise the additional steps of (i) removing any protecting groups present; (ii) Converting a compound of the present disclosure to another compound of the present disclosure; (iii) Forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.

The resulting compounds of the present disclosure may be isolated and purified using techniques well known in the art.

Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the reaction conditions to be responded to. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl ether or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the solvents or with water.

The reaction temperature is suitably between about-100 ℃ and 300 ℃ depending on the reaction step and the conditions used.

The reaction time is generally in the range of a fraction of a minute to several days, depending on the reactivity of the corresponding compound and the corresponding reaction conditions. Suitable reaction times can be readily determined by methods known in the art, such as reaction monitoring. Suitable reaction times are generally in the range between 10min and 48 hours, based on the reaction temperatures given above.

Furthermore, additional compounds of the present disclosure may be readily prepared by utilizing the procedures described herein in conjunction with one of ordinary skill in the art. Those skilled in the art will readily appreciate that known variations of the conditions and procedures of the following preparation procedures may be used to prepare these compounds.

As will be appreciated by those of skill in the art of organic synthesis, the compounds of the present disclosure may be readily obtained from a variety of synthetic pathways, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what types of reagents and reaction conditions should be used and how to apply and adapt, if desired or applicable, in any particular example to obtain the compounds of the disclosure. In addition, some compounds of the present disclosure may be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example by converting one particular functional group or a suitable precursor molecule thereof present in a compound of the present disclosure into another functional group via application of standard synthetic methods (e.g., reduction, oxidation, addition, or substitution reactions); these methods are well known to those skilled in the art. Similarly, one of ordinary skill in the art will apply synthetic protecting (or protective) groups as needed or applicable; suitable protecting groups and methods for their introduction and removal are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in p.g.m.wuts, t.w.greene, greene's Protective Groups in Organic Synthesis in organic synthesis, 4 th edition (2006) (John Wiley & Sons).

The general route for preparing the compounds of the application is described in schemes 1 and 2.

Scheme 1

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Bioassays

After the compounds are designed, selected, and/or optimized by the methods described above, they can be characterized using various assays known to those of skill in the art for determining whether a compound is biologically active. For example, molecules may be characterized by conventional assays, including but not limited to those described below, to determine whether the molecules have predicted activity, binding activity, and/or binding specificity.

In addition, high throughput screening can be used to speed up analysis with such assays. Thus, the activity of the molecules described herein can be rapidly screened using techniques known in the art. For example, the general method for performing high throughput screening is described in DevliN (1998) high throughput screening (High Throughput Screening), marcel Dekker; and U.S. patent No. 5,763,263. The high throughput assay may use one or more different assay techniques, including but not limited to those described below.

Various in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

In some embodiments, the biological assay evaluates the ability of a compound to inhibit cell proliferation.

In some embodiments, cells (e.g., SNU-16 (FGFR 2-expanded) cells) may be suspended and distributed in plates. In some embodiments, cells (e.g., UM-UC-14 (FGFR 3-S249C) cells) may be suspended and distributed in plates. In some embodiments, cells (e.g., DMS-114 (FGFR 1 over-expression) cells) can be suspended and distributed in plates. In some embodiments, the cell (e.g., RT-112 (FGFR 3-Tacc3 fusion) cell) may beSuspended and dispensed in a plate. In some embodiments, to determine the effect of a compound of the present disclosure on cell proliferation, cells (e.g., SNU-16, UM-UC-14, DMS-114, and RT112 cells) can be incubated in the presence of different concentrations of vehicle control (e.g., DMSO) or a compound of the present disclosure, and inhibition of cell growth can be determined by luminescence quantification (e.g., quantification of intracellular ATP content using celltiter glo) according to the manufacturer's protocol. In some embodiments, to determine an IC ₅₀ Values, vehicle-treated cells were normalized to living cells and analyzed for growth using software, e.g., CDD vat software (cooperative drug discovery company (Collaborative Drug Discovery), burlingame, CA).

Pharmaceutical composition

In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from table I. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from table II.

As used herein, the term "composition" is intended to include a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The compounds of the present disclosure may be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of the present disclosure may also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

The formulations of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include excipients selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity/suspending agents, buffering agents and pH adjusting agents, and mixtures thereof.

Any suitable solubility enhancing agent may be used. Examples of solubility enhancers include cyclodextrins, such as those selected from the group consisting of: hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylammonio) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, sulfated beta-cyclodextrin (S-beta-CD), maltosyl-beta-cyclodextrin, beta-cyclodextrin sulfobutyl ether, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, and trimethyl-gamma-cyclodextrin, and mixtures thereof.

Any suitable chelating agent may be used. Examples of suitable chelating agents include chelating agents selected from the group consisting of ethylenediamine tetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl paraben, polyurethane biguanide and butyl paraben, and sorbic acid and mixtures thereof.

The aqueous vehicle may also include tonicity agents to adjust tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerin (glycerol), dextrose, glycerin (glycerol), mannitol, potassium chloride and sodium chloride, and mixtures thereof.

The aqueous vehicle may also contain a viscosity agent/suspending agent. Suitable viscosity agents/suspending agents include those selected from the group consisting of cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with a polyalkenyl ether or a divinyl glycol (carbopol-such as carbopol 934, carbopol 934P, carbopol 971, carbopol 974, and carbopol 974P), and mixtures thereof.

In order to adjust the formulation to an acceptable pH (typically in the pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, especially about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjustor is typically an inorganic acid or a metal hydroxide base selected from the group of potassium hydroxide, sodium hydroxide and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH adjusting agents are added to adjust the formulation to a target acceptable pH range. Thus, it may not be necessary to use both an acid and a base, depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer is selected from the group consisting of phosphate buffers (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (e.g., boric acid or salts thereof, including disodium tetraborate), citrate buffers (e.g., citric acid or salts thereof, including sodium citrate), and epsilon-aminocaproic acid and mixtures thereof.

The formulation may further comprise a humectant. Suitable classes of humectants include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), oxyethylenated octylphenol polymers (tyloxapol), polyoxyethylene 40 stearates, fatty acid glycol esters, fatty acid glycerides, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of tablets, troches or capsules. Oral compositions may also be prepared using a liquid carrier for use as a mouthwash, wherein the compounds in the liquid carrier are administered orally and rinsed and expectorated or swallowed. Pharmaceutically compatible binders and/or auxiliary materials may be included as part of the composition. Tablets, pills, capsules, troches and the like may contain any of the following ingredients or compounds of similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

According to a further aspect of the present disclosure there is provided a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined above, and a pharmaceutically acceptable diluent or carrier.

The compositions of the present disclosure may be in a form suitable for oral use (e.g., as a tablet, lozenge, hard or soft capsule, aqueous or oily suspension, emulsion, dispersible powder or granule, syrup or elixir), suitable for topical use (e.g., as a cream, ointment, gel or aqueous or oily solution or suspension), suitable for administration by inhalation (e.g., as a finely divided powder or liquid aerosol), suitable for administration by insufflation (e.g., as a finely divided powder), or suitable for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

The compositions of the present disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may comprise, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and/or alleviate symptoms associated with an inflammatory-related condition as referred to herein.

The dosage size of the compounds of the present disclosure for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, according to well known medical principles.

Application method

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the methods comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

In some aspects, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

In some aspects, the present disclosure provides at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.

In some aspects, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.

In some aspects, the present disclosure provides the use of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

In some aspects, the present disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

In some aspects, the present disclosure provides the use of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

In some aspects, the present disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

In some aspects, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.

In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides for the use of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical kit comprising at least one compound of the present disclosure or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to the subject a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

In some aspects, the present disclosure provides a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

In some aspects, the present disclosure provides a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.

In some aspects, the present disclosure provides a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

In some aspects, the present disclosure provides for the use of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

In some aspects, the present disclosure provides a pharmaceutical kit comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

In some aspects, the present disclosure provides a pharmaceutical kit comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.

FGFR2 is a human gene located on chromosome 10, which encodes a protein known as FGFR 2. FGFR3 is a human gene located on chromosome 4, which encodes a protein known as FGFR 3. Both FGFR2 and FGFR3 are produced in a variety of different isoforms by alternative splicing. "b isoform" is expressed predominantly in epithelial tissue, while "c isoform" is expressed predominantly in interstitial tissue.

FGFR2 and FGFR3 are members of the fibroblast growth factor receptor family. Members of the fibroblast growth factor receptor family are proteins that are located on the cell surface and bind to various members of the Fibroblast Growth Factor (FGF) protein family. FGFR2 and FGFR3 have extracellular ligand domains consisting of three immunoglobulin-like domains, a single transmembrane helical domain, and an intracellular tyrosine kinase domain. When FGF ligands bind to extracellular ligand domains, the receptors dimerize, and the intracellular tyrosine kinase domains in the dimer cross-phosphorylate each other, activating the kinase domains, allowing them to subsequently bind to adapter proteins and phosphorylate other intracellular signaling molecules. Members of the fibroblast growth factor receptor family are known to regulate a variety of cellular processes including, but not limited to, proliferation and differentiation, particularly in the context of development and tissue repair.

Overexpression of FGFR2 is associated with a variety of different cancers including, but not limited to, gastric cancer and triple negative breast cancer.

Overexpression of FGFR3 is associated with a variety of different cancers including, but not limited to, lung cancer and bladder cancer.

Mutations in the FGFR2 gene that produce mutant FGFR2 proteins are associated with a variety of different cancers, including, but not limited to, endometrial and lung cancers.

Mutations in the FGFR3 gene that produce mutant FGFR3 proteins are associated with a variety of different cancers, including but not limited to bladder cancer.

Fusion of FGFR2 genes to produce fusion of FGFR2 proteins is associated with a variety of different cancers including, but not limited to, bladder cancer and intrahepatic cholangiocarcinoma.

Fusion of FGFR3 genes to produce fusions of FGFR3 proteins has been implicated in a variety of different cancers including, but not limited to, bladder cancer and glioblastoma.

In some embodiments, the subject is a mammal.

In some embodiments, the subject is a human.

In some embodiments, the subject has previously undergone at least one round of anti-cancer therapy. In some embodiments, the subject has previously undergone at least one round of anti-cancer therapy and has acquired resistance to treatment with the anti-cancer therapy. In some embodiments, the anti-cancer therapy may include administration of at least one of fobat tinib, pemitinib, erdasatinib, infliximab, debio-1347.

In some embodiments, the cancer is characterized by at least one oncogenic mutation in the FGFR2 gene.

In some embodiments, the cancer is characterized by at least one oncogenic mutation in the FGFR3 gene.

It is to be understood that the cancer characterized by at least one oncogenic mutation in the FGFR2 gene and/or FGFR3 gene is a cancer that is typically associated with at least one oncogenic mutation in the FGFR2 gene and/or FGFR3 gene, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by at least one oncogenic mutation in the FGFR2 gene and/or FGFR3 gene.

In some embodiments, the cancer is characterized by overexpression of FGFR2 genes.

In some embodiments, the cancer is characterized by overexpression of FGFR3 genes.

It is to be understood that the cancer characterized by overexpression of FGFR2 genes and/or FGFR3 genes is a cancer that is typically associated with overexpression of FGFR2 genes and/or FGFR3 genes, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by overexpression of FGFR2 genes and/or FGFR3 genes.

In some embodiments, the cancer is characterized by at least one oncogenic variant of FGFR 2.

In some embodiments, the cancer is characterized by at least one oncogenic variant of FGFR 3.

It is to be understood that the cancer characterized by at least one oncogenic variant of FGFR2 and/or FGFR3 is a cancer commonly associated with at least one oncogenic variant of FGFR2 and/or FGFR3, including, but not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant of FGFR2 and/or FGFR 3.

In some embodiments, the cancer is characterized by overexpression of FGFR 2.

In some embodiments, the cancer is characterized by overexpression of FGFR 3.

It is to be understood that cancers characterized by overexpression of FGFR2 and/or FGFR3 are cancers that are typically associated with FGFR2 and/or FGFR3 overexpression, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by FGFR2 and/or FGFR3 overexpression.

It is understood that an oncogenic variant of FGFR2 is an FGFR2 protein comprising at least one oncogenic mutation and resulting from expression of an FGFR2 gene comprising the at least one oncogenic mutation.

It is understood that an oncogenic variant of FGFR3 is an FGFR3 protein comprising at least one oncogenic mutation and resulting from expression of an FGFR3 gene comprising the at least one oncogenic mutation.

In some embodiments, the subject has at least one oncogenic mutation in the FGFR2 gene.

In some embodiments, the subject has at least one oncogenic mutation in the FGFR3 gene.

In some embodiments, the subject has a tumor and/or cancer cell that expresses at least one oncogenic variant of FGFR 2.

In some embodiments, the subject has a tumor and/or cancer cell that expresses at least one oncogenic variant of FGFR 3.

In some embodiments, the subject has at least one tumor and/or cancer cell that overexpresses FGFR 2.

In some embodiments, the subject has at least one tumor and/or cancer cell that overexpresses FGFR 3.

As will be appreciated by those of skill in the art, in the case of genes (e.g., FGFR2 and/or FGFR 3), oncogenic mutations may include, but are not limited to, mutations that result in one amino acid being substituted for another amino acid at a particular position within FGFR2 and/or FGFR3, mutations that result in one or more amino acids being substituted for one or more amino acids between two particular positions within FGFR2 and/or FGFR3, mutations that result in one or more amino acids being inserted between two positions within FGFR2 and/or FGFR3, mutations that result in one or more amino acids being deleted between two positions within FGFR2 and/or FGFR3, or portions thereof, being fused to another protein, or portions thereof, or any combination thereof. As the skilled artisan will appreciate, in the context of a gene, oncogenic mutations may include, but are not limited to, missense mutations, non-synonymous mutations, insertions of one or more nucleotides, deletions, inversions, and deletions of one or more nucleotides. As the skilled artisan will appreciate, in the case of genes (e.g., FGRF2 and/or FGFR 3), the genes may have one or more of the foregoing types of oncogenic mutations, including combinations of different types of oncogenic mutations.

As appreciated by the skilled artisan, in the case of a protein (e.g., FGFR2 and/or FGFR 3), oncogenic mutations, but are not limited to, substitution of one amino acid for another at a particular position within FGFR2 and/or FGFR3, substitution of one or more amino acids for one or more amino acids between two particular positions within FGFR2 and/or FGFR3, insertion of one or more amino acids between two positions within FGFR2 and/or FGFR3, deletion of one or more amino acids between two positions within FGFR2 and/or FGFR3, and fusion of FGFR2 and/or FGFR3 or portions thereof with another protein or portions thereof, or any combination thereof. As the skilled artisan will appreciate, in the case of proteins (e.g., FGFR2 and/or FGFR 3), the protein may have one or more of the foregoing types of oncogenic mutations, including combinations of different types of oncogenic mutations.

In some embodiments, the oncogenic mutation of FGFR2 can be any FGFR2 mutation presented in table 1a. In some embodiments, the oncogenic mutation of FGFR2 can be a gatekeeper mutation that results in resistance to existing inhibitors, wherein the gatekeeper mutation is V565I or V565F.

TABLE 1A FGFR2 mutation

S252W	V565F	V565I
			V565I	N550K

In some embodiments, the oncogenic mutation of FGFR3 can be any FGFR3 mutation presented in table 1b. In some embodiments, the oncogenic mutation of FGFR3 can be a gatekeeper mutation that results in resistance to existing inhibitors, wherein the gatekeeper mutation is V555M, V555L or V555F.

TABLE 1b FGFR3 mutation

S249C	Tacc3 fusion	V555L
			V555F	V555M

In some embodiments, the oncogenic variant of FGFR2 can be any of the FGFR2 variants listed in table 1c.

TABLE 1c FGFR2 oncogenic variants

FGFR2-S252W	FGFR2-V565F	FGFR2-S252W+V565F
			FGFR2-V565I	FGFR2-N550K	FGFR2-S252W+V565I
FGRF2-V565I

In some embodiments, the oncogenic variant of FGFR3 can be any of the FGFR3 variants listed in table 1d.

TABLE 1d FGFR3 oncogenic variants

FGFR3-S249C	FGFR3-Tacc3 fusion	FGFR3-S249C+V555M
			FGFR3-V555F	FGFR3-S249C+V555F	FGFR3-S249C+V555L
FGFR3-V555L	FGFR3-V555M

In some embodiments, the oncogenic variant of FGFR2 can comprise a gatekeeper mutation resulting in resistance to an existing inhibitor, wherein the gatekeeper mutation is V565I or V565F.

In some embodiments, the oncogenic variant of FGFR3 can comprise a gatekeeper mutation that results in resistance to an existing inhibitor, wherein the gatekeeper mutation is V555M, V555L or V555F.

As used herein, the term "activating mutation" refers to any oncogenic mutation that results in at least one of the following: a) Increased ligand binding of FGFR2 and/or FGFR 3; b) Ligand-independent dimerization and activation of FGFR2 and/or FGFR 3; and c) increased kinase activity of FGFR2 and/or FGFR 3.

In some embodiments, the cancer is a carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, kidney cancer, stomach cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulval cancer, joint cancer, oral cancer, pharyngeal cancer, or colorectal cancer.

In some embodiments, the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, lymphoid tumor diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, acute myelogenous leukemia, brain low-grade glioma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cyst adenocarcinoma, pancreatic carcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinoma sarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, or gastric cancer. Additional examples of cancers include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary tract cancer, esophageal cancer, anal cancer, salivary gland cancer, vulval cancer, cervical cancer, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), adrenal tumor, anal cancer, cholangiocarcinoma, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, primary unknown Cancer (CUP), cancer that spreads to bone, cancer that spreads to brain, cancer that spreads to liver, cancer that spreads to lung, carcinoid, cervical cancer, childhood cancer, chronic Lymphoblastic Leukemia (CLL), chrome Myelogenous Leukemia (CML), colorectal cancer, otic cancer, endometrial cancer, ocular cancer, follicular dendritic cell sarcoma, gall bladder cancer, gastric cancer gastroesophageal junction cancer, germ cell tumor, gestational trophoblastic disease (GIT)), hairy cell leukemia, head and neck cancer, hodgkin's lymphoma, kaposi's sarcoma, renal cancer, laryngeal cancer, leukemia, plastic gastritis, liver cancer, lung cancer, lymphoma, malignant schwannoma, mediastinal germ cell tumor, melanoma skin cancer, male cancer, merck cell skin cancer, mesothelioma, grape gestation, oral and oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor, non-hodgkin's lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma of the peritoneum, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancer, ring cell carcinoma (Signet cell cancer), skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, T cell childhood non-hodgkin's lymphoma (NHL), testicular cancer, thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumor, uterine cancer, vaginal cancer, vulvar cancer, wilms' tumor, uterine cancer (Womb cancer), and gynecological cancer. Examples of cancers also include, but are not limited to, hematological malignancies, lymphomas, cutaneous T-cell lymphomas, peripheral T-cell lymphomas, hodgkin's lymphoma, non-hodgkin's lymphoma, multiple myeloma, chrome lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, merck cell carcinoma, uveal melanoma, or glioblastoma multiforme.

In some embodiments, the cancer is gastric cancer, triple negative breast cancer, melanoma, hepatobiliary cancer, cancer of unknown primary origin, esophageal cancer, cervical cancer, head and neck cancer, CNS cancer, brain cancer, NSCLC, ovarian cancer, breast cancer, soft tissue sarcoma, pancreatic cancer, prostate cancer, renal cell carcinoma, thyroid cancer, lung cancer, bladder cancer, endometrial cancer, intrahepatic bile duct cancer, or glioblastoma.

Definition of the definition

The following terms, as used in the specification and claims, have the following meanings set forth below, unless otherwise specified.

Without wishing to be limited by this statement, it should be understood that while various options for variables are described herein, the present disclosure is intended to encompass operable embodiments having combinations of options. The present disclosure may be interpreted as excluding the non-operable embodiments resulting from certain combinations of options.

It is to be understood that the compounds of the present disclosure may be described in neutral form, cationic form (e.g., carrying one or more positive charges), or anionic form (e.g., carrying one or more negative charges), all of which are intended to be included within the scope of the present disclosure. For example, when a compound of the present disclosure is described in anionic form, it is to be understood that such description also refers to the various neutral, cationic and anionic forms of the compound. For another example, when a compound of the present disclosure is described in anionic form, it is understood that such description also refers to various salts (e.g., sodium salts) of the anionic form of the compound.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, the age, weight, etc., of the mammal being treated.

As used herein, "alkyl", "C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ Or C ₆ Alkyl "or" C ₁ -C ₆ Alkyl "is intended to include C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ Or C ₆ Linear saturated aliphatic hydrocarbon group and C ₃ 、C ₄ 、C ₅ Or C ₆ Branched saturated aliphatic hydrocarbon groups. For example, C ₁ -C ₆ Alkyl is intended to include C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ And C ₆ An alkyl group. Examples of alkyl groups include moieties having from one to six carbon atoms such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, or n-hexyl. In some embodiments, the linear or branched alkyl groups have six or fewer carbon atoms (e.g., C for linear chains ₁ -C ₆ For branched chains C ₃ -C ₆ ) And in another embodiment, the straight or branched chain alkyl groups have four or fewer carbon atoms.

As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having the specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate (phosphinato), phosphinate (phosphinato), amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylaryl amino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto (sulfhydryl), alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate (sulfonato), sulfamoyl (sulfonamoyl), sulfonamide (sulfonamido), nitro, trifluoromethyl, cyano, nitro, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above but containing at least one double bond. For example, the term "alkenyl" includes straight alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, the linear or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C for a linear chain ₂ -C ₆ For branched chains C ₃ -C ₆ ). The term "C ₂ -C ₆ "comprising alkenyl groups containing from two to six carbon atoms". The term "C ₃ -C ₆ "comprising alkenyl groups containing from three to six carbon atoms".

As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or alkenyl group having the specified substituent replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyl groups. In certain embodiments, the linear or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C for a linear chain ₂ -C ₆ For branched chains C ₃ -C ₆ ). The term "C ₂ -C ₆ "comprising alkynyl groups containing from two to six carbon atoms". The term "C ₃ -C ₆ "comprising alkynyl groups containing from three to six carbon atoms". As used herein, "C ₂ -C ₆ Alkenylene linker "or" C ₂ -C ₆ An alkynylene linker "is intended to include C ₂ 、C ₃ 、C ₄ 、C ₅ Or C ₆ A chain (straight or branched) divalent unsaturated aliphatic hydrocarbon group. For example, C ₂ -C ₆ Alkenylene linkers are intended to contain C ₂ 、C ₃ 、C ₄ 、C ₅ And C ₆ Alkenylene linker groups.

As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having the specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio carbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfonic acid, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl groups include those substituted with one or more alkyl groups, such as 2, 6-tetramethyl-piperidinyl and 2, 6-tetramethyl-1, 2,3, 6-tetrahydropyridinyl.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or multicyclic (e.g., fused, bridged or spiro) system having 3 to 30 carbon atoms (e.g., C ₃ -C ₁₂ 、C ₃ -C ₁₀ Or C ₃ -C ₈ ). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3, 4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cycloalkyl groups, only one ring in the cycloalkyl group needs to be non-aromatic.

As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms (e.g., O, N, S, P or Se), such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, or such as 1,2,3,4, 5 or 6 heteroatoms unless otherwise indicated. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thienyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1, 4-diazayl, 1, 4-oxa, 2-oxa-5-azabicyclo [2.2.1] heptyl, 2, 5-diazabicyclo [2.2.1] heptyl, 2-oxa-6-azaspiro [3.3] heptyl, 2, 6-diazaspiro [3.3] heptyl 1, 4-dioxa-8-azaspiro [4.5] decyl, 1, 4-dioxaspiro [4.5] decyl, 1-oxaspiro [4.5] decyl, 1-azaspiro [4.5] decyl, 3 'H-spiro [ cyclohexane-1, 1' -isobenzofuranyl ] -yl, 7'H-spiro [ cyclohexane-1, 5' -furan [3,4-b ] pyridinyl ] -yl, 3 'H-spiro [ cyclohexane-1, 1' -furan [3,4-c ] pyridinyl ] -yl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [3.1.0] hex-3-yl, 1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazolyl, 3,4,5,6, 7-tetrahydro-1H-pyrazolo [4, 4-c ] pyridinyl, 6, 7-tetrahydro-pyrido [3,4, 6-c ] pyridinyl, 7-tetrahydropyrido, 3, 4-c-pyridinyl, 7-tetrahydropyr [3,4-c ] pyrimidinyl, 2-azaspiro [3.3] heptyl, 2-methyl-2-azaspiro [3.3] heptyl, 2-aza [3.5] nonyl, 2-methyl-2-azaspiro [3.5] nonyl, 2-azaspiro [4.5] decyl, 2-methyl-2-azaspiro [4.5] decyl, 2-oxaazaspiro [3.4] octyl-6-yl and the like. In the case of polycyclic heterocycloalkyl groups, only one ring in the heterocycloalkyl group needs to be non-aromatic (e.g., 4,5,6, 7-tetrahydrobenzo [ c ] isoxazolyl).

As used herein, the term "aryl" includes groups having aromatic character, including "conjugated" or polycyclic ring systems having one or more aromatic rings, and not including any heteroatoms in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. Conveniently, the aryl group is phenyl.

As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic aromatic heterocycles or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycles consisting of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4,5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S (O) _p Where p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic, thereby forming a polycyclic ring system (e.g., 4,5,6, 7-tetrahydrobenzo [ c ] ]Isoxazolyl).

Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings may be substituted at one or more ring positions (e.g., a ring-forming carbon or heteroatom such as N) with such substituents as described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthio, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylaryl amino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, nitro, heterocyclyl, heteroaryl, aryl, heteroaryl, or aromatic moieties. Aryl and heteroaryl groups may also be fused or bridged with alicyclic rings or heterocycles that are not aromatic, so as to form a polycyclic ring system (e.g., tetrahydronaphthalene, methylenedioxyphenyl such as benzo [ d ] [1,3] dioxol-5-yl).

As described herein, the term "substituted" means that any one or more hydrogen atoms on a given atom is replaced by a selection from the indicated group, provided that the normal valency of the given atom is not exceeded, and that the substitution forms a stable compound. When the substituent is oxo or keto (i.e., =o), then 2 hydrogen atoms on the atom are replaced. The keto substituent is not present on the aromatic moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., c= C, C =n or n=n). By "stable compound" and "stable structure" is meant a compound that is sufficiently robust to be isolated to a useful degree of purity from the reaction mixture and formulated into an effective therapeutic agent.

When a bond on a substituent shows a bond that intersects two atoms in the connecting ring, then such substituent may be bonded to any atom in the ring. When substituents are listed without indicating the atoms through which such substituents are bonded to the remainder of a compound of a given formula, then such substituents may be bonded through any atom in such formula. Combinations of substituents and/or variables are permissible, provided that such combinations result in stable compounds.

When any variable (e.g., R) occurs more than one time in the formula of any ingredient or compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2R moieties, the group may optionally be substituted with up to two R moieties, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and/or variables are permissible, provided that such combinations result in stable compounds.

As used herein, the term "hydroxy" or "hydroxyl" includes compounds having the formula-OH or-O ^- Is a group of (2).

As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms.

As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl group having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate (phosphinato), phosphinate (phosphinato), amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylaryl amino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto (sulfhydryl), alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate (sulfonato), sulfamoyl (sulfonamoyl), sulfonamide (sulfonamido), nitro, trifluoromethyl, cyano, nitro, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term "alkoxy" or "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups (alkoxy groups or alkoxyl groups) include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy and pentoxy. Examples of substituted alkoxy groups include haloalkoxy groups. The alkoxy group may be substituted with groups such as: alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio carbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

As used herein, the expressions "one or more of A, B or C", "one or more of A, B or C", "one or more of A, B and C", "one or more of A, B and C", "selected from the group consisting of A, B and C", "selected from A, B and C", and the like are used interchangeably and all refer to the group consisting of A, B and/or C, i.e., one or more a, one or more B, one or more C, or any combination thereof, unless otherwise indicated.

It is to be understood that the present disclosure provides methods for synthesizing compounds of any of the formulae described herein. The present disclosure also provides detailed methods for synthesizing the various disclosed compounds of the present disclosure according to the schemes described below and those shown in the examples.

It should be understood that throughout the description, when a composition is described as having, comprising or containing a particular component, it is contemplated that the composition also consists essentially of or consists of that component. Similarly, when a method or process is described as having, comprising or including a particular process step, the process also consists essentially of or consists of the process step. Further, it should be understood that the order of steps or order of performing certain actions is immaterial so long as the disclosure remains operable. Furthermore, two or more steps or actions may be performed simultaneously.

It is to be understood that the synthetic methods of the present disclosure can tolerate a wide variety of functional groups, and thus a wide variety of substituted starting materials can be used. The method provides substantially the desired final compound at or near the end of the entire process, but for some cases it may be desirable to further convert the compound to a pharmaceutically acceptable salt thereof.

It is to be understood that the compounds of the present disclosure may be prepared in various ways using commercially available starting materials, compounds known in the literature or from readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art or which will be apparent to those skilled in the art in view of the teachings herein. Standard synthetic methods and procedures for organic molecule preparation and functional group transformation and manipulation can be obtained from the relevant scientific literature or from standard textbooks in the art. Although not limited to any one or several sources, classical text such as Smith, m.b., march, j., "macchiato et al organic chemistry: reactions, mechanisms and structures (March's Advanced Organic Chemistry: reactions, mechanisms and Structure), 5 th edition, john Willi parent-child: new york, 2001; greene, t.w., wuts, p.g.m., protecting group in organic synthesis (Protective Groups in Organic Synthesis), 3 rd edition, john wili parent-child company: new york, 1999; larock, comprehensive organic transformation (Comprehensive Organic Transformations), VCH Press, (1989); fieser and M.Fieser, fisher and Fisher reagents for organic synthesis (Fieser and Fieser's Reagents for Organic Synthesis), john Willi father-son company (1994); and l.paquette, encyclopedia of reagents for organic synthesis (Encyclopedia of Reagents for Organic Synthesis), john wili parent-child company (1995) are useful and well-recognized organic synthesis reference textbooks known to those skilled in the art.

One of ordinary skill in the art will note that the order of certain steps may be altered, such as the introduction and removal of protecting groups, during the reaction sequence and synthesis schemes described herein. One of ordinary skill in the art will recognize that certain groups may need to be protected from the reaction conditions via the use of protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. List of protecting groups and how to introduce and remove these groups can be found in t.w., wuts, p.g.m. (Protective Groups in Organic Synthesis) protecting groups in organic synthesis, 3 rd edition, john wili parent-child company: new York, 1999.

It is to be understood that any description of the methods of treatment includes the use of the compounds to provide such treatment or prevention as described herein, as well as the use of the compounds to prepare medicaments for the treatment or prevention of such conditions, unless otherwise indicated. Treatment includes treatment of human or non-human animals, including rodents and other disease models.

As used herein, the term "subject" includes both human and non-human animals, as well as cell lines, cell cultures, tissues and organs. In some embodiments, the subject is a mammal. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. The subject may also be a bird or poultry. In some embodiments, the subject is a human.

As used herein, the term "subject in need thereof" refers to a subject suffering from a disease or having an increased risk of developing the disease. A subject in need thereof may be a subject that has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof may also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof may be a subject having an increased risk of developing a disease or disorder relative to the general population (i.e., a subject susceptible to developing such disorder relative to the general population). A subject in need thereof may have a refractory or drug resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that is or has not responded to treatment). The subject may be resistant at the beginning of the treatment or may become resistant during the treatment. In some embodiments, a subject in need thereof receives all known effective therapies for the diseases or conditions disclosed herein but fails to treat. In some embodiments, the subject in need thereof receives at least one prior therapy.

As used herein, the term "treatment (treating or treat)" describes the management and care of a patient in order to combat a disease, condition, or disorder, and includes administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate symptoms or complications of, or eliminate the disease, condition, or disorder. The term "treatment" may also include treatment of cells or animal models in vitro.

It will be appreciated that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs, or solvates thereof, may or may not also be useful in the prevention of a related disease, condition, or disorder, or in the identification of suitable candidates for such purposes.

As used herein, the term "prevent (preventing or prevent)" or "prevent (protecting against)" describes reducing or eliminating the onset of symptoms or complications of such diseases, conditions, or disorders.

All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will be apparent from the different examples. The examples provided illustrate different components and methods useful in practicing the present disclosure. The examples do not limit the disclosure as claimed. Based on the present disclosure, a skilled artisan can identify and employ other components and methods useful in practicing the present disclosure.

In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such specific configurations should not be construed as limiting the disclosure to one or more isomers, tautomers, positional isomers or stereoisomers nor excluding isomers, tautomers, positional isomers or mixtures of stereoisomers; however, it is understood that a given isomer, tautomer, positional isomer or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer or stereoisomer.

It should be appreciated that those skilled in the art can refer to the general reference text for a detailed description of known techniques or equivalent techniques discussed herein. These texts include Ausubel et al, current protocols for molecular biology (Current Protocols in Molecular Biology), john wili parent company (2005); sambrook et al, molecular cloning (Molecular Cloning), laboratory handbook (A Laboratory Manual) (3 rd edition), cold spring harbor press, cold spring harbor, new york city (2000); coligan et al, current immunology protocol (Current Protocols in Immunology), john Willi parent, new York City; enna et al, current pharmacological protocol (Current Protocols in Pharmacology), john Willi parent, new York City; fingl et al (The Pharmacological Basis of Therapeutics) on the pharmacological basis of therapeutics (1975), remington's Pharmaceutical Sciences, mich publishing company, iston, pa.18 th edition (1990). Of course, reference may also be made to these texts in making or using aspects of the disclosure.

It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein and at least one pharmaceutically acceptable excipient or carrier.

As used herein, the term "pharmaceutical composition" is a formulation comprising a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms including, for example, a capsule, an intravenous bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of a disclosed compound or salt, hydrate, solvate, or isomer thereof) in a unit dose of the composition is an effective amount and varies depending on the particular treatment involved. Those skilled in the art will appreciate that it is sometimes necessary to make routine changes to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers or propellants which may be required.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, anions, cations, materials, compositions, carriers, 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.

As used herein, the term "pharmaceutically acceptable excipient" refers to excipients that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic and biologically or otherwise desirable, and include excipients acceptable for veterinary use and for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipients" include one and more than one such excipient.

It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents, such as water for injection, saline solutions, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine tetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for modulating tonicity, such as sodium chloride or dextrose. The pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be packaged in ampules, disposable syringes or multiple dose vials made of glass or plastic.

It will be appreciated that the compounds or pharmaceutical compositions of the present disclosure may be administered to a subject in a number of well known methods currently used in chemotherapy treatment. For example, the compounds of the present disclosure may be injected into the blood stream or body cavity, or taken orally, or applied through the skin with a patch. The dose selected should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The patient's disease condition (e.g., a disease or disorder disclosed herein) and health condition should preferably be monitored intimately during and for a reasonable period of time after treatment.

As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent that is used to treat, ameliorate or prevent a defined disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The precise effective amount of the subject will depend on the weight, size and health of the subject; the nature and extent of the pathology; and selecting a treatment or combination of treatments for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

It will be appreciated that for any compound, a therapeutically effective amount may be estimated initially in a cell culture assay, such as tumor cells, or in an animal model (typically rat, mouse, rabbit, dog or pig). Animal models can also be used to determine the appropriate concentration ranges and application routesAnd (3) diameter. Such information can then be used to determine useful dosages and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity can be achieved by cell culture or standard pharmaceutical procedures in laboratory animals such as ED ₅₀ (dose effective for 50% of population treatment) and LD ₅₀ (dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD ₅₀ /ED ₅₀ . Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending upon the dosage form employed, the sensitivity of the patient and the route of administration.

The dosage and administration are adjusted to provide a sufficient level of active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combination, response sensitivity, and tolerance/response to therapy. The long acting pharmaceutical composition may be administered every 3 to 4 days, weekly or bi-weekly, depending on the half-life and clearance of the particular formulation.

Pharmaceutical compositions comprising the active compounds of the present disclosure may be manufactured in a generally known manner, for example by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Of course, the appropriate formulation will depend on the route of administration selected.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, cremophor EL ^TM (BASF, pasiposide, n.j.), or Phosphate Buffered Saline (PBS). In all cases, the composition must be sterile and should be of the order in which it is usedTo the extent that there is a fluid that is easily injectable. It must be stable under the conditions of production and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition agents which delay absorption (e.g., aluminum monostearate and gelatin).

Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active compound in a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser (which contains a suitable propellant, e.g., a gas such as carbon dioxide), or nebulizer.

Systemic administration may also be performed by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, detergents for transmucosal administration, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated as ointments, salves, gels, or creams, as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid may be used. Methods for preparing such formulations will be apparent to those skilled in the art as such materials are also commercially available from Alza Corporation and Nova Pharmaceuticals company. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in dosage unit form. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for subjects to be treated; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect with the desired pharmaceutical carrier. The specifications of the dosage unit forms of the present disclosure are determined by and directly dependent upon the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosage of the pharmaceutical composition used according to the present disclosure varies depending on the agent, the age, weight and clinical condition of the patient being treated, and experience and judgment of the clinician or practitioner administering the therapy, as well as other factors affecting the selected dosage. Generally, the dosage should be sufficient to cause a slowing, and preferably regression, of the symptoms of the diseases or disorders disclosed herein, and also preferably a complete regression of the disease or disorder. The dosage may be in the range of about 0.01mg/kg per day to about 5000mg/kg per day. In a preferred aspect, the dosage may be in the range of about 1mg/kg per day to about 1000mg/kg per day. In one aspect, the dosage will be in the range of about 0.1 mg/day to about 50 g/day, about 0.1 mg/day to about 25 g/day, about 0.1 mg/day to about 10 g/day, about 0.1mg to about 3 g/day, or about 0.1mg to about 1 g/day in single, divided, or continuous doses (which may be in m depending on the weight of the patient in kg) ² Body surface area and age in years). An effective amount of the pharmaceutical agent is an amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. An increase in survival and growth indicates degradation. As used herein, the term "dose-effective manner" refers to the amount of active compound that produces a desired biological effect in a subject or cell.

It will be appreciated that the pharmaceutical composition may be contained in a container, package or dispenser together with instructions for administration.

It is to be understood that all such forms are also contemplated to be within the scope of the claimed disclosure for compounds of the present disclosure capable of further salt formation.

As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present disclosure, wherein the parent compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, basic or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, non-toxic salts derived from inorganic and organic acids selected from the group consisting of: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1, 2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylphenylarsonic acid, hexylresorcinol acid, hydrabamic acid (hydrabamic), hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid (napsylic acid), nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, sulfurous acid, succinic acid, sulfamic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and common amino acids, such as glycine, alanine, phenylalanine, arginine, and the like.

In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt.

Other examples of pharmaceutically acceptable salts include caproic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2] -oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when acidic protons present in the parent compound are replaced with metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

It is to be understood that all references to pharmaceutically acceptable salts include solvent-added forms (solvates) or crystalline forms (polymorphs) as defined herein of the same salt.

The compound or pharmaceutically acceptable salt thereof is administered orally, nasally, transdermally, pulmonary, inhaled, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

The dosage regimen utilizing the compound is selected in accordance with a variety of factors including the type, kind, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; route of administration; renal function or liver function in the patient; and the specific compound or salt thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the patient.

Techniques for formulating and administering the disclosed compounds of the present disclosure can be found in "leimington: pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), 19 th edition, iston, pa., mack Publishing Co., easton, pa., 1995. In embodiments, the compounds described herein and pharmaceutically acceptable salts thereof are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

As the skilled artisan will appreciate, the FGFR2 gene is commonly referred to as one of FGFR2, fibroblast growth factor receptor 2, BEK, JWS, BBDS, CEK, CFD1, ECT1, KGFR, TK14, TK25, BFR-1, CD332, cluster of differentiation 332, and K-SAM. Thus, these terms are used interchangeably herein to refer to FGFR2 genes.

As will be appreciated by those of skill in the art, the FGFR2 protein encoded by the FGFR2 gene is commonly referred to as one of FGFR2, fibroblast growth factor receptor 2, BEK, JWS, BBDS, CEK3, CFD1, ECT1, KGFR, TK14, TK25, BFR-1, CD332, cluster of differentiation 332, and K-SAM. Thus, these terms are used interchangeably herein to refer to FGFR2 proteins.

As used herein, the term FGFR2 may refer to any isoform of FGFR2 protein, including, but not limited to FGFR2-IIIB and FGFR2-IIIC.

As the skilled artisan will appreciate, the FGFR3 gene is commonly referred to as one of FGFR3, fibroblast growth factor receptor 3, ACH, CD333, cluster of differentiation 333, CEK2, HSFGFR3EX, and JTK 4. Thus, these terms are used interchangeably herein to refer to the BRAF gene.

As the skilled artisan will appreciate, the FGFR3 protein encoded by the FGFR3 gene is commonly referred to as one of FGFR3, fibroblast growth factor receptor 3, ACH, CD333, cluster of differentiation 333, CEK2, HSFGFR3EX, and JTK 4. Thus, these terms are used interchangeably herein to refer to FGFR3 proteins.

All publications and patent documents cited herein are incorporated by reference as if each such publication or document were specifically and individually indicated to be incorporated by reference. Citation of publications and patent documents is not intended as an admission that any of them is pertinent prior art, nor does it constitute any admission as to the contents or date thereof. Having now described the present disclosure by way of written description, those skilled in the art will recognize that the present disclosure may be practiced in various embodiments, and that the foregoing description and the following examples are for purposes of illustration and not of limitation, the claims that follow.

Exemplary embodiments

Embodiment 1. A compound of formula (I'):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

W ⁴ is C (R) ^W4 ) Or N;

W ⁵ is C (R) ^W5 ) Or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) (-NHC)C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein-NH (C ₁ -C ₆ Alkyl), -NHC (=o) (C ₁ -C ₆ Haloalkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) H, -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^3a Substitution;

each R ^3a Independently halogen, cyano, oxo, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or 5 to10 membered heteroaryl, wherein NHC (=o) O (C ₁ -C ₆ Alkyl) optionally substituted with one or more halogens;

R ⁵ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁶ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

Embodiment 2. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

Embodiment 3. The compound of any one of the preceding embodiments, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

Embodiment 4. The compound of any one of the preceding embodiments, wherein:

Each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogenCyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

Embodiment 5. The compound of any of the preceding embodiments, whereinIs->

Embodiment 6. The compound of any of the preceding embodiments, whereinIs->

Implementation prescriptionCase 7. Compounds according to any one of the preceding embodiments, whereinIs that

Embodiment 8. The compound of any of the preceding embodiments, wherein Is->

Embodiment 9. The compound of any of the preceding embodiments, whereinIs that

Embodiment 10. The compound of any one of the preceding embodiments, whereinIs that

Embodiment 11. The compound of any one of the preceding embodiments, wherein R ¹ H.

Embodiment 12. The compound of any of the preceding embodiments, wherein R ¹ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

Embodiment 13. The compound of any of the preceding embodiments, whereinR ¹ Is C ₁ -C ₆ An alkyl group.

Embodiment 14. The compound of any of the preceding embodiments, wherein R ¹ Is CH ₃ 。

Embodiment 15. The compound of any of the preceding embodiments, wherein R ² H.

Embodiment 16. The compound of any of the preceding embodiments, wherein R ² Is halogen, cyano or C ₁ -C ₆ An alkyl group.

Embodiment 17 the compound of any one of the preceding embodiments, wherein R ³ H.

Embodiment 18. The compound of any one of the preceding embodiments, wherein R ³ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

Embodiment 19 the compound of any one of the preceding embodiments, wherein R ³ Is halogen.

Embodiment 20. The compound of any of the preceding embodiments, wherein R ³ Is Cl.

Embodiment 21. The compound of any one of the preceding embodiments, wherein R ³ Is C ₁ -C ₆ An alkyl group.

Embodiment 22. The compound of any of the preceding embodiments, wherein R ³ Is CH ₃ 。

Embodiment 23. The compound of any one of the preceding embodiments, wherein R ⁴ H.

Embodiment 24. The compound of any of the preceding embodiments, wherein R ⁴ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

Embodiment 25. The compound of any of the preceding embodiments, wherein R ⁴ Is halogen.

Embodiment 26. The compound of any of the preceding embodiments, wherein R ⁴ Is Cl.

Embodiment 27. The compound of any one of the preceding embodiments, wherein R ⁴ Is C ₁ -C ₆ An alkyl group.

Embodiment 28 the compound of any one of the preceding embodiments, wherein R ⁴ Is CH ₃ 。

Embodiment 29. The compound of any of the preceding embodiments wherein Y is absent.

Embodiment 30. The compound of any of the preceding embodiments, wherein Y is C optionally substituted with one or more oxo or-OH ₁ -C ₆ An alkyl group.

Embodiment 31 the compound of any one of the preceding embodiments wherein Y is C ₁ -C ₆ An alkyl group.

Embodiment 32. The compound of any of the preceding embodiments wherein Y is-CH ₂ -。

Embodiment 33. The compound of any one of the preceding embodiments, wherein Y is C substituted with one or more-OH groups ₁ -C ₆ An alkyl group.

Embodiment 34. The compound of any of the preceding embodiments, wherein Z is H.

Embodiment 35. The compound of any one of the preceding embodiments, wherein Z is C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Z And (3) substitution.

Embodiment 36. The compound of any of the preceding embodiments wherein Z is azetidinyl or oxetanyl, wherein azetidinyl or oxetanyl is optionally substituted with one or more R ^Z And (3) substitution.

Embodiment 37. A compound of any one of the preceding embodiments wherein Z is azetidinyl or oxetanyl.

Embodiment 38. The compound of any of the preceding embodiments wherein Z is pyrrolidinyl or tetra Hydrofuranyl, wherein pyrrolidinyl or tetrahydrofuranyl is optionally substituted with one or more R ^Z And (3) substitution.

Embodiment 39. A compound according to any of the preceding embodiments wherein Z is pyrrolidinyl or tetrahydrofuranyl.

Embodiment 40. The compound of any of the preceding embodiments, wherein Z is piperidinyl or tetrahydropyranyl, wherein piperidinyl or tetrahydropyranyl is optionally substituted with one or more R ^Z And (3) substitution.

Embodiment 41. A compound of any of the preceding embodiments, wherein Z is piperidinyl or tetrahydropyranyl.

Embodiment 42. The compound according to any one of the preceding embodiments, wherein at least one R ^Z Oxo, halogen, cyano, -OH.

Embodiment 43. The compound of any one of the preceding embodiments, wherein at least one R ^Z Is NH ₂ 、NH(C ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Wherein NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Optionally by one or more R ^Za And (3) substitution.

Embodiment 44. The compound of any one of the preceding embodiments, wherein at least one R ^Z To optionally be covered by one or more R ^Za substituted-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

Embodiment 45. The compound of any of the preceding embodiments, wherein at least one R ^Z is-C (=O) - (C) ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl), wherein-C (=o) - (C ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl) optionally substituted with one or more R ^Za And (3) substitution.

Embodiment 46. The compound of any of the preceding embodiments, wherein at least one R ^Z is-C (=o) -ch=ch ₂ 。

Implementation prescriptionA compound according to any one of the preceding embodiments, wherein at least one R ^Z Is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy is optionally substituted with one or more R ^Za And (3) substitution.

Embodiment 48. The compound of any one of the preceding embodiments, wherein at least one R ^Z To optionally be covered by one or more R ^Za Substituted C ₁ -C ₆ An alkyl group.

Embodiment 49 the compound of any one of the preceding embodiments, wherein at least one R ^Z Is C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Za And (3) substitution.

Embodiment 50. The compound according to any one of the preceding embodiments, wherein at least one R ^Za Oxo, halogen, cyano or-OH.

Embodiment 51. The compound of any of the preceding embodiments, wherein at least one R ^Za Is NH ₂ 、NH(C ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Wherein NH (C) ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ Optionally by one or more R ^Zb And (3) substitution.

Embodiment 52 the compound of any of the preceding embodiments wherein at least one R ^Za To optionally be covered by one or more R ^Zb substituted-S (=o) ₂ -(C ₁ -C ₆ Alkyl).

Embodiment 53. The compound of any one of the preceding embodiments wherein at least one R ^Za is-C (=O) - (C) ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl group)wherein-C (=O) - (C) ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl) optionally substituted with one or more R ^Zb And (3) substitution.

Embodiment 54. The compound of any of the preceding embodiments, wherein at least one R ^Za is-C (=o) -ch=ch ₂ 。

Embodiment 55. The compound of any one of the preceding embodiments, wherein at least one R ^Za Is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ Alkoxy is optionally substituted with one or more R ^Zb And (3) substitution.

Embodiment 56. The compound of any of the preceding embodiments, wherein at least one R ^Za Is C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Zb And (3) substitution.

Embodiment 57. The compound of any one of the preceding embodiments, wherein at least one R ^Zb Oxo, halogen, cyano or-OH.

Embodiment 58. The compound of any of the preceding embodiments, wherein at least one R ^Zb Is NH ₂ 、NH(C ₁ -C ₆ Alkyl) or N (C) ₁ -C ₆ Alkyl group ₂ 。

Embodiment 59. The compound of any one of the preceding embodiments, wherein at least one R ^Zb is-S (=O) ₂ -(C ₁ -C ₆ Alkyl).

Embodiment 60. The compound of any one of the preceding embodiments, wherein at least one R ^Zb is-C (=O) - (C) ₁ -C ₆ Alkyl) or-C (=o) - (C ₂ -C ₆ Alkenyl).

Description of the embodiments61. The compound according to any one of the preceding embodiments, wherein at least one R ^Zb is-C (=o) -ch=ch ₂ 。

Embodiment 62. A compound of any one of the preceding embodiments, wherein at least one R ^Zb Is C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ An alkoxy group.

Embodiment 63 a compound of any one of the preceding embodiments having formula (I-a), (I-b), (I-c), or (I-d):

or a pharmaceutically acceptable salt or stereoisomer thereof.

Embodiment 64 the compound of any one of the preceding embodiments having formula (II):

Or a pharmaceutically acceptable salt or stereoisomer thereof.

Embodiment 65. A compound of any one of the preceding embodiments having formula (II-a), (II-b), (II-c), or (II-d):

/>

or a pharmaceutically acceptable salt or stereoisomer thereof.

Embodiment 66. A compound according to any one of the preceding embodiments, selected from the group consisting of the compounds described in tables I and II, or a pharmaceutically acceptable salt or stereoisomer thereof.

Embodiment 67. An isotopic derivative of the compound of any one of the preceding embodiments.

Embodiment 68. A method of preparing a compound of any of the preceding embodiments.

Embodiment 69. A pharmaceutical composition comprising a compound of any of the preceding embodiments and one or more pharmaceutically acceptable carriers or excipients.

Embodiment 70. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of any of the preceding embodiments.

Embodiment 71 the compound of any of the preceding embodiments for use in treating or preventing cancer in a subject.

Embodiment 72 the use of a compound according to any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject.

Embodiment 73 the use of a compound according to any one of the preceding embodiments for treating or preventing cancer in a subject.

Embodiment 74. The method, compound or use according to any of embodiments 70-73, wherein the subject is a human.

Embodiment 75. The method, compound or use according to any one of embodiments 70-74, wherein the subject has previously undergone at least one round of anti-cancer therapy.

Embodiment 76 the method, compound or use of any of embodiments 70-75, wherein said cancer is characterized by at least one oncogenic mutation in said FGFR2 gene.

Embodiment 77 the method, compound or use according to any of embodiments 70-75, wherein said cancer is characterized by at least one oncogenic mutation in the FGFR3 gene.

Embodiment 78. The method, compound or use according to any one of embodiments 70-75, wherein the cancer is characterized by overexpression of an FGFR2 gene.

Embodiment 79. The method, compound or use according to any one of embodiments 70-75, wherein said cancer is characterized by overexpression of an FGFR3 gene.

Embodiment 80. The method, compound or use according to any one of embodiments 70-75, wherein the cancer is characterized by at least one oncogenic variant of FGFR 2.

Embodiment 81 the method, compound or use according to any of embodiments 70-75, wherein the cancer is characterized by at least one oncogenic variant of FGFR 3.

Embodiment 82. The method, compound or use according to any one of embodiments 70-75, wherein the cancer is characterized by overexpression of FGFR 2.

Embodiment 83 the method, compound or use of any of embodiments 70-75, wherein the cancer is characterized by overexpression of FGFR 3.

Embodiment 84. The method, compound, or use of any of embodiments 70-83, wherein the cancer is cancer, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, kidney cancer, stomach cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulval cancer, joint cancer, oral cancer, pharyngeal cancer, or colorectal cancer.

Embodiment 85 the method, compound, or use of any of embodiments 70-83, wherein the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, lymphoid tumor diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, acute myelogenous leukemia, brain low-grade glioma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cyst adenocarcinoma, pancreatic carcinoma, pheochromocytoma, paraganglioma, prostate carcinoma, rectal adenocarcinoma, sarcoma, skin melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinoma sarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, kidney cancer, or gastric cancer. Additional examples of cancers include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary tract cancer, esophageal cancer, anal cancer, salivary gland cancer, vulval cancer, cervical cancer, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), adrenal tumor, anal cancer, cholangiocarcinoma, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, primary unknown Cancer (CUP), cancer that spreads to bone, cancer that spreads to brain, cancer that spreads to liver, cancer that spreads to lung, carcinoid, cervical cancer, childhood cancer, chronic Lymphoblastic Leukemia (CLL), chrome Myelogenous Leukemia (CML), colorectal cancer, otic cancer, endometrial cancer, ocular cancer, follicular dendritic cell sarcoma, gall bladder cancer, gastric cancer gastroesophageal junction cancer, germ cell tumor, gestational trophoblastic disease (GIT)), hairy cell leukemia, head and neck cancer, hodgkin's lymphoma, kaposi's sarcoma, renal cancer, laryngeal cancer, leukemia, plastic gastritis, liver cancer, lung cancer, lymphoma, malignant schwannoma, mediastinal germ cell tumor, melanoma skin cancer, male cancer, merck cell skin cancer, mesothelioma, grape gestation, oral and oropharyngeal cancer, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor, non-hodgkin's lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma of the peritoneum, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancer, ring cell carcinoma (Signet cell cancer), skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, T cell childhood non-hodgkin's lymphoma (NHL), testicular cancer, thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumor, uterine cancer, vaginal cancer, vulvar cancer, wilms' cell tumor, uterine cancer, and gynecological cancer. Examples of cancers also include, but are not limited to, hematological malignancies, lymphomas, cutaneous T-cell lymphomas, peripheral T-cell lymphomas, hodgkin's lymphoma, non-hodgkin's lymphoma, multiple myeloma, chrome lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid cancer, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, merck cell carcinoma, uveal melanoma, or glioblastoma multiforme.

Embodiment 86 the method, compound, or use of any of embodiments 70-83, wherein the cancer is gastric cancer, triple negative breast cancer, melanoma, hepatobiliary cancer, primary foci of cancer, esophageal cancer, cervical cancer, head and neck cancer, CNS cancer, brain cancer, NSCLC, ovarian cancer, breast cancer, soft tissue sarcoma, pancreatic cancer, prostate cancer, renal cell carcinoma, thyroid cancer, lung cancer, bladder cancer, endometrial cancer, intrahepatic cholangiocarcinoma, or glioblastoma.

Examples

For exemplary purposes, salts of the compounds of formula (I') and (I) were synthesized and tested in the examples. It will be appreciated that neutral compounds of formulae (I') and (I) can be synthesized and tested similarly using the exemplary procedure described in the examples. Furthermore, it will be appreciated that salts of the compounds of formulae (I') and (I) (e.g., sodium salts) can be converted to the corresponding neutral compounds using techniques conventional in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).

The compounds of formulas (I') and (I) may be prepared using the methods detailed herein. Those skilled in the art can use a variety of starting materials and reagents to prepare the disclosed compounds of formulas (I') and (I) and make further modifications to be able to envisage alternative synthetic routes. For exemplary purposes, salts of some of the compounds of formulas (I') and (I) were synthesized and tested in the examples. It will be appreciated that neutral compounds of formulae (I') and (I) can be synthesized and tested similarly using the exemplary procedure described in the examples. Furthermore, it will be appreciated that salts of the compounds of formula (I') and (I) (e.g., hydrochloride salts) may be converted to the corresponding neutral compounds using techniques conventional in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).

Abbreviations:

aq. Water-based

ACN: acetonitrile

¹ H NMR proton NMR spectroscopy

CDCl ₃ Deuterated chloroform

DCM dichloromethane

DMF: n, N-dimethylformamide

DMSO-d ₆ Hexadeuterated dimethyl sulfoxide

EtOAc ethyl acetate

eq. Equivalent weight

h hours

HPLC high performance liquid chromatography

LC-MS liquid chromatography-mass spectrometry

min

Preparative HPLC preparative high performance liquid chromatography

Et ₃ N-triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Y yield (%)

Synthesis of intermediates

Intermediates 1 and 34: 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline and 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

Step 1.4- (p-toluenesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (500 mg,2.48 mmol) in dichloromethane (10 mL) was added triethylamine (754 mg,7.45 mmol) and p-toluenesulfonyl chloride (947 mg,4.97 mmol). The mixture was stirred at 25℃for 16 hours. After completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with 1M hydrochloric acid (10 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 3/1) to give tert-butyl 4- (p-toluenesulfonyloxy) piperidine-1-carboxylate (600 mg,1.69mmol, 67%) as a white solid.

Step 2.4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] piperidine-1-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (10 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (1 g,1.97 mmol) was added cesium carbonate (1.29 g,3.94 mmol) and tert-butyl 4- (p-toluenesulfonyloxy) piperidine-1-carboxylate (841 mg,2.37 mmol). The mixture was stirred at 80℃for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester (2 g, crude). ¹ H NMR(400MHz,CD ₃ OD)δ9.29(d,J＝2.8Hz,1H),8.76(s,1H),8.48(s,1H),7.74(dd,J＝7.2,8.8Hz,1H),7.56(d,J＝8.0Hz,1H),7.48(dd,J＝9.2,11.2Hz,1H),7.38(dd,J＝2.0,13.8Hz,1H),7.23-7.16(m,1H),5.79-5.64(m,2H),4.38(d,J＝13.2Hz,2H),3.80-3.56(m,4H),2.29-2.08(m,4H),1.62-1.54(m,9H),1.08-0.81(m,2H),0.13-0.08(m,9H)；m/z ES+[M+H] ⁺ 690.4。

Step 3.2- [ [6- [ 5-chloro-3- [1- (4-piperidinyl) pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (20 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of tert-butyl piperidine-1-carboxylate (2 g,2.90 mmol) was added trifluoroacetic acid (4 mL). The mixture was stirred at 25℃for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 50% -55%,10 min) purification to give 2- [ [6- [ 5-chloro-3- [1- (4-piperidinyl) pyrazol-4-yl ] as a yellow solid]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (700 mg,1.19mmol, 41%). ¹ H NMR(400MHz,CD ₃ OD):δ＝9.28(s,1H),8.73(s,1H),8.46(s,1H),8.08-7.93(m,1H),7.77-7.70(m,1H),7.54-7.43(m,1H),7.40-7.38(m,1H),7.32-7.08(m,1H),5.82-5.59(m,2H),4.62-4.45(m,1H),3.83-3.60(m,2H),3.40-3.17(m,2H),2.99-2.86(m,2H),2.77(d,J＝6.4Hz,3H),2.37-2.26(m,2H),1.09-0.83(m,2H),0.08(s,9H)；m/z ES+[M+H] ⁺ 590.1。

Intermediate 2:2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidine-1-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (20 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (2 g,3.94 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (1.67 g,5.92 mmol) was added potassium carbonate (1.09 g,7.89 mmol). The mixture was stirred at 60 ℃ 32h. The reaction mixture was quenched by the addition of water (200 mL) at 20 ℃, then diluted with ethyl acetate (200 mL) and extracted with ethyl acetate (200 ml×3). The combined organic layers were washed with water (100 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Azetidine-1-carboxylic acid tert-butyl ester (2.70 g,3.67mmol, 93%). M/zES + [ M+H ]] ⁺ 662.4。

Step 2.2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (2 mL) and dichloromethane (20 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of tert-butyl azetidine-1-carboxylate (2.5 g,3.77 mmol) was stirred at 25℃for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate (50 mL) at 25 ℃, then diluted with dichloromethane (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with water (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid ]Imidazol-6-yl) oxy) quinoxaline (2.0 g,2.49mmol, 66%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.48-9.37(m,1H),9.27-9.01(m,1H),8.86(s,1H),8.60(s,1H),8.07(d,J＝9.2Hz,1H),7.84(d,J＝9.2Hz,1H),7.56-7.48(m,2H),7.31(dd,J＝2.4,8.8Hz,1H),5.66-5.49(m,1H),4.70(s,1H),4.60-4.39(m,4H),4.02(q,J＝7.2Hz,2H),1.98(s,2H)；m/z ES+[M+H] ⁺ 562.4。

Intermediate 3:5- (((tert-butyldiphenylsilyl) oxy) methyl) -1, 2-thiazine-1, 1-dioxide

Step 1.2- (cyanomethyl) acrylic acid methyl ester

Tetrabutylammonium fluoride (1M in THF, 128.48 mL) was added dropwise to a solution of methyl 2- (bromomethyl) acrylate (23.0 g,128 mmol), trimethylsilyl carbonitrile (12.7 g,128 mmol) in acetonitrile (500 mL) at 25℃and the mixture stirred at 25℃for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1) to give methyl 2- (cyanomethyl) acrylate (13.0 g,103mmol, 80%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ6.40(d,J＝0.8Hz,1H),6.01(s,1H),3.75(d,J＝0.8Hz,3H),3.35(s,2H)。

Step 2.3- (benzylthio) -2- (cyanomethyl) propanoic acid methyl ester

To a solution of methyl 2- (cyanomethyl) acrylate (6.50 g,51.9 mmol) in tetrahydrofuran (80 mL) was added triethylamine (15.7 g,155 mmol) and phenylmethanethiol (7.74 g,62.3 mmol), and the mixture was stirred at 20℃for 1 hour. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=30:1 to 15:1) to give methyl 3- (benzylthio) -2- (cyanomethyl) propionate (22.0 g,88.2mmol, 85%) as a colorless oil.

Step 3.4-amino-2- ((benzylthio) methyl) butan-1-ol

Lithium aluminum hydride (4.57 g,120 mmol) was added carefully in portions to a solution of methyl 3- (benzylthio) -2- (cyanomethyl) propanoate (10.0 g,40.1 mmol) in tetrahydrofuran (200 mL) at 0deg.C. The mixture was stirred at 25℃for 1 hour. The mixture was carefully quenched with sodium sulfate decahydrate (10 g) and water (5 mL). The resulting precipitate was filtered. The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to give 4-amino-2- ((benzylthio) methyl) butan-1-ol (9 g, crude) as a yellow oil.

Step 4.4- (benzylthio) -3- (((tert-butyldiphenylsilyl) oxy) methyl) butan-1-amine

A solution of 4-amino-2- ((benzylthio) methyl) butan-1-ol (7 g,31.0 mmol), tert-butylchlorodimethylsilane (8.54 g,31.0 mmol) and imidazole (3.17 g,46.5 mmol) in dichloromethane (50 mL) was stirred at 25℃for 16 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 4- (benzylthio) -3- (((tert-butyldiphenylsilyl) oxy) methyl) butan-1-amine (6.60 g,14.2mmol, 45%) as a yellow oil. M/zES + [ M+H ] ] ⁺ 464.2。

Step 5.4-amino-2- (((tert-butyldiphenylsilyl) oxy) methyl) butane-1-sulfonyl chloride

To a solution of 4- (benzylthio) -3- (((tert-butyldiphenylsilyl) oxy) methyl) butan-1-amine (3 g,6.47 mmol) in acetic acid (30 mL) and water (9 mL) was added N-chlorosuccinimide (2.59 g,19.4 mmol). The reaction was stirred at 25℃for 0.5 h. The mixture was concentrated under reduced pressure to give 4-amino-2- (((tert-butyldiphenylsilyl) oxy) methyl) butane-1-sulfonyl chloride (2.80 g, crude) as a yellow oil.

Step 6.3- (benzylthio) -2- (cyanomethyl) propanoic acid methyl ester

4-amino-2- [ [ tert-butyl (diphenyl) silyl ] in dichloromethane (30 mL)]Oxymethyl group]A solution of butane-1-sulfonyl chloride (2.8 g,6.36 mmol) and triethylamine (1.93 g,19.0 mmol) was stirred at 25℃for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 3/1) to give 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1, 2-thiazine 1, 1-dioxide (1 g,2.48mmol, 38%) as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.64(d,J＝7.2Hz,4H),7.56-7.36(m,7H),3.73-3.26(m,4H),2.82(t,J＝12.8Hz,1H),2.52(s,1H),1.55-1.38(m,2H),1.13-1.04(m,9H)。

Intermediates 4 and 5:3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutan-1-one and 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutan-1-one

Step 1.2- (1- (5, 8-dioxaspiro [3.4] oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (9 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (830 mg,1.65 mmol) and 2-bromo-5, 8-dioxaspiro [3.4]]To a solution of octane (350 mg,1.80 mmol) was added potassium carbonate (680 mg,4.90 mmol) and potassium iodide (27.0 mg,165 umol). The mixture was stirred at 100℃for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with brine (25 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol=100:1 to 10:1) to give 2- (1- (5, 8-dioxaspiro [ 3.4) as a yellow solid]Oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (680 mg,1.05mmol, 64%). M/zES + [ M+H ]] ⁺ 619.1。

Step 2.3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutanone

To 2- [ [6- [ 5-chloro-3- [1- (5, 8-dioxaspiro [3.4 ]) in dichloromethane (6.8 mL) and water (0.5 mL)]Oct-2-yl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (680 mg,1.10 mmol) was added formic acid (8.30 g,180 mmol). The mixture was stirred at 40℃for 12 hours. The reaction mixture was concentrated under reduced pressure, then diluted with water (20 mL). By saturated carbonic acidSodium hydrogen (30 mL) the mixture was adjusted to ph=8-9 and then extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with brine (25 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a white solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutanone (550 mg, crude). M/zES + [ M+H ]] ⁺ 575.3。

Step 3.3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutanone

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (3.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of cyclobutanone (350 mg,0.61 mmol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure, then diluted with water (30 mL). The mixture was adjusted to ph=9 with saturated sodium carbonate solution and then extracted with ethyl acetate (100 ml x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid ]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutanone (300 mg, crude). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.33(s,1H),8.95(s,1H),8.45(s,1H),7.96(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.23(d,J＝2.0Hz,1H),6.96(dd,J＝2.4,8.8Hz,1H),5.41-5.31(m,1H),3.70-3.64(m,4H),2.50(s,3H)；m/z ES+[M+H] ⁺ 445.0。

Intermediate 6:2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] azetidine-1-carboxylic acid tert-butyl ester

To at N, N-dimethyl2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in formamide (15 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (1 g,1.97 mmol) was added cesium carbonate (1.29 g,3.94 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (614 mg,2.17 mmol). The mixture was stirred at 50℃for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C, 18, 150X 40mm X15. Mu.m; mobile phase: [ water (0.1% TFA) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 35% -65%,11 mm) purification to 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a white solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Azetidine-1-carboxylic acid tert-butyl ester (800 mg,1.21mmol, 61%). M/zES + [ M+1 ]] ⁺ 662.4。

Step 2.2- [1- (azetidin-3-yl) pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A mixture of tert-butyl azetidine-1-carboxylate (79mg, 1.19 mmol) was stirred at 25℃for 6 hours. The reaction mixture was concentrated under reduced pressure to give 2- [1- (azetidin-3-yl) pyrazol-4-yl as a yellow solid]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (500 mg, crude, TFA salt). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.37(s,1H),9.26(d,J＝6.4Hz,1H),8.86(s,1H),8.59(s,1H),8.02(d,J＝9.2Hz,1H),7.72-7.63(m,1H),7.42(d,J＝9.2Hz,1H),7.37(d,J＝2.4Hz,1H),7.15-7.09(m,1H),5.64-5.54(m,1H),4.54-4.39(m,4H),2.64(s,3H)；m/z ES+[M+1] ⁺ 432.2。

Intermediate 7: N-tert-Butoxycarbonyl-N- (3, 5-difluoro-2-nitro-phenyl) carboxylic acid tert-butyl ester

Step 1N-tert-Butoxycarbonyl-N- (3, 5-difluoro-2-nitro-phenyl) carboxylic acid tert-butyl ester

To a solution of 3, 5-difluoro-2-nitro-aniline (500 mg,2.87 mmol) in dichloromethane (8 mL) was added 4-dimethylaminopyridine (35.1 mg,287 mmol), di-tert-butyl dicarbonate (1.25 g,5.74 mmol) and triethylamine (872 mg,8.62 mmol) and the mixture was stirred at 25℃for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 4/1) to give tert-butyl N-tert-butoxycarbonyl-N- (3, 5-difluoro-2-nitro-phenyl) carboxylate (800 mg,1.34mmol, 74%) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.35-6.98(m,1H),6.94-6.82(m,1H),1.44(s,18H)。

Intermediate 8: (3, 3-Difluorocyclobutyl) methyl methanesulfonate

(3, 3-Difluorocyclobutyl) methyl methanesulfonate

To a solution of (3, 3-difluorocyclobutyl) methanol (5 g,41.0 mmol) and triethylamine (10.4 g,102 mmol) in dichloromethane (60 mL) at 0deg.C was added methanesulfonyl chloride (7.04 g,61.4mmol,4.75 mL) and the mixture was stirred at 20deg.C for 1 hr. The reaction mixture was quenched with water (15 mL) and then extracted with ethyl acetate (3X 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (3, 3-difluorocyclobutyl) methyl methanesulfonate (9 g, crude) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ4.25(d,J＝6.4Hz,2H),3.03(d,J＝1.2Hz,3H),2.79-2.65(m,2H),2.63-2.50(m,1H),2.49-2.32(m,2H)。

Intermediates 9, 10 and 11: 7-bromo-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline and 3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol and 5-chloro-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol

Step 1.7-bromo-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline

To a mixture of 7-bromo-2-chloro-quinoxaline (3 g,12.3 umol) and 1-tetrahydropyran-2-yl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (3.61 g,13.0 umol) in dioxane (30 mL) and water (6 mL) was added potassium acetate (3.63 g,37.0 umol) and cyclopent-2, 4-dien-1-yl (diphenyl) phosphine; palladium dichloride; iron (II) (902 mg,1.23 umol). The mixture was stirred under nitrogen at 60 ℃ for 12 hours. After completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (125 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=30:1 to 0:1) to give 7-bromo-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline (2.80 g, crude) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ9.06(s,1H),8.41(s,1H),8.29-8.20(m,2H),7.92(d,J＝8.8Hz,1H),7.76(dd,J＝2.0,8.8Hz,1H),5.54-5.45(m,1H),4.21-4.08(m,1H),3.83-3.72(m,1H),2.23-2.15(m,2H),2.12-2.06(m,1H),1.76-1.66(m,3H)。

Step 2.7-bromo-2- (1H-pyrazol-4-yl) quinoxaline

To a solution of 7-bromo-2- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxaline (5.20 g,14.5 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (20 mL) and the mixture was stirred at 20 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline (5 g, crude) as a black solid. M/zES + [ M+H ]] ⁺ 274.7。

Step 3.7-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxaline

To a solution of 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline (2.30 g,8.36 mmol) in N, N-dimethylformamide (40 mL) was added potassium carbonate (2.31)g,16.7 mmol) and (3, 3-difluorocyclobutyl) methyl methanesulfonate (1.67 g,8.36 mmol), and the mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give a residue. The residue was triturated with petroleum ether/ethyl acetate (20:1, 40 mL) for 30min at 20 ℃ to give 7-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxaline (800 mg,2.11mmol, 12%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.43-9.31(m,1H),8.73(s,1H),8.34(s,1H),8.20(d,J＝2.0Hz,1H),7.99(d,J＝8.8Hz,1H),7.88(dd,J＝2.0,8.8Hz,1H),4.37(d,J＝6.0Hz,2H),3.30(s,1H),2.77-2.57(m,4H)；m/z ES+[M+H] ⁺ 378.8。

Step 4.3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol

7-bromo-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] in dioxane (10 mL) and water (2 mL)]Pyrazol-4-yl]Quinoxaline (600 mg,1.58 mmol), tris (dibenzylideneacetone) dipalladium (145 mg,158 umol), di-tert-butyl- [2- (2, 4, 6-triisopropylphenyl) phenyl]A mixture of phosphane (67.2 mg,158 mmole) and potassium hydroxide (88 mg,15.8 mmol) was degassed and purged 3 times with nitrogen, and the mixture was then stirred under nitrogen atmosphere at 100℃for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give 3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol (400 mg,1.26mmol, 68%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d6)δ＝10.69-10.25(m,1H),9.05(s,1H),8.66(s,1H),8.28(s,1H),7.86(d,J＝9.2Hz,1H),7.28(dd,J＝2.4,9.2Hz,1H),7.18(d,J＝2.4Hz,1H),4.34(d,J＝5.6Hz,2H),2.75-2.56(m,4H),2.47(s,1H)；m/z ES+[M+H] ⁺ 317.1。

Step 5.5-chloro-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol

To 3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in chloroform (5 mL)]Pyrazol-4-yl]Quinoxalin-6-ol (400 mg, 1).To a solution of 26 mmol) was added N-chlorosuccinimide (338 mg,2.53 mmol), nickel chloride (164 mg,1.26 mmol) and triethylamine (128 mg,1.26 mmol). The mixture was stirred at 60℃for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give 5-chloro-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol (500 mg,1.43mmol, 95%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.14(s,1H),8.69(s,1H),8.32(s,1H),7.86(d,J＝9.2Hz,1H),7.48(d,J＝9.2Hz,1H),4.37(d,J＝6.0Hz,2H),3.16(s,1H),2.77-2.59(m,4H)；m/z ES+[M+H] ⁺ 351.0。

Intermediate 12: N-tert-Butoxycarbonyl-N- (5-fluoro-2-nitro-phenyl) carbamic acid tert-butyl ester

Step 1N-tert-Butoxycarbonyl-N- (5-fluoro-2-nitro-phenyl) carbamic acid tert-butyl ester

To a solution of 5-fluoro-2-nitro-aniline (10 g,64.1 umol) in methylene chloride (100 mL) were added di-tert-butyl dicarbonate (28.0 g,128 umol), triethylamine (19.5 g,192 umol) and N, N-dimethylpyridin-4-amine (783 mg,6.41 umol). The mixture was stirred at 20℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 8/1) to give tert-butyl N-t-butoxycarbonyl-N- (5-fluoro-2-nitro-phenyl) carbamate (20 g,56.1umol, 88%) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ＝8.14(dd,J＝5.6,9.2Hz,1H),7.23-7.14(m,1H),7.05(dd,J＝2.8,8.4Hz,1H),1.40(s,18H)。

Intermediate 13:2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethylmethanesulfonate

Step 1.2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] ethanol

To) 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (15 mL) ]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a mixture of ethyl-trimethyl-silane (2 g,3.94 mmol) and 2-bromoethanol (1.48 g,11.83mmol, 840. Mu.L) was added potassium carbonate (1.64 g,11.83 mmol). The mixture was heated to 80 ℃ and stirred for 16 hours. After completion, the reaction mixture was quenched with water (150 mL) at 20 ℃ and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (50 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol=100:1 to 20:1) to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethanol (2.5 g,3.86mmol, 98%). M/zES + [ M+H ]] ⁺ 551.4。

Step 2.2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] ethylmethanesulfonate

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in dichloromethane (30 mL) at 0deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl ]To a mixture of ethanol (2.5 g,4.54 mmol) was added triethylamine (1.38 g,13.61 mmol) and methanesulfonyl chloride (1.04 g,9.07 mmol). The mixture was stirred at 0 ℃ for 2 hours. After completion, the reaction mixture was quenched with water (30 mL) at 0 ℃ and then extracted with dichloromethane (30 ml×3). The combined organic layers were washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl methanesulfonate (2.6 g,3.64mmol, 80%). M/zES + [ M+H ]] ⁺ 629.4。

Intermediates 14, 23 and 15: (3S, 4S) -4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-carboxylic acid tert-butyl ester, 8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1 (3S, 4R) -3-fluoro-4- ((methylsulfonyl) oxy) piperidine-1-carboxylic acid tert-butyl ester

To a solution of (3 s,4 r) -3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (500 mg,2.28 mmol) in dichloromethane (5 mL) were added methanesulfonyl chloride (390 mg,3.42 mmol) and triethylamine (692 mg,6.84 mmol), and the mixture was stirred at 0 ℃ for 0.5 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3 s,4 r) -3-fluoro-4- ((methylsulfonyl) oxy) piperidine-1-carboxylate (720 mg, crude) as an orange solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ4.99-4.92(m,1H),4.91-4.83(m,1H),4.13-4.02(m,1H),3.88(s,1H),3.26(s,3H),3.24-3.07(m,1H),3.06-2.86(m,1H),1.91-1.77(m,2H),1.39(s,9H)。

(3S, 4S) -4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (4 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (600 mg,1.18 mmol) was added potassium carbonate (491 mg,3.55 mmol) and (3S, 4R) -3-fluoro-4- ((methylsulfonyl) oxy) piperidine-1-carboxylic acid tert-butyl ester (704 mg,2.37 mmol) the mixture was stirred at 100℃for 12 hours. The reaction mixture was quenched with water (0.5 mL) and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 85-90% acetonitrile, 5 min) to give (3 s,4 s) -4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as an off-white solid ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (600 mg,849umol, 72%). ¹ H NMR(400MHz,DMSO-d6)δ9.33(d,J＝3.6Hz,1H),8.87(s,1H),8.44(s,1H),8-7.95(m,1H),7.70-7.57(m,1H),7.47-7.29(m,2H),7.10-6.99(m,1H),5.65-5.52(m,2H),5.01-4.80(m,1H),4.78-4.70(m,1H),4.41-4.27(m,1H),4.10-3.96(m,1H),3.57-3.46(m,2H),3.10-2.93(m,2H),2.57(d,J＝6.8Hz,3H),2.17-2(m,2H),1.45(s,9H),0.87-0.77(m,2H),-0.06--0.15(m,9H)；m/z ES+[M+H] ⁺ 708.3。

Step 3.8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

(3S, 4S) -4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (300 mg,424 umol) was stirred at 25 ℃ for 1.5H. The reaction mixture was concentrated under reduced pressure to give 8-chloro-2- (1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) quinoxaline (250 mg, crude). ¹ HNMR(400MHz,DMSO-d6)δ＝9.52-9.45(m,1H),8.89(s,1H),8.53(s,1H),8.43(s,2H),8.10(d,J＝9.2Hz,1H),7.83-7.72(m,1H),7.60-7.42(m,2H),7.25-7.12(m,1H),5.81-5.61(m,2H),4.77-4.66(m,1H),4.17(q,J＝7.2Hz,1H),3.63(d,J＝7.6Hz,3H),3.52-3.43(m,3H),3.17-3.05(m,2H),2.71(d,J＝6.4Hz,3H),2.37-2.25(m,3H),1.02-0.90(m,2H),0.09-0.01(m,9H)；m/zES+[M+H] ⁺ 608.3。

Step 4.8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in tetrahydrofuran (2 mL) ]To a solution of imidazol-6-yl) oxy quinoxaline (250 mg,411 umol) was added pyridine hydrofluoric acid (407 mg,4.11 mmol), and the mixture was stirred at 80℃for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (0.1% formic acid condition, 30% -40% acetonitrile, 5 min) to give 8-chloro-2- (1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) quinoxaline (120 mg,251 mol, 55%). M/zES + [ M+H ]] ⁺ 478.2。

Intermediate 16: (2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) boronic acid

Step 1.6-bromo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazole

To a solution of 5-bromo-2-methyl-1H-benzimidazole (20 g,94.8 mmol) in THF (400 mL) was added NaH (7.58 g,189mmol,60% in mineral oil) in portions at 0 ℃. The reaction was stirred at 0℃for 0.5 h. (2- (chloromethoxy) ethyl) trimethylsilane (23.7 g,142mmol,25 mL) was then added dropwise at 0deg.C. The mixture was stirred at 25℃for 1.5h. After completion, the reaction mixture was slowly poured into ice water (700 mL) and then extracted with ethyl acetate (300 mL x 4). The combined organic layers were washed with brine (100 ml×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-bromo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a white solid ]Imidazole (39 g, crude, mixture of regioisomers). ¹ H NMR(400MHz,DMSO-d6)δ＝7.87(s,0.5H),7.73(s,0.5H),7.58(d,J＝8.4Hz,0.5H),7.48(d,J＝8.4Hz,0.5H),7.36(dd,J＝8.4,1.2Hz,0.5H),7.34(dd,J＝8.4,1.2Hz,0.5H),5.58(s,2H),3.60–3.50(m,4H),2.65–2.47(m,6H),0.90–0.70(m,4H),0.10–-0.80(m,18H)；m/z ES+[M+H] ⁺ 341.1。

Step 2.2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazole

To 2- [ (5-bromo-2-methyl-benzoimidazol-1-yl) methoxy in dioxane (600 mL)]To a solution of ethyl-trimethyl-silane (39.29 g,115mmol, mixture of regioisomers) and 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1,3, 2-dioxapentaborane (87.69 g,345 mmol) was added potassium acetate (33.89 g,345 mmol) and cyclopent-2, 4-dien-1-yl (diphenyl) phosphine; palladium dichloride; iron (II) (8.42 g,11.51 mmol). The mixture was stirred under nitrogen at 60 ℃ for 12 hours. After completion, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 0/1) to give 2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazole (44.2 g,114mmol,99%, mixture of regioisomers). M/zES + [ M+H ]] ⁺ 389.3。

(2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) boronic acid

To trimethyl- [2- [ [ 2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzimidazol-1-yl ] in tetrahydrofuran (250 mL) and water (250 mL)]Methoxy group]Ethyl group]To a solution of silane (25 g,64.37 mmol) was added sodium periodate (41.30 g,193 mmol) and ammonium acetate (14.89 g,193 mmol). The mixture was stirred at 30℃for 12 hours. After completion, the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (300 ml×4). The combined organic layers were washed with saturated sodium sulfite (250 ml×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (column: I.D.100 mM. H400 mM, mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%) 20-75%,40min;75%,35 min) to give (2%) as a white solidMethyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ]]Imidazol-6-yl) boronic acid (8.2 g,26.78mmol, 42%). ¹ H NMR(400MHz,DMSO-d6)δ＝8.01(d,J＝7.2Hz,1H),7.94(s,1H),7.92(s,1H),7.67–7.60(m,1H),7.52(d,J＝8.4Hz,0.5H),7.48(d,J＝8.4Hz,0.5H),5.56(d,J＝4.0Hz,2H),3.52(q,J＝7.6Hz,2H),2.56(d,J＝4.4Hz,3H),0.84(dd,J＝14.0,8.0Hz,2H),-0.09(d,J＝2.0Hz,9H)；m/z ES+[M+H] ⁺ 307.2。

Intermediates 17, 20 and 30: 8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline, 3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline-6-ol and 8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline

Step 1.3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-ol

To a solution of 7-bromo-2- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxaline (4.90 g,13.6 mmol) in dioxane (50 mL) and water (25 mL) was added tris (dibenzylideneacetone) dipalladium (1.25 g,1.36 mmol), di-tert-butyl- [2- (2, 4, 6-triisopropylphenyl) phenyl]Phosphane (579 mg,1.36 mmol) and potassium hydroxide (7.65 g,136 mmol). The mixture was degassed and purged 3 times with nitrogen and then stirred under nitrogen at 100 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to give 3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-ol (1.70 g,5.39mmol, 39%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ＝10.44(s,1H),9.10(s,1H),8.78(s,1H),8.28(s,1H),7.87(d,J＝8.8Hz,1H),7.29(dd,J＝2.4,9.2Hz,1H),7.20(d,J＝2.4Hz,1H),5.50(dd,J＝2.0,9.6Hz,1H),3.97(d,J＝11.6Hz,1H),3.72-3.62(m,1H),2.22-2.10(m,1H),2.03-1.92(m,2H),1.77-1.64(m,1H),1.58(d,J＝3.6Hz,2H)；m/z ES+[M+H] ⁺ 297.1。

Step 2.5-bromo-3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-ol

To a solution of 3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (1.70 g,5.74 mmol) in chloroform (34 mL) was added N-bromosuccinimide (1.53 g,8.61 mmol), nickel dichloride (744 mg,5.74 mmol) and triethylamine (581 mg,5.74 mmol). The mixture was stirred at 60℃for 2 hours. The reaction mixture was cooled to 25 ℃ and filtered. The filtrate was washed with saturated sodium bicarbonate solution (2×50 mL), dried over sodium sulfate, filtered and concentrated to give 5-bromo-3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-ol (2.80 g, crude) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.13(s,1H),8.79(s,1H),8.31(s,1H),7.87(d,J＝9.2Hz,1H),7.46(d,J＝9.2Hz,1H),5.54(dd,J＝2.0,9.6Hz,1H),4.02-3.96(m,1H),3.74-3.61(m,1H),2.19-2.09(m,1H),2.04-1.93(m,2H),1.77-1.66(m,1H),1.61-1.54(m,2H)。

Step 3.8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline

To 5-bromo-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (1.40 g,3.73 mmol) and [ 2-methyl-1- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in 1, 2-dimethoxyethane (30 mL)]To a solution of boric acid (1.22 g,3.99 mmol) was added cesium carbonate (2.67 g,8.21 mmol),MS (1.50 g) and copper (II) acetate (813 mg,4.48 mmol). The mixture was stirred at 60 ℃ for 6 hours under an oxygen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1 to 1/5) to give 8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline (670 mg, 480 umol, 26%). M/zES + [ M+H ]] ⁺ 637.2。

Step 4.8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline

To 2- [ [6- [ 5-bromo-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl ] in methanol (7 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (640 mg,1.05 mmol) was added hydrochloric acid (1M, 7 mL) and the mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/3 to 0/1) to give 8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (360 mg,587umol, 55%). M/zES + [ M+H ]] ⁺ 553.1。

Step 5.8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-bromo-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (6 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (290 mg, 526. Mu. Mol) and (3, 3-difluorocyclobutyl) methyl methanesulfonate (158 mg, 789. Mu. Mol) was added potassium carbonate (218 mg,1.58 mmol). The mixture was stirred at 80℃for 3 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were washed with brine (20 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid ]Imidazol-6-yl) oxy) quinoxaline (430 mg, crude). M/zES + [ M+H ]] ⁺ 657.2。

Intermediate 18: 8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline

Step 1.5-chloro-3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-ol

To a solution of 3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (4.50 g,15.2 mmol) in chloroform (90 mL) was added 1-chloropyrrolidine-2, 5-dione (4.06 g,30.4 mmol), nickel dichloride (1.97 g,15.2 mmol) and diisopropylethylamine (2.94 g,22.8 mmol). The mixture was stirred at 60℃for 2 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give 2-chloro-3- (2-fluoro-5-methoxyphenoxy) -6-nitroaniline (7 g,21.2mmol,70% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d6)δ＝11.05(s,1H),9.19(s,1H),8.80(s,1H),8.32(s,1H),7.87(d,J＝9.2Hz,1H),7.50(d,J＝9.2Hz,1H),5.53(dd,J＝2.0,9.6Hz,1H),3.98(d,J＝12.8Hz,1H),3.72-3.64(m,1H),2.21-2.09(m,1H),2.04-1.98(m,2H),1.77-1.66(m,1H),1.61-1.54(m,2H)；m/z ES+[M+H] ⁺ 331.0。

Step 2.3- ((5-chloro-3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) -2-fluoro-6-nitroaniline

To a solution of 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (5.90 g,17.8 mmol) and 2, 3-difluoro-6-nitro-aniline (3.11 g,17.8 mmol) in N, N-dimethylformamide (160 mL) was added potassium carbonate (4.93 g,35.7 mmol). The mixture was stirred at 130℃for 4 hours. After completion, the reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (200 ml×3). The combined organic layers were washed with brine (200 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 0/1). The resulting solid was triturated with petroleum ether/ethyl acetate (1/2, 30 mL) to give 3-chloro-4- (2-fluoro-5-methoxyphenoxy) benzene-1, 2-propanoic acid as a yellow solid Diamine (6.59 g,12.2mmol, 69%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.44(s,1H),8.90(s,1H),8.38(s,1H),8.09(d,J＝9.2Hz,1H),7.86(dd,J＝1.6,9.6Hz,1H),7.69(d,J＝9.2Hz,1H),7.48(s,2H),6.27(dd,J＝7.6,9.6Hz,1H),5.56(dd,J＝2.0,9.6Hz,1H),3.99(d,J＝11.6Hz,1H),3.74-3.66(m,1H),2.21-2.10(m,1H),2.04-1.93(m,2H),1.78-1.67(m,1H),1.62-1.55(m,2H)；m/z ES+[M+H] ⁺ 485.1。

Step 3.4- ((5-chloro-3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) -3-fluorobenzene-1, 2-diamine

To 3- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl in ethanol (80 mL) and water (40 mL)]To a solution of oxy-2-fluoro-6-nitro-aniline (6.59 g,13.6 mmol) was added ammonium chloride (7.27 g,136 mmol) and iron powder (3.80 g,68.0 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted in water (100 mL) and extracted with dichloromethane (150 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1 to 1/2) to give 4- ((5-chloro-3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) -3-fluorobenzene-1, 2-diamine (4.40 g,9.38mmol, 69%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d6)δ＝9.32(s,1H),8.86(s,1H),8.37(s,1H),7.94(d,J＝9.2Hz,1H),7.23(d,J＝9.2Hz,1H),6.42-6.31(m,2H),5.55(dd,J＝2.4,9.6Hz,1H),4.84(s,2H),4.72(s,2H),4.02-3.95(m,1H),3.74-3.66(m,1H),2.21-2.11(m,1H),2.06-1.97(m,2H),1.78-1.67(m,1H),1.62-1.55(m,2H)；m/z ES+[M+H] ⁺ 455.1。

Step 4.8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline

To 4- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl in methanol (100 mL) ]Sulfamic acid (1.88 g,19.4 mmol) was added to a solution of oxy-3-fluoro-benzene-1, 2-diamine (4.40 g,9.67 mmol) and 1, 1-trimethoxyethane (5.81 g,48.4 mmol). The mixture was stirred at 25℃for 1 hour. After completion, willThe reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), then diluted with water (200 mL) and extracted with ethyl acetate (200 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline (4.80 g, crude). M/zES + [ M+H ]] ⁺ 479.0。

Step 5.8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline

To 8-chloro-7- [ (4-fluoro-2-methyl-3H-benzimidazol-5-yl) oxy in tetrahydrofuran (60 mL) at 0deg.C]To a solution of 2- (1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxaline (2.60 g,5.43 mmol) was added sodium hydride (543 mg,13.6mmol,60% in mineral oil) in portions. The mixture was then stirred at 0 ℃ for 0.5 hours. A solution of ((2- (chloromethoxy) ethyl) trimethylsilane (1.36 g,8.14 mmol) in dry tetrahydrofuran (5 mL) was then added dropwise at 0deg.C the mixture was stirred at 25deg.C for 1 hour after completion the reaction mixture was poured into 50mL of water and extracted with ethyl acetate (30 mL. Times.3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give 8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] methyl) as a yellow solid ]Imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline (2.90 g,4.76mmol, 88%). M/z ES+ [ M+H ]] ⁺ 609.2。

Step 6.8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl ] in methanol (29 mL)]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (2.90 g,4.76 mmol) was added aqueous hydrochloric acid (1N, 29 mL). The mixture was subjected to a temperature of 25 ℃Stirring is carried out for 12 hours. The reaction mixture was basified with saturated aqueous sodium bicarbonate until ph=8 and extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a white solid]Imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (2.60 g, crude product). m/z ES ⁺ [M+H] ⁺ 525.2。

Intermediate 19:3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutan-1-one

Step 1.2- (1- (5, 8-dioxaspiro [3.4] oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (8 mL)]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (500 mg, 952. Mu. Mol) and 2-bromo-5, 8-dioxaspiro [3.4]]To a solution of octane (276 mg,1.43 mmol) was added potassium carbonate (399mg, 2.86 mmol) and potassium iodide (15.8 mg, 95.2. Mu. Mol). The mixture was stirred at 100℃for 24h. After completion, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 1/3) to give 2- (1- (5, 8-dioxaspiro [ 3.4) as a yellow solid]Oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (460 mg,686 mu mol, 72%). ¹ H NMR(400MHz,DMSO-d6)δ9.32(d,J＝2.8Hz,1H),8.82(s,1H),8.42(s,1H),7.95(dd,J＝2.4,9.2Hz,1H),7.56-7.44(m,1H),7.28-7.12(m,2H),5.63(d,J＝10.4Hz,2H),4.89(t,J＝8.0Hz,1H),3.96-3.84(m,4H),3.59-3.54(m,2H),2.95-2.79(m,4H),2.61(d,J＝7.2Hz,3H),0.87-0.80(m,2H),0.07(s,4H),0.13(s,5H)；m/z ES+[M+H] ⁺ 637.2。

Step 2.3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanone

To 2- [ [6- [ 5-chloro-3- [1- (5, 8-dioxaspiro [3.4 ]) in dichloromethane (1.8 mL) and water (0.5 mL)]Oct-2-yl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (360 mg, 565. Mu. Mol) was added formic acid (4.39 g,95.4mmol,3.6 mL). The mixture was stirred at 40℃for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and then adjusted to pH 8-9 with saturated aqueous sodium bicarbonate. The mixture was then extracted with ethyl acetate (20 mL. Times.2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/3) to give 3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl cyclobutanone (280 mg,467 μmol, 83%). M/z ES+ [ M+H ] ] ⁺ 593.2。

Intermediate 21:7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline

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Step 1.2, 4-difluoro-6-nitro-3- ((3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) aniline

To a solution of 3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (3 g,10.1 mmol) in 1-methylpiperidin-2-one (30 mL) was added cesium carbonate (6.60 g,20.3 mmol) and 2,3, 4-trifluoro-6-nitro groupAniline (1.94 g,10.1 mmol). The mixture was stirred at 110℃for 2 hours. After completion, the reaction mixture was diluted with water (100 mL). The resulting precipitate was collected by filtration to give 2, 4-difluoro-6-nitro-3- ((3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) aniline (3.9 g, crude) as a brown solid. ¹ H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.83(s,1H),8.28(s,1H),8.14-7.95(m,2H),7.69(dd,J＝2.8,9.2Hz,1H),7.49(s,2H),7.39(d,J＝2.8Hz,1H),5.49(dd,J＝2.4,10.0Hz,1H),3.95(d,J＝11.6Hz,1H),3.75-3.63(m,1H),2.14-2.08(m,1H),2.02-1.95(m,2H),1.78-1.64(m,1H),1.61-1.51(m,2H)；m/z ES+[M+H] ⁺ 469.2。

Step 2.3,5-difluoro-4- ((3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) benzene-1, 2-diamine

To a solution of 2, 4-difluoro-6-nitro-3- ((3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) aniline (3.9 g,8.33 mmol) in ethanol (60 mL) and water (6 mL) was added iron powder (2.32 g,41.6 mmol) and ammonium chloride (4.45 g,83.3 mmol). The mixture was stirred at 60℃for 2 hours. After completion, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 3, 5-difluoro-4- ((3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) benzene-1, 2-diamine (5 g, crude) as a yellow solid. M/zES + [ M+H ] ] ⁺ 439.0。

Step 3.7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline

To a solution of 3, 5-difluoro-4- ((3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) benzene-1, 2-diamine (5 g,11.4 mmol) in methanol (80 mL) was added 1, 1-trimethoxyethane (6.85 g,57.0 mmol) and sulfamic acid (2.21 g,22.8 mmol). The mixture was stirred at 20℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/methanol=1/0 to 10/1) to give 7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline (3.9 g,6.75mmol,59％)。 ¹ H NMR(400MHz,CDCl ₃ )δ8.96(s,1H),8.43-7.93(m,3H),7.71-7.40(m,2H),7.11(s,1H),5.43(s,1H),4.06(d,J＝10.4Hz,1H),3.86(s,3H),3.81-3.64(m,1H),2.17-1.97(m,3H),1.77-1.56(m,3H)；m/z ES+[M+H] ⁺ 463.3。

step 4.7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline

To 7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] in anhydrous tetrahydrofuran (60 mL) at 0deg.C]To a solution of imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline (2.0 g,4.32 mmol) was added sodium hydride (1.04 g,26.0mmol,60% in mineral oil). The mixture was stirred at 0 ℃ for 2 hours. (2- (chloromethoxy) ethyl) trimethylsilane (865 mg,5.19 mmol) was then added. The mixture was stirred at 20℃for 14 hours. After completion, the reaction mixture was quenched with water (50 mL), and then extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give 7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid ]Imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline (600 mg, 810. Mu. Mol, 19%). M/zES + [ M+18 ]] ⁺ 593.4。

Step 5.7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline

To 7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in methanol (5 mL)]To a solution of imidazol-6-yl) oxy) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) quinoxaline (450 mg, 759. Mu. Mol) was added hydrochloric acid (1M, 4.5 mL). The mixture was stirred at 20℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to give 7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy)-2- (1H-pyrazol-4-yl) quinoxaline (600 mg, crude). ¹ H NMR(400MHz,CDCl ₃ )δ9.45-8.96(m,1H),8.61-8.51(m,1H),8.30(s,1H),8.18-7.99(m,1H),7.75-7.54(m,1H),7.27(s,1H),7.26-7.13(m,1H),5.90-5.37(m,2H),3.76-3.49(m,2H),3.10-2.70(m,3H),1.06-0.78(m,2H),0.06--0.08(m,9H)；m/z ES+[M+H] ⁺ 509.3。

Intermediate 22:4, 4-Difluorocyclohexyl methane sulfonate

Step 1.4,4-Difluorocyclohexyl methanesulfonate

To a solution of 4, 4-difluorocyclohexanol (500 mg,3.67 mmol) and triethylamine (743 mg,7.35 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (631 mg,5.51 mmol). The mixture was stirred at 0 ℃ for 1 hour. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 3:1) to give 4, 4-difluorocyclohexyl methanesulfonate (750 mg,3.50mmol, 95%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ4.95-4.92(m,1H),3.07(s,3H),2.13-1.87(m,8H)。

Intermediate 23:4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclohex-1-one

Step 1.1, 4-dioxaspiro [4.5] decan-8-ylmethyl methanesulfonate

To 1, 4-dioxaspiro [4.5] in dichloromethane (5 mL) d]To a solution of decane-8-ylmethanol (500 mg,2.90 mmol) and triethylamine (552 mg,5.75 mmol) was added methanesulfonyl chloride (447 mg,3.88 mmol). The mixture was stirred at 0 ℃ for 1 hour. The mixture was washed with water (10 mL)Quench and extract with ethyl acetate (12 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 1, 4-dioxaspiro [4.5] as a yellow oil]Decane-8-ylmethyl mesylate (850 mg, crude). ¹ H NMR(400MHz,CDCl ₃ )δ4.05-3.95(m,2H),3.94-3.88(s,4H),2.99(s,3H),1.85-1.72(m,5H),1.54-1.51(m,1H),136-1.31(m,1H)。

Step 2.2- [ [6- [ 5-chloro-3- [1- (1, 4-dioxaspiro [4.5] dec-8-ylmethyl) pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 1, 4-dioxaspiro [4.5] in N, N-dimethylformamide (8 mL)]Decan-8-ylmethyl methanesulfonate (370 mg,1.48 mmol) and 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl ]Methoxy group]To a solution of ethyl-trimethyl-silane (500 mg,986 mmole) was added potassium carbonate (300 mg,2.17 mmole). The mixture was stirred at 80℃for 12 hours. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (8 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 2- [ [6- [ 5-chloro-3- [1- (1, 4-dioxaspiro [4.5 ] as a yellow oil]Decan-8-ylmethyl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (900 mg, crude). M/zES + [ M+H ]] ⁺ 661.3。

Step 3.4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] cyclohexanone

To 2- [ [6- [ 5-chloro-3- [1- (1, 4-dioxaspiro [4.5 ] in dichloromethane (4 mL) ]]Decan-8-ylmethyl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (900 mg,1.36 mmol) was added formic acid (4 mL). The mixture was stirred at 25℃for 8 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water (2 mL) and adjusted to ph=7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 4- [ [ as a yellow oil 4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Cyclohexanone (780 mg, crude). M/zES + [ M+H ]] ⁺ 617.3。

Intermediate 24:3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutan-1-one

Step 1.2- [ [6- [ 5-chloro-3- [1- [ (3, 3-dimethoxycyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (1.5 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (150 mg, 298 mol) and (3, 3-dimethoxycyclobutyl) methyl methanesulfonate (79.6 mg,355 mol) were added potassium carbonate (123 mg,887 mol) and potassium iodide (49.1 mg, 298 mol), the mixture was stirred at 80℃for 16 hours, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3X 3 mL), the combined organic layers were washed with brine (3X 3 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 2- [ [6- [ 5-chloro-3- [1- [ (3, 3-dimethoxycyclobutyl) methyl ] as a yellow oil ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (180 mg, crude). M/zES + [ M+H ]] ⁺ 635.3。

Step 2.3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] cyclobutanone

To 2- [ [6- [ 5-chloro-3- [1- [ (3, 3-dimethoxycyclobutyl) methyl ] in dichloromethane (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Formic acid (13.6 mg,283 umol) was added to a solution of ethyl-trimethyl-silane (180 mg, 284 umol), and the mixture was stirred in the presence of waterStirred at 25℃for 2 hours. The reaction mixture was concentrated in vacuo. The residue was washed with saturated sodium bicarbonate solution (3 mL) and then extracted with ethyl acetate (3X 5 mL). The combined organic layers were washed with brine (3×5 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow gum]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Cyclobutanone (110 mg, crude). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.31(d,J＝4.4Hz,1H),8.77(s,1H),8.38(s,1H),7.98-7.93(m,2H),7.70-7.56(m,1H),7.48-7.26(m,2H),7.11-6.96(m,1H),5.75-5.30(m,2H),4.49(br d,J＝6.4Hz,2H),3.58-3.45(m,2H),3.14(dt,J＝6.4,11.8Hz,2H),3.01(br t,J＝4.8Hz,2H),2.57(br d,J＝6.4Hz,3H),0.93-0.71(m,2H),-0.05--0.17(m,9H)；m/z ES+[M+H] ⁺ 589.3。

Intermediate 25:4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -4- (2-hydroxyethyl) piperidine-1-carboxylic acid tert-butyl ester

Step 1.4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -4- (2-ethoxy-2-oxoethyl) piperidine-1-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in acetonitrile (10 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (1 g,1.97 mmol) was added 4- (2-ethoxy-2-oxo-ethylene) piperidine-1-carboxylic acid tert-butyl ester (595 mg,2.21 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (330 mg,2.17 mmol). The mixture was stirred at 60℃for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=1/0 to 80/1) to give 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) as a yellow solidRadical) -1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -4- (2-ethoxy-2-oxoethyl) piperidine-1-carboxylic acid tert-butyl ester (900 mg,1.04mmol, 53%). M/zES + [ M+H ]] ⁺ 776.5。

Step 2.4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -4- (2-hydroxyethyl) piperidine-1-carboxylic acid tert-butyl ester

To 4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in tetrahydrofuran (14 mL) at 0deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of tert-butyl 4- (2-ethoxy-2-oxo-ethyl) piperidine-1-carboxylate (700 mg, 902. Mu. Mol) was added diisobutylaluminum hydride (1M in toluene, 2.7 mL). The mixture was stirred at 0℃for 1.5h. The reaction mixture was carefully quenched with water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=1/0 to 80/1) to give 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -4- (2-hydroxyethyl) piperidine-1-carboxylic acid tert-butyl ester (350 mg, 451. Mu. Mol, 50%). M/zES + [ M+H ]] ⁺ 734.1。

Intermediate 26:2- (1- ((2-azabicyclo [2.2.1] heptan-5-yl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.5- (hydroxymethyl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To 2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] in tetrahydrofuran (6 mL) at 0deg.C]To a solution of heptane-5-carboxylic acid (500 mg,2.07 mmol) was added dropwise borane tetrahydrofuran complex (1M, 12.4 mL). Will be mixedThe mixture was stirred at 25℃for 12 hours. After completion, the reaction mixture was carefully quenched with methanol (60 mL) at 25 ℃ and then stirred at 60 ℃ for 30min. The reaction was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether/ethyl acetate=1/1) to give 5- (hydroxymethyl) -2-azabicyclo [2.2.1] as a yellow oil]Heptane-2-carboxylic acid tert-butyl ester (460 mg,2.03mmol, 78%). ¹ H NMR(400MHz,DMSO-d ₆ )δ4.55(t,J＝4.8Hz,1H),3.95(d,J＝8.8Hz,1H),3.50-3.37(m,1H),3.28-3.18(m,2H),3.05-2.94(m,1H),2.48(s,1H),2.11(dt,J＝5.6,9.6Hz,1H),1.76-1.59(m,2H),1.52-1.42(m,1H),1.39(s,9H),1.01-0.89(m,1H)。

Step 2.5- (((methylsulfonyl) oxy) methyl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To 5- (hydroxymethyl) -2-azabicyclo [2.2.1 in dichloromethane (6 mL)]To a solution of tert-butyl heptane-2-carboxylate (460 mg,2.02 mmol) was added triethylamine (514 mg,6.07mmol,0.845 mL) and methanesulfonyl chloride (348 mg,3.04mmol,0.235 mL). The mixture was stirred at 0 ℃ for 1 hour. After completion, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5- (((methylsulfonyl) oxy) methyl) -2-azabicyclo [ 2.2.1) as an orange solid ]Heptane-2-carboxylic acid tert-butyl ester (760 mg, crude). ¹ H NMR(400MHz,DMSO-d ₆ )δ4.37-4.27(m,1H),4.15-4.05(m,2H),3.25(s,3H),3.24(d,J＝2.0Hz,1H),3.18-3.07(m,1H),2.50-2.38(m,1H),1.93-1.81(m,1H),1.72(t,J＝10.8Hz,1H),1.64-1.58(m,1H),1.45(s,9H),1.24(t,J＝7.2Hz,1H),1.15(t,J＝7.2Hz,1H)。

Step 3.5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (4 mL)]Dissolution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (360 mg, 710. Mu. Mol)Potassium carbonate (294 mg,2.13 mmol) and 5- (((methylsulfonyl) oxy) methyl) -2-azabicyclo [ 2.2.1) are added to the solution]Heptane-2-carboxylic acid tert-butyl ester (433 mg,1.42 mmol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 95% -100% acetonitrile, 8 min) to give 5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as an orange solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (430 mg,0.60mmol, 85%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.33(d,J＝4.0Hz,1H),8.80-8.75(m,1H),8.39-8.36(m,1H),7.97(dd,J＝1.2,9.2Hz,1H),7.70-7.58(m,1H),7.44(d,J＝2.0Hz,1H),7.37-7.29(m,2H),7.10-6.99(m,1H),5.62(s,1H),5.55(s,1H),4.36-4.18(m,2H),4.06(d,J＝12.0Hz,1H),3.56(t,J＝8.0Hz,1H),3.51-3.45(m,2H),3.19-3.07(m,1H),2.68(d,J＝2.0Hz,1H),2.58(d,J＝7.2Hz,3H),2.34(d,J＝2.0Hz,1H),1.92-1.81(m,1H),1.70-1.61(m,1H),1.59-1.53(m,1H),1.44(d,J＝3.6Hz,9H),1.38(s,1H),1.24(s,1H),0.89-0.78(m,2H),-0.06--0.14(m,9H)；m/z ES+[M+H] ⁺ 716.2。

Step 4.2- (1- ((2-azabicyclo [2.2.1] heptan-5-yl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (0.1 mL) and dichloromethane (1C)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -2-azabicyclo [2.2.1]A solution of tert-butyl heptane-2-carboxylate (400 mg, 558. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give 2- (1- (2-azabicyclo [ 2.2.1) as a yellow oil]Heptane-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (340 mg, crude). M/zES + [ M+H ]] ⁺ 616.1。

Intermediate 27:2- (1- (azetidin-3-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (10 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group ]To a solution of ethyl-trimethyl-silane (500 mg,986 umol) and tert-butyl 3- (iodomethyl) azetidine-1-carboxylate (290 mg,976 umol) was added cesium carbonate (1 g,3.07 mmol). The mixture was stirred at 100℃for 14 hours. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=30/1 to 10/1) to give 3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Azetidine-1-carboxylic acid tert-butyl ester (800 mg, crude product). M/zES + [ M+H ]] ⁺ 676.1。

Step 2.2- (1- (azetidin-3-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (4 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of tert-butyl azetidine-1-carboxylate (400 mg,591 umol) was stirred at 25℃for 1.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: [ water (0.1% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,8 min) purification to give 2- [1- (azetidin-3-ylmethyl) pyrazol-4-yl as a yellow solid]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (240 mg)538umol,91% formate). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.32(s,1H),8.73(s,1H),8.43-8.37(m,2H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.97-6.90(m,1H),4.51(d,J＝7.2Hz,2H),3.87(d,J＝8.8Hz,2H),3.75(t,J＝8.0Hz,2H),3.33-3.22(m,1H),2.49(s,3H)；m/z ES+[M+H] ⁺ 446.0。

Intermediate 28: 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (5-methyl-1H-pyrazol-4-yl) quinoxaline

Step 1.3-methyl-1- (tetrahydro-2H-pyran-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

To a solution of 5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (18.0 g,86.5 mmol) in toluene (200 mL) was added p-toluenesulfonic acid (1.49 g,8.65 mmol) and 3, 4-dihydro-2H-pyran (8.73 g,103 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to give 5-methyl-1-tetrahydropyran-2-yl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (20 g,68.4mmol, 64%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.83(s,1H),5.33-5.29(m,1H),4.09-4.03(m,1H),3.69-3.64(m,1H),2.41(s,3H),2.04-1.97(m,2H),1.71-1.55(m,4H),1.30(s,12H)。

Step 2.7-bromo-2- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxaline

7-bromo-2-chloro-quinoxaline (16.0 g,65.7 mmol), 5-methyl-1-tetrahydropyran-2-yl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (20.0 g,68.4 mmol) in dioxane (200 mL) and water (40 mL),A mixture of tetrakis (triphenylphosphine) palladium (3.95 g,3.42 mmol), potassium phosphate (29.1 g,136 mmol) was degassed and purged 3 times with nitrogen, and the mixture was stirred at 80℃under a nitrogen atmosphere for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 3/1) to give 7-bromo-2- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxaline (26.0 g,69.6mmol, 93%) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.99(s,1H),8.22(s,1H),8.19(d,J＝2.0Hz,1H),7.88(d,J＝8.8Hz,1H),7.73-7.69(m,1H),5.41-5.32(m,1H),3.77-3.67(m,1H),2.68(s,3H),2.31-2.25(m,3H),2.15-2.10(m,2H),1.76-1.59(m,4H)。

Step 3.3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-ol

A mixture of 7-bromo-2- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxaline (26.0 g,69.6 mmol), potassium hydroxide (39.0 g,696 mmol), tris (dibenzylideneacetone) dipalladium (6.38 g,6.97 mmol) and t-Bu XPhos (5.92 g,13.9 mmol) in dioxane (300 mL) and water (50 mL) was degassed and purged with nitrogen 3 times, and the mixture was stirred under nitrogen atmosphere at 100℃for 3 hours. After completion, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 0/1) to give 3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-ol (17.0 g,54.8mmol, 60%) as a white solid. M/zES + [ M+H ] ] ⁺ 311.1。

Step 4.5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-ol

To a solution of 3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-ol (16.0 g,51.5 mmol) in chloroform (300 mL) were added chlorosuccinimide (13.7 g,103 mmol), nickel chloride (6.68 g,51.5 mmol) and triethylamine (5.22 g,51.5 mmol). The mixture was stirred at 60℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleumEther/ethyl acetate=10/1 to 1/1) to give 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-ol (7 g,20mmol, 39%) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.93(s,1H),8.26(s,1H),7.91(d,J＝9.2Hz,1H),7.45(d,J＝9.2Hz,1H),5.53-5.28(m,1H),4.20-4.12(m,1H),3.81-3.70(m,1H),2.79(s,3H),2.19-2.12(m,2H),1.80-1.67(m,4H)。

Step 5.5- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl ] oxy-2-nitro-aniline

To a solution of 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-ol (1.30 g,3.77 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (1.56 g,11.31 mmol) and 5-fluoro-2-nitroaniline (765 mg,4.90 mmol). The mixture was stirred at 120℃for 12 hours. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=1/0 to 100/5) to give 5- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl as a yellow solid ]Oxy-2-nitro-aniline (500 mg,1.04mmol, 22%). M/zES + [ M+H ]] ⁺ 481.1

Step 6.4- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl ] oxybenzene-1, 2-diamine

To 5- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl in ethanol (10 mL) and water (5 mL)]To a solution of oxy-2-nitro-aniline (500 mg,1.04 mmol) was added iron powder (460 mg,8.32 mmol) and ammonium chloride (444 mg,8.32 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the reaction mixture was filtered. The filtrate was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl as a yellow solid]Oxybenzene-1, 2-diamine (350 mg, crude). M/zES + [ M+H ]] ⁺ 451.1

Step 7.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxaline

To 4- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl in methanol (10 mL)]To a solution of oxybenzene-1, 2-diamine (800 mg,1.77 mmol) was added sulfamic acid (344 mg,3.55 mmol) and 1, 1-trimethoxyethane (1.07 g,8.87 mmol). The mixture was stirred at 25℃for 2 hours. After completion, the reaction pH was adjusted to pH about 8 with saturated ammonium hydroxide, then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=1/0 to 10/1) to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow solid ]-2- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxaline (1 g,2.11mmol, 89%). ¹ H NMR(400MHz,CDCl ₃ )δ8.99(s,1H),8.29(s,1H),7.86(d,J＝9.2Hz,1H),7.56(d,J＝8.8Hz,1H),7.29(s,1H),7.25(d,J＝2.0Hz,1H),7.07-7.02(m,1H),5.44-5.38(m,1H),3.79-3.70(m,2H),2.81(s,3H),2.67(s,3H),2.13-2.04(m,2H),1.76-1.63(m,4H)。

Step 8.2- [ [6- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in tetrahydrofuran (10 mL) at 0deg.C]To a solution of 2- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxaline (800 mg,1.68 mmol) was added sodium hydroxide (134 mg,3.37mmol,60% in mineral oil). The mixture was stirred at 0℃for 0.5 h. (2- (chloromethoxy) ethyl) trimethylsilane (426 mg,2.53 mmol) was then added dropwise and the mixture was stirred at 25℃for 1.5 hours. After completion, the reaction mixture was quenched with water (20 mL) at 25 ℃ and then extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=1/0 to 20/1) to give 2- [ [6- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl ] as a yellow solid]Oxy-2-methyl-benzimidazol-1-yl ]Methoxy group]Ethyl-trimethyl-silane900mg，3.14mmol，85％)。m/z ES+[M+H] ⁺ 605.2

Step 9.2- [ [6- [ 5-chloro-3- (5-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxalin-6-yl ] in methanol (9 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (0.90 g,1.49 mmol) was added aqueous hydrochloride (1M, 9 mL). The mixture was stirred at 25℃for 1 hour. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 2- [ [6- [ 5-chloro-3- (5-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl as a yellow solid]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (1.1 g, crude). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.32(d,J＝4.0Hz,1H),7.93(d,J＝9.2Hz,1H),7.66(d,J＝8.8Hz,1H),7.59(d,J＝8.8Hz,1H),7.42(d,J＝2.4Hz,1H),7.29(d,J＝1.6Hz,1H),6.99(d,J＝2.4Hz,1H),5.65-5.50(m,2H),3.59-3.41(m,2H),2.56(d,J＝7.2Hz,3H),2.50(s,3H),0.88-0.75(m,2H),-0.07--0.16(m,9H)。

Intermediate 29:2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) acetic acid

Step 1.2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] acetic acid

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in tetrahydrofuran (7 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethylsilane (500 mg,986 umol) was added sodium hydride (118 mg,2.96mmol,60% in mineral oil),the mixture was stirred at 25℃for 30min. And then 2-bromoacetic acid (206 mg,1.48 mmol) was added, and the mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was quenched with saturated citric acid (7 mL) and then filtered. The filtered cake was dried in vacuo to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Acetic acid (556 mg,984umol, 99%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.35(s,1H),8.72(s,1H),8.40(s,1H),7.97(d,J＝9.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.45(d,J＝2.0Hz,1H),7.33(d,J＝9.2Hz,1H),7.02(dd,J＝2.4,8.8Hz,1H),5.54(s,2H),5.13(s,2H),3.48(t,J＝8.0Hz,2H),2.56(s,3H),0.79(t,J＝8.0Hz,2H),-0.11--0.20(m,9H)；m/z ES+[M+H] ⁺ 565.2。

Intermediates 31 and 32: (tetrahydro-2H-thiopyran-4-yl) methyl mesylate and 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((tetrahydro-2H-thiopyran-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

(tetrahydro-2H-thiopyran-4-yl) methanol

To a solution of tetrahydrothiopyran-4-carbaldehyde (0.20 g,1.54 mmol) in ethanol (5 mL) was added sodium borohydride (581 mg,15.7 mmol) and the mixture was stirred at 25℃for 2 hours. After completion, the reaction mixture was poured into water (80 mL) and methanol (10 mL), followed by extraction with ethyl acetate (30 ml×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give tetrahydrothiopyran-4-yl methanol (0.20 g, crude) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ3.47(d,J＝6.0Hz,2H),2.75–2.60(m,4H),2.08(dd,J＝13.2,2.8Hz,2H),1.60–1.50(m,1H),1.45–1.35(m,2H)。

(tetrahydro-2H-thiopyran-4-yl) methyl methanesulfonate

Tetrahydrothiopyran-4-yl methanol in dichloromethane (2 mL) at 0 ℃ (180 mg,to a solution of 1.36 mmol) were added methanesulfonyl chloride (312 mg,2.72 mmol) and triethylamine (413 mg,4.08 mmol), and the mixture was stirred at 25℃for 1 hour. After completion, the reaction mixture was poured into an aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tetrahydrothiopyran-4-ylmethyl mesylate (344 mg, crude) as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ4.04(d,J＝6.4Hz,2H),3.02(s,3H),2.71-2.63(m,4H),1.81-1.80(m,1H),1.50-1.40(m,4H)。

Step 3.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((tetrahydro-2H-thiopyran-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

To tetrahydrothiopyran-4-ylmethyl mesylate (0.30 g,1.43 mmol) and 2- [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl in N, N-dimethylformamide (5 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a mixture of ethyl-trimethyl-silane (323 mg,1.43 mmol) was added potassium carbonate (390 mg,2.85 mL), and the mixture was stirred at 80℃for 12 hours. After completion, the mixture was concentrated under reduced pressure. The crude product was triturated with water (30 mL) at 15℃for 40min to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid ]Imidazol-6-yl) oxy) -2- (1- ((tetrahydro-2H-thiopyran-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (0.20 g,0.32mmol, 23%). M/zES + [ M+H ]] ⁺ 621.3。

Intermediate 33:2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

(3S, 4S) -3-fluoro-4- (4- (8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

To (3 s,4 s) -4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dioxane (5 mL) and water (0.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of tert-butyl 3-fluoro-piperidine-1-carboxylate (220 mg, 311. Mu. Mol) and methylboronic acid (186 mg,3.11 mmol) were added sodium carbonate (98.8 mg, 932. Mu. Mol) and methanesulfonyl (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (36.7 mg, 46.6. Mu. Mol). The mixture was stirred under nitrogen at 110 ℃ for 12 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/8) to give (3 s,4 s) -3-fluoro-4- (4- (8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (140 mg,203umol, 66%); M/zES + [ M+H ]] ⁺ 688.4。

Step 2.2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To (3S, 4S) -3-fluoro-4- [4- [ 8-methyl-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of tert-butyl piperidine-1-carboxylate (130 mg, 189. Mu. Mol) was added trifluoroacetic acid (460 mg,4.05 mmol). The mixture was stirred at 25℃for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate (30 mL) and extracted with dichloromethane (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (100 mg, crude). M/z ES+ [ M+H ]] ⁺ 588.2。

Intermediates 35 and 36:4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester and 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (10 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (500 mg,0.99 mmol) and tert-butyl 4- (bromomethyl) piperidine-1-carboxylate (302 mg,1.08 mmol) was added potassium carbonate (169 mg,2.96 mmol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was treated with H ₂ O (30 mL) was diluted and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=100/1 to 10/1) to give 4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) piperidine-1-carboxylic acid tert-butyl ester (700 mg, 974. Mu. Mol, 99%). M/zES + [ M+H ]] ⁺ 704.3。

Step 2.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline

To 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in dichloromethane (10 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (700 mg,0.99 mmol) was added trifluoroacetic acid (1.54 g,13.51mmol,1 mL)). The mixture was stirred at 25℃for 3 hours. The reaction mixture was diluted with saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (20 ml×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 8-chloro-7- ((2-methoxypyridin-4-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline (680 mg, crude) as a yellow solid. M/z ES+ [ M+H ]] ⁺ 604.1。

Intermediate 37: 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (2- (piperidin-4-yl) ethyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.4- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] ethyl ] piperidine-1-carboxylic acid tert-butyl ester

To) 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (10 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group ]To a solution of ethyl-trimethyl-silane (830 mg,1.64 mmol) was added potassium carbonate (681 mg,4.93 mmol) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (480 mg,1.64 mmol). The mixture was stirred at 80℃for 2 hours. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]Piperidine-1-carboxylic acid tert-butyl ester (1.20 g, crude). M/zES + [ M+H ]] ⁺ 718.2。

Step 2.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- (4-piperidinyl) ethyl ] pyrazol-4-yl ] quinoxaline

4- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (6 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]Piperidine-1-carboxylic acid tert-butyl ester500mg, 696. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow oil ]-2- [1- [2- (4-piperidinyl) ethyl ]]Pyrazol-4-yl]Quinoxaline (500 mg, crude). M/zES + [ M+H ]] ⁺ 488.1。

Intermediate 38: 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((4- (methylsulfanyl) cyclohexyl) methyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.4- (p-toluenesulfonyloxy) cyclohexanecarboxylic acid ethyl ester

To a solution of ethyl 4-hydroxycyclohexane carboxylate (1 g,5.81 mmol) in dichloromethane (20 mL) were added 4-methylbenzenesulfonyl chloride (1.22 g,6.39 mmol), triethylamine (640 mg,6.39 mmol) and 4-dimethylaminopyridine (70.9 mg, 581umol), and the mixture was stirred at 20℃for 24 hours. After completion, the mixture was quenched with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (50/1 to 10/1 petroleum ether/ethyl acetate) to give ethyl 4- (p-toluenesulfonyloxy) cyclohexanecarboxylate (1.7 g,5.21mmol, 87%) as a colorless oil. . ¹ HNMR(400MHz,CDCl ₃ )δ7.82(d,J＝8.4Hz,2H),7.36(d,J＝8.0Hz,2H),4.17-4.08(m,2H),3.25(q,J＝7.2Hz,1H),2.47(s,3H),2.35-2.20(m,1H),2.04-1.94(m,3H),1.92-1.85(m,1H),1.77-1.67(m,1H),1.55-1.43(m,3H),1.26(q,J＝7.2Hz,3H)。

Step 2.4-methylsulfanyl cyclohexane carboxylic acid ethyl ester

To a solution of ethyl 4- (p-toluenesulfonyloxy) cyclohexanecarboxylate (1.2 g,3.68 mmol) in ethanol (20 mL) was added sodium methyl mercaptide (1.29 g,18.38 mmol) and the mixture was stirred at 80℃for 2 h. After completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). Combining the organic layers Dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate 20/1 to 5/1) to give ethyl 4-methylsulfanyl cyclohexane carboxylate (550 mg,2.72mmol, 74%) as a colorless oil. ¹ HNMR(400MHz,CDCl ₃ )δ4.15(s,2H),2.86-2.77(m,1H),2.50-2.42(m,1H),2.09(s,3H),2.08-2.01(m,2H),1.88-1.64(m,5H),1.54-1.31(m,1H),1.30-1.26(m,3H)。

(4-methylsulfanyl cyclohexyl) methanol

To a solution of ethyl 4-methylsulfanyl cyclohexanecarboxylate (150 mg,741 umol) in tetrahydrofuran (10 mL) was added lithium borohydride (48.5 mg,2.22 mmol) at 0deg.C, and the mixture was stirred at 20deg.C for 2 hours. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate 10/1 to 3/1) to give (4-methylsulfanyl cyclohexyl) methanol (60 mg,370umol, 50%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ3.54(d,J＝6.0Hz,2H),3.01-2.95(J＝4.0Hz,1H),2.09(s,3H),1.90-1.72(m,4H),1.64-1.47(m,5H)。

(4-methylsulfanyl cyclohexyl) methyl methanesulfonate

To a solution of (4-methylsulfanyl cyclohexyl) methanol (60.0 mg,374 umol) and diisopropylethylamine (145 mg,1.12 mmol) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (98.6 mg,861 umol), and the mixture was stirred at 20℃for 1 hour. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (4-methylsulfanyl cyclohexyl) methyl methanesulfonate (70 mg, crude) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ4.13-4.03(m,2H),3.70(s,3H),3.09-2.95(m,4H),2.14-2.08(m,3H),1.89-1.75(m,4H),1.65-1.53(m,4H)。

Step 5.2- [ [6- [ 5-chloro-3- [1- [ (4-methylsulfanyl-cyclohexyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A mixture of ethyl-trimethyl-silane (100 mg, 197umol), (4-methylsulfanyl cyclohexyl) methyl methanesulfonate (68.2 mg, 284 umol) and potassium carbonate (81.8 mg,592 umol) was stirred at 80℃for 1 hour. After completion, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane/methanol=100/1 to 20/1) to give 2- [ [6- [ 5-chloro-3- [1- [ (4-methylsulfanyl cyclohexyl) methyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (35 mg,54.0umol, 22%). M/zES + [ M+H ]] ⁺ 649.2。

Intermediate 39: 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) methyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.1-tetrahydropyran-2-yloxy cyclopropanecarboxylic acid methyl ester

To a solution of methyl 1-hydroxycyclopropane carboxylate (1 g,8.61 mmol) in methylene chloride (15 mL) were added pyridinium p-toluenesulfonate (216 mg,861 umol) and 3, 4-dihydro-2H-pyran (761 mg,9.04 mmol). The mixture was stirred at 25℃for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 6/1) to give methyl 1-tetrahydropyran-2-yloxy cyclopropanecarboxylate (1.15 g,5.74mmol, 67%) as a white oil. ¹ H NMR(400MHz,DMSO-d ₆ )δ4.86-4.81(m,1H),3.76-3.72(m,1H),3.64(s,1H),3.45-3.40(m,1H),1.71-1.65(m,2H),1.71-1.65(m,2H),1.58-1.34(m,6H),1.20-1.10(m,2H)。

(1-tetrahydropyran-2-yloxycyclopropyl) methanol

To a mixture of methyl 1-tetrahydropyran-2-yloxy cyclopropanecarboxylate (100 mg,499 umol) in tetrahydrofuran (1 mL) was added lithium aluminum hydride (37.9 mg,998 umol) in portions under a nitrogen atmosphere at 0℃and the reaction mixture was stirred at 0℃for 0.5 hours. The reaction mixture was quenched with water (3 mL), sodium hydroxide solution (4 n,3 mL) and then filtered. The filtrate was concentrated under reduced pressure to give (1-tetrahydropyran-2-yloxycyclopropyl) methanol (80.0 mg, 460 umol, 93%) as a white oil without further purification. ¹ H NMR(400MHz,CDCl ₃ )δ4.73-4.63(m,1H),4.11-3.98(m,2H),3.68-3.58(m,1H),3.11(d,J＝12.8Hz,1H),1.87-1.79(m,1H),1.71-1.64(m,1H),1.61-1.54(m,3H),1.53-1.50(m,1H),0.96-0.89(m,1H),0.85-0.78(m,1H),0.76-0.69(m,1H),0.66-0.56(m,1H)。

Step 3.2- [ [6- [ 5-chloro-3- [1- [ (1-tetrahydropyran-2-yloxycyclopropyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To (1-tetrahydropyran-2-yloxycyclopropyl) methanol (100 mg,580 mol), 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in toluene (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (245 mg,483 umol) was added triphenylphosphine (190 mg,725 umol), the reaction was degassed and purged 3 times with nitrogen. Diisopropyl azodicarboxylate (146 mg, 720 umol) was then added dropwise, and the mixture was stirred at 60℃for 1.5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate=1:1) to give 2- [ [6- [ 5-chloro-3- [1- [ (1-tetrahydropyran-2-yloxy-cyclopropyl) methyl ] as a yellow oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (200 mg,32.0umol, 62) ％)。m/zES+[M+H] ⁺ 661.1。

Intermediate 40:4- ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

Step 1.4- [ [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] methyl ] piperidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 4- (bromomethyl) piperidine-1-carboxylate (500 mg,1.80 mmol) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (365 mg,1.89 mmol) in N, N-dimethylformamide (8 mL) was added potassium carbonate (500 mg,3.62 mmol). The mixture was then stirred at 80℃for 12 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1 to 2:1) to give 4- [ [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl as a colorless oil]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (450 mg,1.15mmol, 57%). ¹ H NMR(400MHz,CDCl ₃ )δ7.92(s,1H),7.71(s,1H),4.19(d,J＝6.4Hz,2H),4.14-4.07(m,2H),2.72-2.63(m,2H),2.26-2.13(m,1H),1.57(d,J＝12.4Hz,2H),1.45(s,9H),1.24(s,12H),1.21-1.11(m,2H)；m/z ES+[M+H] ⁺ 392.0。

Example 1.synthesis of 1- [4- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -quinoxalin-2-yl ] pyrazol-1-yl ] ethyl ] -1-piperidinyl ] prop-2-en-1-one.

Step 1 to a solution of 7-bromo-2-chloro-quinoxaline (5 g,20.5 mmol) in dichloroethane (50 mL) was added BBr ₃ (25.7 g,102 mmol). The mixture was stirred at 80℃for 12 hours. After completion, willThe reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2, 7-dibromoquinoxaline (5.8 g, crude) as a red solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.86(s,1H),8.21(d,J＝2.0Hz,1H),8.01-7.95(m,1H),7.90-7.84(m,1H)。

Step 2. Will be described in dioxane (100 mL) and H ₂ 2, 7-Dibromoquinoxaline (5.8 g,20.1 mmol), 1-tetrahydropyran-2-yl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (5.32 g,19.1 mmol), KOAC (5.93 g,60.4 mmol), pd (dppf) Cl in O (10 mL) ₂ (1.47 g,2.01 mmol) and N ₂ Purge 3 times, then the mixture was taken over N ₂ Stirring is carried out for 12 hours at 60℃under an atmosphere. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 2/1) to give 7-bromo-2- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxaline (3.5 g, 34%) as a red solid. M/z ES+ [ M+H ] ] ⁺ 359.1。

Step 3. To be added in dioxane (30 mL) and H ₂ 7-bromo-2- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxaline (3.5 g,9.74 mmol), pd in O (10 mL) ₂ (dba) ₃ (892 mg, 974. Mu. Mol), t-BuXPhos (413 mg, 974. Mu. Mol) and KOH (5.47 g,97.4 mmol) were degassed with N ₂ Purge 3 times, then the mixture was taken over N ₂ Stirring is carried out for 2 hours at 100℃under an atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to give 3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (1.10 g, 38%) as a red solid. M/z ES+ [ M+H ]] ⁺ 297.2。

Step 4. To a solution of 3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (3.4 g,11.4 mmol) in acetonitrile (50 mL) was added N-chlorosuccinimide (1.53 g,11.4 mmol) in portions. The mixture was stirred at 80℃for 12 hours. At the endAfter completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to give 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (2.5 g, 62%) as a yellow solid. M/z ES+ [ M+H ]] ⁺ 330.9。

Step 5 to a solution of 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-ol (1 g,3.02 mmol) in DMF (20 mL) was added K ₂ CO ₃ (835 mg,6.05 mmol) and 5-fluoro-2-nitro-aniline (707 mg,4.53 mmol). The mixture was stirred at 120℃for 12 hours. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to give 5- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl as a yellow solid]Oxy-2-nitro-aniline (800 mg, 36%). M/z ES+ [ M+H ]] ⁺ 467.1。

Step 6. To ethanol (10 mL) and H ₂ 5- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl in O (2 mL)]To a solution of oxy-2-nitro-aniline (800 mg,1.71 mmol) was added iron powder (765 mg,13.7 mmol) and NH ₄ Cl (733 mg,13.7 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure, then the residue was diluted with water (25 mL), and extracted with ethyl acetate (25 ml×3)). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 0/1) to give 4- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl as a yellow solid ]Oxybenzene-1, 2-diamine (300 mg, 36%). M/z ES+ [ M+H ]] ⁺ 504.4。

Step 7. To 4- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl in methanol (3 mL)]To a solution of oxybenzene-1, 2-diamine (250 mg, 572. Mu. Mol) were added sulfamic acid (111 mg,1.14 mmol) and 1, 1-trimethoxyethane (343 mg,2.86 mmol). The mixture was stirred at 25℃for 2 hours. At the position ofAfter completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a red solid]-2- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxaline (400 mg, crude). M/z ES+ [ M+H ]] ⁺ 461.4。

Step 8. At 0deg.C, 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in THF (5 mL)]To a solution of 2- (1-tetrahydropyran-2-yl-pyrazol-4-yl) quinoxaline (380 mg, 824. Mu. Mol) was added NaH (65.9 mg,1.65mmol,60% purity), and the mixture was stirred at 0℃for 0.5 hours. SEM-Cl (206 mg,1.24 mmol) was then added and the mixture was stirred at 25℃for 1.5 h. After completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 0/1) to give 2- [ [6- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl ] as a yellow solid ]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (220 mg, 35%). M/zES + [ M+H ]] ⁺ 591.3。

Step 9. 2- [ [6- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl ] in dichloromethane (3 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (170 mg, 287. Mu. Mol) was added TFA (460 mg,4.05mmol,0.3 mL). The mixture was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (0.1% ammonium hydroxide) to give 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl as a red oil]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (50 mg, crude). M/z ES+ [ M+H ]] ⁺ 507.2。

Step 10 to 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in DMF (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]K was added to a solution of ethyl-trimethyl-silane (45 mg, 88.7. Mu. Mol) ₂ CO ₃ (36.8 mg, 266. Mu. Mol) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (25.9 mg, 88.7. Mu. Mol). The mixture was stirred at 80℃for 2 hours.After completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 ml×3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give 4- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]Piperidine-1-carboxylic acid tert-butyl ester (50 mg, crude). M/z ES+ [ M+H ]] ⁺ 718.3。

Step 11 4- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in TFA (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]A solution of tert-butyl piperidine-1-carboxylate (45 mg, 62.6. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a red oil]-2- [1- [2- (4-piperidinyl) ethyl ]]Pyrazol-4-yl]Quinoxaline (50 mg, crude). M/z ES+ [ M+H ]] ⁺ 488.0。

Step 12. To a reaction mixture of THF (0.5 mL) and H ₂ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in O (0.5 mL)]-2- [1- [2- (4-piperidinyl) ethyl ]]Pyrazol-4-yl]NaHCO was added to a solution of quinoxaline (35 mg, 71.7. Mu. Mol) ₃ (18.1 mg, 215. Mu. Mol) and prop-2-enoyl chloride (9.74 mg, 108. Mu. Mol). The mixture was stirred at 0℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the B%:15% -45%,7 min) to give 1- [4- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]-1-piperidinyl group]Prop-2-en-1-one (18.4 mg, 46%). M/z ES+ [ M+H ]] ⁺ 542.5； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.33(br s,1H),9.31(s,1H),8.75(s,1H),8.36(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.0Hz,1H),7.38-7.16(m,2H),6.98-6.91(m,1H),6.85-6.75(m,1H),6.11-6.03(m,1H),5.68-5.61(m,1H),4.40(d,J＝11.6Hz,1H),4.33-4.26(m,2H),4.03(d,J＝13.2Hz,1H),3.05-2.94(m,1H),2.64-2.54(m,1H),2.49(s,3H),1.87-1.73(m,4H),1.59-1.46(m,1H),1.16-0.99(m,2H)。

EXAMPLE 2 Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [ (1, 2-trimethyl-4-piperidinyl) methyl ] pyrazol-4-yl ] quinoxaline

Step 1 to a solution of (methoxymethyl) triphenylphosphonium chloride (4.52 g,13.2 mmol) in THF (15 mL) was added tBuOK (1.48 g,13.2 mmol) in portions at 0deg.C. The mixture was stirred at 0deg.C for 1 hour, then tert-butyl 2, 2-dimethyl-4-oxo-piperidine-1-carboxylate (2 g,8.8 mmol) in THF (15 mL) was added. The mixture was stirred at 30℃for 15 hours. The reaction mixture was concentrated under reduced pressure, then diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 ml x 3), dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=50/1 to 20/1) to give 4- (methoxymethylene) -2, 2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 76%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ5.93(s,1H),5.84(s,1H),3.58(s,4H),2.36-2.33(m,2H),2.22(t,J＝6.0Hz,3H),2.11(s,2H),1.39(s,9H),1.37(s,6H)。

Step 2. To a solution of tert-butyl 4- (methoxymethylene) -2, 2-dimethyl-piperidine-1-carboxylate (1.7 g,6.66 mmol) in acetonitrile (170 mL) was added HCl (1M, 7.99 mL) at 0deg.C. The mixture was stirred at 25℃for 16 hours. The reaction mixture was passed through saturated NaHCO ₃ The solution (20 mL) was quenched and concentrated under reduced pressure. The residue was then diluted with water (50 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine (50 ml x 3), dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give 4-formyl-2, 2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 99%) as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ9.68(d,J＝0.8Hz,1H),3.57(ddd,J＝4.4,8.0,13.6Hz,1H),3.48-3.37(m,1H),2.69-2.56(m,1H),1.99-1.87(m,1H),1.84-1.69(m,3H),1.50(s,3H),1.47(s,9H),1.39(s,3H)。

Step 3 to a solution of tert-butyl 4-formyl-2, 2-dimethyl-piperidine-1-carboxylate (1.6 g,6.63 mmol) in ethanol (15 mL) was added NaBH ₄ (276 mg,7.29 mmol). The mixture was stirred at 25℃for 2 hours. The reaction mixture was quenched with water (30 mL) at 0 ℃ and extracted with dichloromethane (20 ml×3). The combined organic layers were washed with brine (30 ml x 3), dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give tert-butyl 4- (hydroxymethyl) -2, 2-dimethyl-piperidine-1-carboxylate (1.45 g, 90%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ5.39-5.22(m,1H),3.66(ddd,J＝4.4,6.4,13.6Hz,1H),3.55-3.42(m,2H),3.32-3.16(m,1H),1.84(br s,2H),1.56-1.54(m,1H),1.50(s,3H),1.46(s,9H),1.38(br d,J＝12.8Hz,1H),1.32(s,3H),1.27-1.13(m,1H)。

Step 4. 4- (hydroxymethyl) -2, 2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg,2.05 mmol) and CBr ₄ (886 mg,2.67 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0deg.C, then PPh was added ₃ (647 mg,2.47 mmol). The mixture was stirred at 25℃for 2 hours. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 ml×3). The combined organic layers were washed with brine (10 mL. Times.3), and dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=50/1 to 30/1) to give tert-butyl 4- (bromomethyl) -2, 2-dimethyl-piperidine-1-carboxylate (550 mg, 87%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ3.72(ddd,J＝4.4,6.0,13.6Hz,1H),3.29(d,J＝6.4Hz,2H),3.21(ddd,J＝4.0,9.2,13.6Hz,1H),2.08-1.86(m,2H),1.62-1.56(m,1H),1.52(s,3H),1.46(s,9H),1.41(br d,J＝12.8Hz,1H),1.30(s,3H),1.28-1.20(m,1H)。

Step 5 to 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in DMF (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]K was added to a solution of ethyl-trimethyl-silane (80 mg, 158. Mu. Mol) ₂ CO ₃ (65.4 mg, 473. Mu. Mol), 4- (bromomethyl) -2, 2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (72.47 mg, 237. Mu. Mol)mol). The mixture was stirred at 100℃for 2 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 ml×3). The combined organic layers were washed with brine (3 ml x 3), dried over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-2, 2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, crude). m/z ES ⁺ [M+H] ⁺ 732.3。

Step 6 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in TFA (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of tert-butyl-2, 2-dimethyl-piperidine-1-carboxylate (120 mg, 164. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo to give 8-chloro-2- [1- [ (2, 2-dimethyl-4-piperidinyl) methyl ] as a yellow oil]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (100 mg, crude). m/z ES ⁺ [M+H] ⁺ 502.0。

Step 7. To 8-chloro-2- [1- [ (2, 2-dimethyl-4-piperidinyl) methyl ] in DMF (1 mL)]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (90 mg, 146. Mu. Mol, TFA) was added formic acid (140 mg,2.92 mmol) and paraformaldehyde (87.7 mg,2.92 mmol). The mixture was stirred at 60℃for 12 hours. The reaction mixture was filtered and concentrated in vacuo, which was purified by preparative HPLC (column: unisil 3-100C18 Ultra 150*50mm*3um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B%:5% -35%,10 min) to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as an off-white solid ]-2- [1- [ (1, 2-trimethyl-4-piperidinyl) methyl]Pyrazol-4-yl]Quinoxaline (40.7 mg, 54%). M/z ES+ [ M+H ]] ⁺ 516.3； ¹ HNMR(400MHz,DMSO-d ₆ )δ12.29(br s,1H),9.31(s,1H),8.71(s,1H),8.40(s,1H),8.15(s,1H),7.96(d,J＝9.2Hz,1H),7.49(br s,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.97-6.88(m,1H),4.22-4.08(m,2H),3.10–3.00(m,1H),2.98-2.89(m,1H),2.50(s,6H),2.35-2.26(m,1H),1.65–1.55(m,2H),1.47-1.31(m,2H),1.28-1.21(m,3H),1.15(s,3H)。

Example 3.4 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylpiperidin-2-one

Step 1 to a solution of tert-butyl 4- (bromomethyl) piperidine-1-carboxylate (9.5 g,34 mmol) in DMF (90 mL) was added K ₂ CO ₃ (9.4 g,68 mmol) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (6.9 g,36 mmol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was treated with H ₂ O (150 mL) was diluted and extracted with ethyl acetate (80 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1 to 3/1) to give 1- (4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ]) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl piperidin-1-yl) ethanone (7.2 g, 51%). ¹ H NMR(400MHz,CDCl ₃ )δppm 7.80(s,1H)7.65(s,1H)4.13(d,J＝7.2Hz,2H)4.01(d,J＝7.2Hz,2H)2.66(t,J＝12.4Hz,2H)2.15–2.05(m,1H)1.54(d,J＝12.8Hz,2H)1.45(s,9H)1.32(s,12H)1.20–1.12(m,2H)。

Step 2. To a reaction between dioxane (200 mL) and H ₂ 4- [ [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] in O (40 mL)]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (20 g,51 mmol) and 2, 7-dibromoquinoxaline (18 g,61 mmol) was added KOAC (15 g,0.15 mol) and Pd (dppf) Cl ₂ (3.7 g,5.1 mmol). The mixture is put under N ₂ Stirred at 70℃for 36 hours. The reaction mixture was taken up in water H ₂ O (500 mL) was diluted and extracted with dichloromethane (300 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 1/2) to give 4- ((4- (7-bromoquinoxalin-2-yl) -1H-pyrazole-1) as a yellow solid-methyl) piperidine-1-carboxylic acid tert-butyl ester (27 g, 54%). ¹ H NMR(400MHz,CDCl ₃ )δppm 9.05(s,1H)8.21(s,2H)8.14(s,1H)7.92(d,J＝8.8Hz,1H)7.75(dd,J＝8.8,2.0Hz,1H)4.10(d,J＝7.2Hz,4H)2.71(t,J＝12.0Hz,2H)2.24-2.11(m,1H)1.63(d,J＝12.4Hz,2H)1.46(s,9H)1.31-1.18(m,2H)。

Step 3. To a reaction between dioxane (280 mL) and H ₂ 4- [ [4- (7-bromoquinoxalin-2-yl) pyrazol-1-yl ] in O (140 mL)]Methyl group]Pd was added to a solution of tert-butyl piperidine-1-carboxylate (27 g,58 mmol) ₂ (dba) ₃ (5.30 g,5.8 mmol), t-BuXPhos (2.5 g,5.8 mmol) and KOH (32 g,0.58 mol). The mixture was degassed and used with N ₂ Purge 3 times, and then put it under N ₂ The reaction mixture was stirred at 100℃for 3 hours with water H ₂ O (500 mL) was diluted and extracted with dichloromethane (300 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to dichloromethane/methanol=20/1) to give tert-butyl 4- ((4- (7-hydroxyquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (20 g, 84%) as a yellow solid. m/z ES ⁺ [M+H] ⁺ 410.0。

Step 4 to 4- [ [4- (7-hydroxyquinoxalin-2-yl) pyrazol-1-yl ] in acetonitrile (100 mL)]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (10 g,12 mmol) was added N-chlorosuccinimide (1.5 g,11 mmol) in portions. The mixture was stirred at 80℃for 12 hours. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to dichloromethane/methanol=20/1) to give tert-butyl 4- ((4- (8-chloro-7-hydroxyquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (7.9 g, 68%) as a yellow solid. m/zES ⁺ [M+H] ⁺ 444.1。

Step 5 to 4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl ] in DMF (50 mL)]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (4.7 g,11 mmol) and 5-fluoro-2-nitro-aniline (2 g,13 mmol) was added K ₂ CO ₃ (4.4 g,32 mmol) and KI (0.17 g,1.1 mmol). The mixture is mixedStirred at 120℃for 12 hours. The reaction mixture was treated with H ₂ O (100 mL) was diluted and extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/4) to give 4- ((4- (7- (3-amino-4-nitrophenoxy) -8-chloroquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (3 g, 39%) as a yellow solid. M/z ES+ [ M+H ] ] ⁺ 580.2。

Step 6. To ethanol (40 mL) and H ₂ 4- [ [4- [7- (3-amino-4-nitro-phenoxy) -8-chloro-quinoxalin-2-yl ] in O (20 mL)]Pyrazol-1-yl]Methyl group]Iron powder (1.2 g,21 mmol) and NH were added to a solution of tert-butyl piperidine-1-carboxylate (3 g,4.1mmol,80% purity) ₄ Cl (2.2 g,41 mmol). The mixture was stirred at 60℃for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to remove ethanol. The reaction mixture was extracted with dichloromethane (30 ml×3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1 to 0/1) to give tert-butyl 4- ((4- (8-chloro-7- (3, 4-diaminophenoxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (1.6 g, 68%) as a yellow solid. M/z ES+ [ M+H ]] ⁺ 550.1。

Step 7 to 4- [ [4- [ 8-chloro-7- (3, 4-diaminophenoxy) quinoxalin-2-yl ] in methanol (30 mL)]Pyrazol-1-yl]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (1.6 g,2.9 mmol) and 1, 1-trimethoxyethane (1.7 g,14mmol,1.8 mL) was added sulfamic acid (0.56 g,5.7 mmol). The mixture was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure to give 4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a yellow solid ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl methyl) piperidine-1-carboxylic acid tert-butyl ester (2.5 g, crude product). M/z ES+ [ M+H ]] ⁺ 574.2。

Step 8. At 0deg.C, to 4- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in THF (15 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (1)To a solution of 1g,1.9 mmol) was added NaH (0.15 g,3.8mmol,60% purity), and the mixture was stirred at 0deg.C for 30min. Then, SEM-Cl (0.48 g,2.9mmol,0.51 mL) was added at 0deg.C. The mixture was stirred at 25℃for 1.5 hours. The reaction mixture was treated with H ₂ O (100 mL) was diluted and extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=100/1 to 20/1) to give 4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl piperidine-1-carboxylic acid tert-butyl ester (1 g,1.3mmol, 67%). M/z ES+ [ M+H ]] ⁺ 704.3。

Step 9. To 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in dichloromethane (15 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (1.2 g,1.7 mmol) was added TFA (2.30 g,20mmol,1.5 mL). The mixture was stirred at 25℃for 5 hours. The reaction mixture was treated with NaHCO ₃ The solution (50 mL) was diluted and extracted with dichloromethane (20 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a brown solid]Imidazol-6-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline (1.30 g, crude). M/z ES+ [ M+H ]] ⁺ 604.2。

Step 10 to 2- [ [6- [ 5-chloro-3- [1- (4-piperidinylmethyl) pyrazol-4-yl ] in DMF (2 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (0.1 mg,0.17 mmol) was added paraformaldehyde (99 mg,3.3 mmol) and formic acid (0.16 g,3.3 mmol). The mixture was stirred at 60℃for 12 hours. The reaction mixture was treated with NaHCO ₃ The solution (20 mL) was diluted and extracted with dichloromethane (10 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure to obtain 8-chloro-7- ((2-methyl-1- (. About.) as yellow oil 2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) -2- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (90 mg, crude). M/z ES+ [ M+H ]] ⁺ 618.3。

Step 11, at H ₂ 2- [ [6- [ 5-chloro-3- [1- [ (1-methyl-4-piperidinyl) methyl ] in O (4 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Hg (OAc) was added to a solution of ethyl-trimethyl-silane (80 mg,0.13 mmol) ₂ (0.1 g,0.32 mmol) and 2- [2- [ bis (carboxymethyl) amino ]]Ethyl- (carboxymethyl) amino group]Acetic acid (91 mg,0.31 mmol). The mixture was stirred at 100℃for 16 hours. The reaction mixture was treated with NaHCO ₃ The solution (20 mL) was diluted and extracted with dichloromethane (10 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=100 to 20/1) to give 4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylpiperidin-2-one (12 mg,19 μmol, 14%). M/z ES+ [ M+H ]] ⁺ 632.3。

Step 12 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) -benzimidazol-5-yl ] in TFA (0.3 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of-1-methyl-piperidin-2-one (12 mg, 19. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (neutral condition column: waters Xbridge150 x 25mM x 5um; mobile phase: [ water (10 mM NH ₄ HCO ₃ ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:8% -38%,10 min) to give 4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) -quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -1-methylpiperidin-2-one (6 mg,12 μmol, 62%). M/z ES+ [ M+H ]] ⁺ 502.1； ¹ H NMR(400MHz,DMSO)δppm 9.33(s,1H),8.72(s,1H),8.40(s,1H),7.98(d,J＝9.2Hz,1H),7.59(d,J＝8.8Hz,1H),7.36(d,J＝9.2Hz,1H),7.28(d,J＝2.0Hz,1H),7.04(dd,J ₁ ＝8.8,2.4Hz,1H),4.21(d,J＝6.8Hz,2H),3.22-3.29(m,2H),2.80(s,3H),2.56(s,3H),2.46-2.37(m,1H),2.25-2.16(m,1H),2.11-2.02(m,1H),1.80(d,J＝12.4Hz,1H),1.58-1.46(m,1H)。

EXAMPLE 4 Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- (4-piperidinyl) pyrazol-4-yl ] quinoxaline

Step 1. To be added in dioxane (10 mL) and H ₂ 7-bromo-2-chloro-quinoxaline (750 mg,3.08 mmol), 4- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl in O (2 mL)]Piperidine-1-carboxylic acid tert-butyl ester (1.1 g,2.93 mmol), KOAC (307 mg,9.24 mmol), pd (dppf) Cl ₂ (225 mg, 308. Mu. Mol) and N ₂ Purge 3 times, then the mixture was taken over N ₂ Stirring is carried out for 12 hours at 60℃under an atmosphere. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 3/1) to give 4- [4- (7-bromoquinoxalin-2-yl) pyrazol-1-yl as a white solid ]Piperidine-1-carboxylic acid tert-butyl ester (630 mg, 45%). M/z ES+ [ M+H ]] ⁺ 458.1。

Step 2. To a reaction between dioxane (6 mL) and H ₂ 4- [4- (7-bromoquinoxalin-2-yl) pyrazol-1-yl in O (2 mL)]To a solution of tert-butyl piperidine-1-carboxylate (600 mg,1.31 mmol) was added KOH (284 mg,13.1 mmol), pd ₂ (dba) ₃ (119 mg, 131. Mu. Mol) and t-BuXPhos (55.6 mg, 131. Mu. Mol). The mixture was stirred under nitrogen at 100 ℃ for 1 hour. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/1) to give 4- [4- (7-hydroxyquinoxalin-2-yl) pyrazol-1-yl as a white solid]Piperidine-1-carboxylic acid tert-butyl ester (400 mg, 77%). ¹ H NMR(400MHz,CD ₃ OD)δ8.98(s,1H),8.56(s,1H),8.29(s,1H),7.88(d,J＝8.8Hz,1H),7.33(dd,J＝2.8,9.0Hz,1H),7.29(d,J＝2.4Hz,1H),4.55-4.45(m,1H),4.27(d,J＝13.8Hz,2H),3.02(s,2H),2.18(d,J＝11.7Hz,2H),2.09-1.92(m,2H),1.51(s,9H)。

Step 3 to 4- [4- (7-Hydroxyquinoxalin-2-yl) pyrazol-1-yl in acetonitrile (35 mL)]To a solution of tert-butyl piperidine-1-carboxylate (350 mg, 885. Mu. Mol) was added N-chlorosuccinimide (118 mg, 885. Mu. Mol). The mixture was stirred at 80℃for 16 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2/1 to 1/1) to give 4- [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl as a yellow solid ]Piperidine-1-carboxylic acid tert-butyl ester (350 mg, 92%). M/z ES+ [ M+H ]] ⁺ 430.3。

Step 4 to 4- [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl in DMF (1 mL)]K was added to a solution of tert-butyl piperidine-1-carboxylate (100 mg, 233. Mu. Mol), 5-fluoro-2-nitro-aniline (72.6 mg, 465. Mu. Mol) ₂ CO ₃ (96.5 mg, 697. Mu. Mol). The mixture was stirred at 120℃for 3 hours. After completion, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: [ water/formic acid-acetonitrile)]) Purification to give 4- [4- [7- (3-amino-4-nitro-phenoxy) -8-chloro-quinoxalin-2-yl as a yellow solid]Pyrazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester (50 mg, 38%). M/z ES+ [ M+H ]] ⁺ 566.5。

Step 5. To ethanol (5 mL) and H ₂ 4- [4- [7- (3-amino-4-nitro-phenoxy) -8-chloro-quinoxalin-2-yl in O (5 mL)]Pyrazol-1-yl]Iron powder (14.8 mg, 265. Mu. Mol) and NH were added to a solution of tert-butyl piperidine-1-carboxylate (30 mg, 53. Mu. Mol) ₄ Cl (14.2 mg, 265. Mu. Mol). The mixture was stirred at 60℃for 16 hours. After completion, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: [ water/formic acid-acetonitrile)]) Purification to give 4- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid ]Quinoxalin-2-yl]Pyrazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester (25 mg, 84%). M/z ES+ [ M+H ]] ⁺ 560.3。

Step (a)6. 4- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in HCl/ethyl acetate (4M, 1.25 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]A solution of tert-butyl piperidine-1-carboxylate (25 mg, 44.6. Mu. Mol) was stirred at 25℃for 10min. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:2% -32%,7 min) to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as an off-white solid]-2- [1- (4-piperidinyl) pyrazol-4-yl]Quinoxaline (7.95 mg, 39%). M/z ES+ [ M+H ]] ⁺ 460.2； ¹ H NMR(400MHz,CD ₃ OD)δ9.16(s,1H),8.65(s,1H),8.39(s,1H),8.37(s,2H),7.90(d,J＝9.2Hz,1H),7.55(d,J＝8.8Hz,1H),7.36(d,J＝9.2Hz,1H),7.20(d,J＝2.2Hz,1H),7.03(dd,J＝2.4,8.8Hz,1H),4.70–4.60(m,1H),3.73-3.58(m,2H),3.31-3.18(m,2H),2.60(s,3H),2.49-2.32(m,4H)。

Example 5.Synthesis of 2- (4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidin-1-yl) ethanol

Step 1 to 2- [ [6- [ 5-chloro-3- [1- (4-piperidinylmethyl) pyrazol-4-yl ] in acetonitrile (1 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (50 mg, 82.75. Mu. Mol) and 2-iodopropane (17 mg, 99. Mu. Mol) was added K ₂ CO ₃ (23 mg,0.17 mmol). The mixture was stirred at 80℃for 3 hours. The reaction mixture was concentrated under reduced pressure to give 8-chloro-2- (1- ((1-isopropylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid ]Imidazol-6-yl) oxy) quinoxaline (53 mg, crude). M/z ES+ [ M+H ]] ⁺ 646.4。

Step 2- [ [6- [ 5-chloro-3- [1- [ (1-isopropyl-4-piperidinyl) methyl ] in TFA (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethylA solution of silane (53 mg, 82. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions; column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM NH ₄ HCO ₃ ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:22% -52%,10 min) to give 8-chloro-2- (1- ((1-isopropylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (15 mg,32% as formate salt). M/z ES+ [ M+H ]] ⁺ 516.2； ¹ H NMR(400MHz,DMSO-d ₆ )δppm 9.34(s,1H),9.15(s,1H),8.74(s,1H),8.42(s,1H),8.14(s,1H),7.99(d,J＝9.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.37(d,J＝9.2Hz,1H),7.30(d,J＝2.4Hz,1H),7.04(dd,J＝8.8,2.4Hz,1H),4.22(d,J＝6.4Hz,2H),3.46-3.33(m,3H),3.02-2.90(m,2H),2.58(s,3H),2.28–2.18(m,1H),1.85–1.75(m,2H),1.54(q,J＝12.4Hz,2H),1.22(d,J＝6.8Hz,6H)。

Examples 6 and 7.2- [ [6- [ 5-chloro-3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxalin-6-yl ] oxy-2-methyl-benzimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane and Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [ 5-methyl-1- [ (1-methyl-4-piperidinyl) methyl ] pyrazol-4-yl ] quinoxaline

Step 1 to a solution of 5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (5 g,24 mmol) in DMF (50 mL) was added K ₂ CO ₃ (9.96 g,72.1 mmol) and tert-butyl 4- (bromomethyl) piperidine-1-carboxylate (6.69 g,24 mmol). The mixture was stirred at 100℃for 12 hours. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 3/1) to give 4- [ [ 3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole-1 as a colorless oil-base group]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (5 g, 40%). M/z ES+ [ M+H ]] ⁺ 406.5。

Step 2. Will be described in dioxane (50 mL) and H ₂ 4- [ [ 3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] in O (10 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (5 g,12.3 mmol), 7-bromo-2-chloro-quinoxaline (3.30 g,13.5 mmol), KOAC (3.63 g,37 mmol), pd (dppf) Cl ₂ A mixture of (902 mg,1.23 mmol) was degassed and N ₂ Purge 3 times, then the mixture was taken over N ₂ Stirring is carried out for 3 hours at 60℃under an atmosphere. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 2/1) to give 4- [ [4- (7-bromoquinoxalin-2-yl) -3-methyl-pyrazol-1-yl ] as a yellow solid ]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 50%). ¹ H NMR(400MHz,CDCl ₃ )δ9.03(d,J＝18.4Hz,1H),8.24-8.18(m,1H),8.10-7.95(m,1H),7.93

-7.88(m,1H),7.78-7.70(m,1H),4.25-4.08(m,2H),4.06-3.98(m,2H),2.80

-2.62(m,5H),2.23-2.07(m,1H),1.63(d,J＝12.0Hz,2H),1.46(d,J＝1.2Hz,9H),1.29-1.19(m,2H)。

Step 3. To be added in dioxane (30 mL) and H ₂ 4- [ [4- (7-bromoquinoxalin-2-yl) -3-methyl-pyrazol-1-yl ] in O (10 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (2.8 g,5.76 mmol), KOH (3.23 g,57.5 mmol), t-BuXPhos (244 mg, 575. Mu. Mol) and Pd ₂ (dba) ₃ (227 mg, 575. Mu. Mol) and N ₂ Purge 3 times, then the mixture was taken over N ₂ Stirring is carried out for 2 hours at 100℃under an atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to give 4- [ [4- (7-hydroxyquinoxalin-2-yl) -3-methyl-pyrazol-1-yl ] as a yellow solid]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 72.3%). M/z ES+ [ M+H ]] ⁺ 424.1。

Step 4. To 4- [ [4- (7-hydroxy) in acetonitrile (20 mL)Quinoxalin-2-yl) -3-methyl-pyrazol-1-yl]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (1.7 g,4.01 mmol) was added N-chlorosuccinimide (534 mg,4.01 mmol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to give 4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) -3-methyl-pyrazol-1-yl ] as a yellow solid ]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 56%). M/z ES+ [ M+H ]] ⁺ 458.0。

Step 5.4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) -3-methyl-pyrazol-1-yl ] methyl ] piperidine-1-carboxylic acid tert-butyl ester (1.1 g,2.4 mmol) was isolated by SFC (column: daicel ChiralPak IG (250 x 30mm,10 um); mobile phase: [ 0.1% aqueous ammonium hydroxide in methanol ]; B%:60% -60%,5.9min;60 min) to give 4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) -3-methyl-pyrazol-1-yl ] methyl ] piperidine-1-carboxylic acid tert-butyl ester (450 mg, 38%) as a yellow solid and 4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) -5-methyl-pyrazol-1-yl ] methyl ] piperidine-1-carboxylic acid tert-butyl ester (350 mg, 29%) as a yellow solid.

Step 6 4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) -3-methyl-pyrazol-1-yl ] in dichloroethane (5 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (200 mg, 436. Mu. Mol), [ 2-methyl-1- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Boric acid (200 mg, 655. Mu. Mol), cu (OAc) ₂ (39.6 mg, 218. Mu. Mol), triethylamine (132 mg,1.31 mmol) and O ₂ Purge 3 times, then mix at O ₂ Stirring is carried out for 12 hours at 60℃under an atmosphere. After completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified twice by preparative TLC (silica gel, dichloromethane/methanol=10/1) to give 4- [ [4- [ 8-chloro-7- [ 2-methyl-1- (2-trimethylsilylethoxymethyl) -benzimidazol-5-yl as a yellow oil ]Oxy-quinoxalin-2-yl]-3-methyl-pyrazol-1-yl]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (60 mg, 16%). M/z ES+ [ M+H ]] ⁺ 539.3。

Step 7 4- [ [4- [ 8-chloro-7- [ 2-methyl-1- (2-trimethylmethyl) in TFA (1 mL)Silanylethoxymethyl) benzimidazol-5-yl]Oxy-quinoxalin-2-yl]-3-methyl-pyrazol-1-yl]-methyl group]A solution of tert-butyl piperidine-1-carboxylate (50 mg, 69.6. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a red oil]-2- [ 3-methyl-1- (4-piperidinylmethyl) pyrazol-4-yl]Quinoxaline (50 mg, crude). M/z ES+ [ M+H ]] ⁺ 488.1。

Step 8. To 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in DMF (1 mL)]-2- [ 3-methyl-1- (4-piperidinylmethyl) pyrazol-4-yl]To a solution of quinoxaline (50 mg, 102.46. Mu. Mol) were added paraformaldehyde (61.5 mg,2.05 mmol) and formic acid (98.4 mg,2.05 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the solids were removed by filtration and the filtrate was concentrated. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:5% -35%,7 min) to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a brown solid ]-2- [ 3-methyl-1- [ (1-methyl-4-piperidinyl) methyl]Pyrazol-4-yl]Quinoxaline (7.86 mg, 15%). M/z ES+ [ M+H ]] ⁺ 502.5； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.50(br s,1H),9.23(s,1H),8.77(s,1H),7.95(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.22(d,J＝2.4Hz,1H),6.99-6.93(m,1H),4.21-4.03(m,2H),3.43(d,J＝12Hz,2H),2.99-2.87(m,2H),2.74(s,3H),2.71(s,3H),2.49(s,3H),2.20-2.07(m,1H),1.79(d,J＝12.4Hz,2H),1.55-1.38(m,2H)。

Step 9 4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) -5-methyl-pyrazol-1-yl ] in dichloroethane (5 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (200 mg, 436. Mu. Mol), [ 2-methyl-1- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Boric acid (200 mg, 655. Mu. Mol), cu (OAc) ₂ (39.6 mg, 218. Mu. Mol), triethylamine (132 mg,1.31 mmol) and O ₂ Purge 3 times, then mix at O ₂ Stirring is carried out for 12 hours at 60℃under an atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane/methanol=10/1) purification twice to give 4- [ [4- [ 8-chloro-7- [ 2-methyl-1- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow oil]Oxy-quinoxalin-2-yl]-5-methyl-pyrazol-1-yl]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (50 mg, 13%). M/z ES+ [ M+H ]] ⁺ 507.2。

Step 10 4- [ [4- [ 8-chloro-7- [ 2-methyl-1- (2-trimethylsilyl-ethoxymethyl) benzimidazol-5-yl ] in TFA (1 mL)]Oxy-quinoxalin-2-yl]-5-methyl-pyrazol-1-yl]Methyl group ]A solution of tert-butyl piperidine-1-carboxylate (50 mg, 69.6. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a red oil]-2- [ 5-methyl-1- (4-piperidinylmethyl) pyrazol-4-yl]Quinoxaline (50 mg, crude). M/z ES+ [ M+H ]] ⁺ 488.1。

Step 11. 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in DMF (1 mL)]-2- [ 5-methyl-1- (4-piperidinylmethyl) pyrazol-4-yl]To a solution of quinoxaline (50 mg, 102.46. Mu. Mol) were added paraformaldehyde (61.5 mg,2.05 mmol) and formic acid (98.4 mg,2.05 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the solids were removed by filtration and the filtrate was concentrated. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:5% -35%,7 min) to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a brown solid]-2- [ 5-methyl-1- [ (1-methyl-4-piperidinyl) methyl]Pyrazol-4-yl]Quinoxaline (18.2 mg, 35%). M/z ES+ [ M+H ]] ⁺ 502.4； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.29(br s,1H),9.34(s,1H),8.46(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.0Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(s,1H),6.94(d,J＝8.4Hz,1H),4.16(d,J＝6.4Hz,2H),3.40–3.34(m,2H),2.96–2.85(m,5H),2.71(s,3H),2.49(s,3H),2.23-2.09(m,1H),1.77(d,J＝12.0Hz,2H),1.60-1.40(m,2H)。

EXAMPLE 8 Synthesis of 8-fluoro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [ (1-methyl-4-piperidinyl) methyl ] pyrazol-4-yl ] quinoxaline

Step 1 to a solution of 4-bromo-3-fluoro-benzene-1, 2-diamine (4.5 g,21.95 mmol) in ethanol (50 mL) was added ethyl 2-oxoacetate (4.48 g,22 mmol). The mixture was stirred at 60℃for 16 hours. After cooling to room temperature, the solid formed was isolated by filtration and the filter cake was washed with petroleum ether (50 mL) to give 7-bromo-8-fluoro-quinoxalin-2-ol (5 g, 94%) as a dark brown solid.

Step 2, the POCl ₃ A solution of 7-bromo-8-fluoro-quinoxalin-2-ol (5 g,20.6 mmol) in (15 mL) was stirred at 100℃for 1 hour. After completion, the mixture was concentrated under reduced pressure to give a residue. Then add NaHCO ₃ Aqueous solution (50 mL) and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 50/1) to give 7-bromo-2-chloro-8-fluoro-quinoxaline (4 g, 74%) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.85(s,1H),7.95-7.76(m,2H)。

Step 3. To be added in dioxane (40 mL) and H ₂ 7-bromo-2-chloro-8-fluoro-quinoxaline (4 g,15.3 mmol), 4- [ [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl in O (20 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (6.58 g,16.8 mmol), pd (dppf) Cl ₂ (560 mg, 764. Mu. Mol), KOAC (4.5 g,45.89 mmol) and N ₂ Purge 3 times, then the mixture was taken over N ₂ Stirring is carried out for 16 hours at 60℃under an atmosphere. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 3/1) to give 4- [ [4- (7-bromo-8-fluoro-quinoxalin-2-yl) pyrazol-1-yl ] as a dark brown solid]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (5 g, 66%). M/z ES+ [ M+H ]] ⁺ 436.3。

Step 4. To dioxane (50 mL), H ₂ 4- [ [4- (7-bromo-8-fluoro-quinoxalin-2-yl) pyrazol-1-yl ] in O (25 mL)]Methyl group]Pd was added to a solution of tert-butyl piperidine-1-carboxylate (3 g,6.12 mmol) ₂ (dba) ₃ (280 mg,305. Mu. Mol), KOH (3.43 g,61.18 mmol) and t-BuXPhos (130 mg, 305.89. Mu. Mol). The mixture was stirred under nitrogen at 100 ℃ for 1 hour. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/1) to give 4- [ [4- (8-fluoro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl ] as a yellow solid ]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 57%). Then 4- [ [4- (8-fluoro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl]Methyl group]Tert-butyl piperidine-1-carboxylate (1.4 g) was prepared by SFC (column: DAICEL CHIRALCEL OJ (250 mm. Times.30 mm,10 um); mobile phase: [ 0.1% aqueous ammonium hydroxide in methanol)]The method comprises the steps of carrying out a first treatment on the surface of the B%:55% -55%,5min;40 min) to give 4- [ [4- (8-fluoro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl) as a yellow solid]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 78%) and 4- [ [4- (5-fluoro-6-hydroxy-quinoxalin-2-yl) pyrazol-1-yl ] as a yellow solid]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (300 mg, 21%). ¹ H NMR(400MHz,CD ₃ OD)δ9.03(s,1H),8.53(s,1H),8.33(s,1H),7.72(d,J＝8.8Hz,1H),7.43(t,J＝8.4Hz,1H),4.18-4.09(m,4H),2.85–2.75(m,2H),2.21-2.15(m,1H),1.68–1.58(m,2H),1.46(s,9H),1.30-1.11(m,2H)。

Step 5 4- [ [4- (8-fluoro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl ] in acetonitrile (10 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (300 mg, 701. Mu. Mol), [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Boric acid (429 mg,1.4 mmol), cu (OAc) ₂ (63.7mg，351μmol)、MS (10 mg) and Cs ₂ CO ₃ A mixture of (457 mg,1.4 mmol) in O ₂ Stirring was carried out at 60℃for 16 hours under an atmosphere of (15 psi). After completion, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (siliconGum, dichloromethane/methanol=50/1) to give 4- [ [4- [ 8-fluoro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (140 mg, 29%). M/z ES+ [ M+H ]] ⁺ 688.6。

Step 6 4- [ [4- [ 8-fluoro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in TFA (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of tert-butyl piperidine-1-carboxylate (70 mg, 102. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the mixture was concentrated under reduced pressure to give 8-fluoro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow oil]-2- [1- (4-piperidinylmethyl) pyrazol-4-yl]Quinoxaline (45 mg, crude). M/z ES+ [ M+H ]] ⁺ 458.4。

Step 7. 8-fluoro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in DMF (1 mL)]-2- [1- (4-piperidinylmethyl) pyrazol-4-yl]To a solution of quinoxaline (45 mg, 98.3. Mu. Mol) was added paraformaldehyde (29.5 mg, 983. Mu. Mol) and formic acid (47.2 mg, 983. Mu. Mol). The mixture was stirred at 60℃for 16 hours. After completion, the solids were removed by filtration and the filtrate was concentrated. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:2% -32%,7 min) to give 8-fluoro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy) as a brown solid ]-2- [1- [ (1-methyl-4-piperidinyl) -methyl]Pyrazol-4-yl]Quinoxaline (22.1 mg, 47%). M/z ES+ [ M+H ]] ⁺ 472.5； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.32(s,1H),8.73(s,1H),8.39(s,1H),8.17(s,1H),7.85(d,J＝9.2Hz,2H),7.51-7.39(m,2H),7.22(s,1H),6.96(d,J＝8.4Hz,1H),4.17(d,J＝6.8Hz,2H),3.10(d,J＝11.6Hz,2H),2.49(s,3H),2.43(s,3H),2.42–2.35(m,2H),2.02(s,1H),1.64-1.56(m,2H),1.43-1.34(m,2H)。

Example 9: synthesis of 8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

Step 1 4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl ] in toluene (10 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (600 mg,1.4 mmol), methylboronic acid (809 mg,14 mmol), K ₃ PO ₄ (860 mg,4.1 mmol), SPhos (55 mg,0.14 mmol) and Pd (OAc) ₂ (61 mg,0.27 mmol) in N ₂ Stirring was carried out at 80℃for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 1/1) to give 4- [ [4- (7-hydroxy-8-methyl-quinoxalin-2-yl) pyrazol-1-yl ] as a yellow solid]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (250 mg, 37%). M/z ES+ [ M+H ]] ⁺ 424.4； ¹ H NMR(400MHz,CDCl ₃ )δppm 8.89(s,1H),8.23(s,1H),8.13(s,1H),7.82(d,J＝9.2Hz,1H),7.31(d,J＝9.2Hz,1H),4.11(d,J＝7.2Hz,2H),2.79-2.70(m,2H),2.69(s,3H),2.15-2.10(m,1H),1.70-1.63(m,2H),1.46(s,9H),1.32-1.16(m,4H)。

Step 2 to 4- [ [4- (7-hydroxy-8-methyl-quinoxalin-2-yl) pyrazol-1-yl ] in dichloroethane (2 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (240 mg,0.28 mmol), [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Cu (OAc) was added to a solution of boric acid (350 mg,0.57 mmol) ₂ (102mg，0.28mmol)、MS (400 mg) and Cs ₂ CO ₃ (370 mg,0.57 mmol). The mixture is treated with O ₂ (15 psi) at 60℃for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane/methanol=20/1) to give 4- [ [4- [ 8-methyl-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (44 mg, 11%). M/z ES+ [ M+H ]] ⁺ 684.3。

Step 3 4- [ [4- [ 8-methyl-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) -benzimidazole ] in TFA (0.5 mL)-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of piperidine-1-carboxylic acid ester (44 mg, 64. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 8-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow oil]-2- [1- (4-piperidinylmethyl) pyrazol-4-yl]Quinoxaline (35 mg, crude). M/z ES+ [ M+H ]] ⁺ 454.3。

Step 4. 8-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in DMF (0.5 mL)]-2- [1- (4-piperidinylmethyl) pyrazol-4-yl]To a solution of quinoxaline (35 mg, 77. Mu. Mol) were added paraformaldehyde (46 mg,1.5 mmol) and formic acid (74 mg,1.5 mmol). The mixture was stirred at 60℃for 12 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (neutral; waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM NH) ₄ HCO ₃ ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:24% -54%,10 min) to give 8-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a white solid]-2- [1- [ (1-methyl-4-piperidinyl) methyl]Pyrazol-4-yl]Quinoxaline (8.54 mg, 19%). M/z ES+ [ M+H ]] ⁺ 468.5； ¹ H NMR(400MHz,DMSO-d ₆ )δppm 9.23(s,1H),8.68(s,1H),8.36(s,1H),8.24(s,1H),7.84(d,J＝9.2Hz,1H),7.46(d,J＝8.4Hz,1H),7.24(d,J＝9.2Hz,1H),7.06(d,J＝2.0Hz,1H),6.87(dd,J＝8.8,2,2Hz,1H),4.14(d,J＝7.2Hz,2H),2.95(d,J＝11.6Hz,2H),2.69(s,3H),2.47(s,3H),2.31(s,3H),2.16(t,J＝10.8Hz,2H),1.94(s,1H),1.57(d,J＝11.6Hz,2H),1.42-1.25(m,2H)。

EXAMPLE 10 Synthesis of 8-chloro-7- ((2-methylimidazo [1,2-a ] pyridin-7-yl) oxy) -2- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

Step 1, the direction is H ₂ To a solution of 4-bromopyridin-2-amine (7 g,40 mmol) and 1-bromo-2, 2-dimethoxy-propane (36 g,198.25mmol,26.68 mL) in O (0.14L) was added p-toluenesulfonic acid (1.32 g,7.69 mmol). The mixture was stirred at 105℃for 18 hours. With saturated NaHCO ₃ The reaction mixture was adjusted to ph=9 with aqueous solution and extracted with ethyl acetate (100 ml×2). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 2/1) to give 7-bromo-2-methylimidazo [1,2-a ] as a yellow solid]Pyridine (2.9 g,13.7mmol, 34%). M/z ES+ [ M+H ]] ⁺ 213.0。

Step 2. 7-bromo-2-methyl-imidazo [1,2-a ] in dioxane (40 mL)]To a solution of pyridine (1 g,4.74 mmol) was added 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1,3, 2-dioxapentaborane (6.02 g,23.69 mmol), KOAC (1.86 g,18.95 mmol) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (387 mg,0.47 mmol). The mixture is put under N ₂ Stirring was carried out at 110℃for 5 hours. The reaction mixture was treated with H ₂ O (150 mL) was diluted and extracted with dichloromethane (100 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (mobile phase: [ water/formic acid-acetonitrile]) Purification to give (2-methylimidazo [1, 2-a) as a white solid]Pyridin-7-yl) boronic acid (480 mg,2.73mmol, 58%). M/z ES+ [ M+H ]] ⁺ 177.0。

Step 3 to 4- [ [4- (8-chloro-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl ] in dichloroethane (1 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (50 mg,0.11 mmol) and (2-methylimidazo [1, 2-a)]Cu (OAc) was added to a solution of pyridin-7-yl) boronic acid (39.64 mg,0.23 mmol) ₂ (24.6mg，0.14mmol)、MS (100 mg) and Cs ₂ CO ₃ (73.4 mg,0.23 mmol). The mixture is treated with O ₂ Stirred at 15psi for 2 hours at 60 ℃. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to dichloromethane/methanol=30/1) to give 4- ((4- (8-chloro-7- ((2-methylimidazo [1, 2-a) as a yellow oil]Pyridin-7-yl) Oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl methyl) piperidine-1-carboxylic acid tert-butyl ester (12 mg, 17.4. Mu. Mol, 15%). M/z ES+ [ M+H ] ] ⁺ 574.2。/>

Step 4. To 4- [ [4- [ 8-chloro-7- (2-methylimidazo [1,2-a ] in dichloromethane (0.3 mL)]Pyridin-7-yl) oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (10 mg, 14.5. Mu. Mol) was added TFA (154 mg,1.35mmol,0.1 mL). The mixture was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the desired 8-chloro-7- ((2-methylimidazo [1, 2-a) as a yellow oil]Pyridin-7-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline (10 mg, crude, as TFA salt). M/z ES+ [ M+H ]] ⁺ 474.2。

Step 5 to 8-chloro-7- (2-methylimidazo [1, 2-a) in DMF (0.5 mL)]Pyridin-7-yl) oxy-2- [1- (4-piperidinylmethyl) pyrazol-4-yl]To a solution of quinoxaline (10 mg, 17. Mu. Mol, TFA salt) was added aqueous paraformaldehyde (13.8 mg, 170. Mu. Mol,37% purity). The mixture was stirred at 25℃for 0.5 h. NaBH (OAc) is then added ₃ (18 mg, 85. Mu. Mol). The mixture was stirred at 25℃for 1 hour. The reaction mixture was treated with H ₂ O (5 mL) was diluted and extracted with ethyl acetate (5 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions; column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM NH ₄ HCO ₃ ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:18% -48%,10 min) to give 8-chloro-7- ((2-methylimidazo [1, 2-a) as a yellow solid]Pyridin-7-yl) oxy) -2- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (1.41 mg,2.68 μmol, 16%). M/z ES+ [ M+H ]] ⁺ 488.1； ¹ H NMR(400MHz,DMSO-d ₆ )δppm 9.37(s,1H),8.70(s,1H),8.51(d,J＝7.2Hz,1H),8.37(s,1H),8.07(d,J＝9.2Hz,1H),7.64(d,J＝7.2Hz,2H),6.85-6.77(m,2H),4.13(d,J＝7.2Hz,2H),2.74(d,J＝11.2Hz,2H),2.28(s,3H),2.12(s,3H),1.87-1.73(m,3H),1.49(d,J＝11.2Hz,2H),1.29-1.23(m,2H)。

EXAMPLE 11 Synthesis of 5- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] -3- [ (1-methyl-4-piperidinyl) methyl ] isoxazole

Step 1. To a solution of tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate (1 g,4.4 mmol) hydroxylamine (367 mg,5.28 mmol) in methanol (10 mL) at 0deg.C was added dropwise NaOH (3M, 1.76 mL) and the mixture was stirred at 25deg.C for 16 h. After completion, the mixture was concentrated under reduced pressure, then poured into water (50 mL), and extracted with ethyl acetate (30 ml×3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4- [ (2E) -2-hydroxyiminoethyl ] as a colorless oil]Piperidine-1-carboxylic acid tert-butyl ester (1 g, 94%). ¹ H NMR(400MHz,CDCl ₃ )δ9.79(s,1H),7.45(t,J＝6.4Hz,1H),6.95(s,1H),4.16-4.05(m,2H),2.80-2.60(m,2H),2.46-2.35(m,1H),2.18(t,J＝6.4Hz,1H),1.79-1.59(m,3H),1.46(s,9H),1.25-1.10(m,2H)。

Step 2. To 4- [ (2E) -2-Hydroxyiminoethyl in dichloromethane (10 mL)]To a solution of tert-butyl piperidine-1-carboxylate (1 g,4.13 mmol) was added N-chlorosuccinimide (553mg, 4.13 mmol) and pyridine (32.6 mg, 412. Mu. Mol). The mixture was stirred at 25℃for 16 hours. After completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and 4- [ (2Z) -2-chloro-2-hydroxyimino-ethyl was obtained as a white solid ]Piperidine-1-carboxylic acid tert-butyl ester (1.4 g, crude). ¹ H NMR(400MHz,CDCl ₃ )δ9.19(s,1H),8.58-8.20(m,1H),7.97-7.83(m,1H),4.04(d,J＝13.4Hz,2H),2.69-2.56(m,2H),2.35(d,J＝7.2Hz,2H),1.90-1.82(m,1H),1.68-1.54(m,2H),1.38(s,9H),1.13-1.02(m,2H)。

Step 3 to a solution of 4- [ (2Z) -2-chloro-2-hydroxyimino-ethyl ] piperidine-1-carboxylic acid tert-butyl ester (1 g,3.61 mmol) 7-bromo-2-ethynyl-quinoxaline (400 mg,1.72 mmol) in THF (3 mL) was added triethylamine (174 mg,1.72 mmol). The mixture was stirred at 25℃for 16 hours. After completion, the mixture was concentrated under reduced pressure to remove the solvent and obtain a residue. The residue was triturated with methanol (20 mL) to give tert-butyl 4- [ [5- (7-bromoquinoxalin-2-yl) isoxazol-3-yl ] methyl ] piperidine-1-carboxylate (600 mg, 73%) as a white solid.

Step 4. To a reaction between dioxane (10 mL) and H ₂ 4- [ [5- (7-bromoquinoxalin-2-yl) isoxazol-3-yl ] in O (2 mL)]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (650 mg,1.37 mmol) was added KOH (770 mg,13.7 mmol), t-BuXPhos (58.3 mg, 137. Mu. Mol) and Pd ₂ (dba) ₃ (125 mg, 137. Mu. Mol). The mixture was stirred under nitrogen at 100 ℃ for 1 hour. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/1) to give 4- [ [5- (7-hydroxyquinoxalin-2-yl) isoxazol-3-yl ] as a yellow solid ]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (270 mg, 47%). ¹ H NMR(400MHz,CD ₃ OD)δ9.23(s,1H),7.95(d,J＝9.2Hz,1H),7.60(d,J＝9.2Hz,1H),7.27(s,1H),4.11(d,J＝13.4Hz,2H),2.78(d,J＝7.2Hz,4H),2.11-1.89(m,1H),1.78(d,J＝12.4Hz,2H),1.47(s,9H),1.33-1.15(m,2H)。

Step 5 4- [ [5- (7-hydroxyquinoxalin-2-yl) isoxazol-3-yl ] in acetonitrile (1 mL)]Methyl group]A solution of tert-butyl piperidine-1-carboxylate (220 mg, 535. Mu. Mol), N-chlorosuccinimide (85.8 mg, 643. Mu. Mol) was stirred at 80℃for 16 hours. After completion, the reaction mixture was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 3/1) to give 4- [ [5- (8-chloro-7-hydroxy-quinoxalin-2-yl) isoxazol-3-yl ] as a yellow solid]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (200 mg, 84%). ¹ H NMR(400MHz,CD ₃ OD)δ9.23(s,1H),7.95(d,J＝9.2Hz,1H),7.60(d,J＝9.2Hz,1H),7.27(s,1H),4.11(d,J＝13.2Hz,2H),2.78(d,J＝7.2Hz,4H),2.11-1.89(m,1H),1.78(d,J＝12.4Hz,2H),1.47(s,9H),1.33-1.15(m,2H)。

Step 6 4- [ [5- (8-chloro-7-hydroxy-quinoxalin-2-yl) isoxazol-3-yl ] in dichloroethane (10 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (180 mg, 404. Mu. Mol), [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Boric acid (247 m)g，809μmol)、Cu(OAc) ₂ (36.7mg，202μmol)、A mixture of MS (5 mg, 405. Mu. Mol) and triethylamine (81.8 mg, 809. Mu. Mol) in O ₂ Stirring was carried out at 60℃for 16 hours under an atmosphere (15 psi). After completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 5:1 to 3:1 and dichloromethane/methanol=1/0 to 100/1) and reverse phase HPLC (mobile phase: [ water/formic acid-acetonitrile ]) Purification to give 4- [ [5- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow oil]Oxy-quinoxalin-2-yl]Isoxazol-3-yl]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (30 mg, 42.5. Mu. Mol, 11%). M/z ES+ [ M+H ]] ⁺ 705.2。

Step 7 4- [ [5- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in TFA (1 mL)]Oxy-quinoxalin-2-yl]Isoxazol-3-yl]Methyl group]A solution of tert-butyl piperidine-1-carboxylate (25 mg, 35.4. Mu. Mol) was stirred at 25℃for 10min. After completion, the mixture was concentrated under reduced pressure to remove the solvent, and 5- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy was obtained as a yellow oil]Quinoxalin-2-yl]-3- (4-piperidinylmethyl) isoxazole (16 mg, crude). M/z ES+ [ M+H ]] ⁺ 475.1。

Step 8. 5- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in DMF (1 mL)]Quinoxalin-2-yl]To a solution of 3- (4-piperidinylmethyl) isoxazole (16 mg, 33.7. Mu. Mol) was added formic acid (16.2 mg, 336. Mu. Mol), paraformaldehyde (10.1 mg, 336. Mu. Mol). The mixture was stirred at 60℃for 16 hours. After completion, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the B%:5% -35%,7 min) to give 5- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]-3- [ (1-methyl-4-piperidinyl) methyl]Isoxazole (8.73 mg, 53%). M/z ES+ [ M+H ]] ⁺ 489.1； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.47(s,1H),8.21(s,1H),8.07(d,J＝9.2Hz,1H),7.56-7.47(m,3H),7.26(s,1H),6.97(d,J＝8.4Hz,1H),2.87(d,J＝11.2Hz,2H),2.72(d,J＝6.8Hz,2H),2.49(s,3H),2.25(s,3H),2.04(t,J＝11.6Hz,2H),1.80-1.64(m,3H),1.43-1.25(m,2H)。

EXAMPLE 12 Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- (tetrahydrofurane-3-ylmethyl) pyrazol-4-yl ] quinoxaline

Step 1 to a solution of tetrahydrofuran-3-yl-methanol (200 mg,1.96 mmol) in dichloromethane (3 mL) were added methanesulfonyl chloride (336 mg,2.94 mmol) and triethylamine (594 mg,5.87 mmol). The mixture was stirred at 0 ℃ for 1 hour. After completion, the reaction mixture was treated with NaHCO ₃ The solution (5 mL) was diluted and extracted with ethyl acetate (5 mL. Times.3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tetrahydrofuran-3-ylmethyl mesylate (400 mg, crude) as a white oil. ¹ H NMR(400MHz,CDCl ₃ )δ4.25-4.07(m,2H),3.94-3.70(m,3H),3.67-3.61(m,1H),3.03(s,3H),2.75-2.62(m,1H),2.16-2.06(m,1H),1.74-1.58(m,1H)。

Step 2 to 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in DMF (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (50 mg, 98.6. Mu. Mol) was added K ₂ CO ₃ (40.8 mg, 295. Mu. Mol) and tetrahydrofuran-3-ylmethyl mesylate (30 mg, 166. Mu. Mol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- [ [6- [ 5-chloro-3- [1- (tetrahydrofuran-3-ylmethyl) pyrazol-4-yl ] as a white solid ]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (50 mg, crude). M/z ES+ [ M+H ]] ⁺ 591.1。

Step 3 to 2- [ [6- [ 5-chloro-3- [1 ] in TFA (0.5 mL)- (tetrahydrofuran-3-ylmethyl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (50 mg, 84.5. Mu. Mol) was added TFA (770 mg,6.75 mmol). The mixture was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:15% -45%,7 min) to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow solid]-2- [1- (tetrahydrofuran-3-ylmethyl) pyrazol-4-yl]Quinoxaline (15.2 mg, 39%). M/z ES+ [ M+H ]] ⁺ 461.1； ¹ H NMR(400MHz,CDCl ₃ )δ8.99(s,1H),8.27(s,1H),8.25(br s,1H),8.23(s,1H),7.86(d,J＝9.2Hz,1H),7.58(d,J＝8.8Hz,1H),7.29(d,J＝4.0Hz,1H),7.11-7.04(m,1H),4.22(d,J＝7.6Hz,2H),3.99-3.91(m,1H),3.87-3.75(m,2H),3.70-3.63(m,1H),3.02-2.88(m,1H),2.74(s,3H),2.17-2.04(m,1H),1.79-1.68(m,1H)。

EXAMPLE 13 Synthesis of azetidin-1-yl (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) methanone

Step 1.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidine-1-carboxylic acid 4-nitrophenyl ester

To 2- [ [6- [3- [1- (azetidin-3-yl) pyrazol-4-yl ] in dichloromethane (10 mL) under nitrogen]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Triethylamine (180 mg,1.78 mmol) was added in one portion to a mixture of ethyl-trimethyl-silane (500 mg, 889. Mu. Mol) and (4-nitrophenyl) chloroformate (178 mg, 889. Mu. Mol). The mixture was stirred at 20℃for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) as a yellow solidRadical) -1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl azetidine-1-carboxylic acid 4-nitrophenyl ester (0.6 g,578umol, 65%). M/zES + [ M+H ]] ⁺ 727.4

Step 2. Azetidin-1-yl (3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) methanone

Azetidine (118 mg,2.06 mmol) and 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (5 mL) were added]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]The mixture of azetidine-1-carboxylic acid (4-nitrophenyl) ester (300 mg,413 umol) was stirred at 25℃for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give azetidin-1-yl- [3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]Methanone (70 mg,86.8umol, 21%). M/z ES+ [ M+H ]] ⁺ 645.4

Step 3. Azetidin-1-yl (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) methanone

Azetidin-1-yl- [3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]A solution of methanone (70.0 mg, 108. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25.mu.m.150.mu.m; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 11% -41%,10 min) purification to give azetidin-1-yl- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as an off-white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]Methanone (16.8 mg,32.7umol, 30%). 1H NMR (400 MHz, CD3 OD) δ9.18 (s, 1H), 8.65 (s, 1H), 8.41 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.34-7.26(m,2H),5.40-5.29(m,1H),4.52-4.44(m,2H),4.43-4.36(m,2H),4.05(t,J＝7.6Hz,4H),2.81(s,3H),2.39-2.25(m,2H).m/z ES+[M+H] ⁺ 514.1

EXAMPLE 14.7 Synthesis of- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -3-oxa-9-azabicyclo [3.3.1] nonane

Step 1.7-hydroxy-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester

To a solution of tert-butyl 7-oxo-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylate (450 mg,1.87 mmol) in methanol (5 mL) was added sodium borohydride (141 mg,3.73 mmol) in portions. The mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (10 mL) at 0 ℃, then diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7-hydroxy-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester (400 mg,1.65mmol, 88%) as a white solid. 1H NMR (400 mhz, cdcl 3) δ=5.59-5.43 (m, 1H), 4.15 (d, j=2.4 hz, 1H), 4.06-3.93 (m, 2H), 3.90-3.81 (m, 2H), 3.79-3.70 (m, 2H), 2.23-2.08 (m, 2H), 1.82 (dd, j=3.2, 14.8hz, 2H), 1.47 (s, 9H).

Step 2.7-methylsulfonyloxy-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester

To 7-hydroxy-3-oxa-9-azabicyclo [3.3.1] in dichloromethane (2 mL) at 0deg.C]Triethylamine (83.1 mg,82 umol) was added to a solution of tert-butyl nonane-9-carboxylate (100 mg,411 umol). Methanesulfonyl chloride (70.6 mg,616 umol) was then added. The mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with water (10 mL) at 0 ℃ and then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate 1:1) to give white 7-methylsulfonyloxy-3-oxa-9-azabicyclo [3.3.1] as a color solid]Nonane-9-carboxylic acid tert-butyl ester (60.0 mg, 187. Mu. Mol, 45%). ¹ H NMR(400MHz,CDCl ₃ )δ＝4.91-4.86(m,1H),4.20(d,J＝6.4Hz,1H),4.06(d,J＝7.2Hz,1H),3.78-3.70(m,2H),3.68-3.61(m,2H),3.03(s,3H),2.44-2.30(m,2H),2.05-1.99(m,2H),1.48(s,9H)。

Step 3.7- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (47.3 mg,93.3 umol) and 7-methylsulfonyloxy-3-oxa-9-azabicyclo [3.3.1]]To a solution of tert-butyl nonane-9-carboxylate (36.0 mg, 112. Mu. Mol) was added cesium carbonate (60.8 mg, 186. Mu. Mol) and 4-pyrrolidin-1-ylpyridine (13.8 mg, 93.3. Mu. Mol). The mixture was stirred at 80℃for 12 hours. The mixture was filtered and concentrated in vacuo and the residue was purified by preparative HPLC (column Phenomenex Synergi C18:150:25 mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 46% -79%,11 min) purification to give 7- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-3-oxa-9-azabicyclo [3.3.1]Nonane-9-carboxylic acid tert-butyl ester (28.0 mg,32.8umol, 40%). M/zES + [ M+1 ]] ⁺ 732.0。

Step 4.7- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -3-oxa-9-azabicyclo [3.3.1] nonane

7- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-3-oxa-9-azabicyclo [3.3.1]A solution of tert-butyl nonane-9-carboxylate (20.0 mg, 27.3. Mu. Mol) was stirred at 25℃for 0.5 h. The mixture was concentrated in vacuo and the residue was purified by prep HPLC (column Phenomenex Synergi C18, 150 x 25mm x 10um; mobile phase: [ water (formic acid) -bNitrile (II)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -26%,10 min) purification to give 7- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as an off-white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-3-oxa-9-azabicyclo [3.3.1]Nonane (13.4 mg,26.7umol,85% formate). ¹ H NMR(400MHz,CD ₃ OD)δ＝9.13(s,1H),8.65(s,1H),8.39-8.35(m,2H),7.88(d,J＝9.6Hz,1H),7.53(d,J＝8.6Hz,1H),7.34(d,J＝9.6Hz,1H),7.19(d,J＝2.0Hz,1H),7.01(dd,J＝2.4,8.8Hz,1H),5.77-5.68(m,1H),4.20-4.14(m,2H),4.11-4.04(m,2H),3.71(s,2H),2.77-2.64(m,2H),2.60-2.53(m,5H).m/z ES+[M+1] ⁺ 502.0。

EXAMPLE 15 Synthesis of (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) (3-hydroxyazetidin-1-yl) methanone

Step 1.4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid 4-nitrophenyl ester

To 2- [ [6- [ 5-chloro-3- [1- (4-piperidinyl) pyrazol-4-yl ] in dichloromethane (1.5 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (170 mg,288 mol) was added 4-nitrophenyl chloroformate (116 mg,576 mol) and triethylamine (87.4 mg,864 mol). The mixture was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid 4-nitrophenyl ester (190 mg,242umol, 84%). M/zES + [ M+H ]] ⁺ 755.2。

Step 2. (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) (3-hydroxyazetidin-1-yl) methanone

To 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in tetrahydrofuran (1.5 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid 4-nitrophenyl ester (170 mg,225 umol) triethylamine (68.3 mg,675 umol) and azetidin-3-ol (74.0 mg,675umol, HCl) were added. The mixture was stirred at 60℃for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were washed with brine (3 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) (3-hydroxyazetidin-1-yl) methanone (140 mg,203umol, 90%). M/zES + [ M+H ]] ⁺ 689.1。

Step 3. (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) (3-hydroxyazetidin-1-yl) methanone

(4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (0.5 mL) ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) (3-hydroxyazetidin-1-yl) methanone (70.0 mg,102 umol) was stirred at 25 ℃ for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25.mu.m.150.mu.m; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 9% -39%,10 min) to give 4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ]) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) (3-hydroxyazetidin-1-yl) methanone (24.8 mg,44.2umol, 44%). ¹ H NMR(400MHz,CD ₃ OD)δ9.18(s,1H),8.64(s,1H),8.36(s,1H),8.12(s,1H),7.92(d,J＝9.2Hz,1H),7.58(d,J＝8.8Hz,1H),7.38(d,J＝9.2Hz,1H),7.20(d,J＝2.0Hz,1H),7.07(dd,J＝2.4,8.8Hz,1H),4.59-4.47(m,2H),4.31-4.22(m,2H),4.04(d,J＝13.6Hz,2H),3.86(dd,J＝4.8,9.2Hz,2H),3.04(t,J＝12.0Hz,2H),2.63(s,3H),2.25-2.14(m,2H),2.10-2.01(m,2H)；m/z ES+[M+H] ⁺ 559.0。

EXAMPLE 16 Synthesis of 6- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] -N, N-dimethyl-pyridin-2-amine

Step 1.6- [3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] -N, N-dimethyl-pyridin-2-amine

To 2- [ [6- [3- [1- (azetidin-3-yl) pyrazol-4-yl ] in dioxane (3 mL)]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group ]To a solution of ethyl-trimethyl-silane (130 mg, 230. Mu. Mol) and 6-bromo-N, N-dimethyl-pyridin-2-amine (51.0 mg, 250. Mu. Mol) were added tris (dibenzylideneacetone) dipalladium (21.0 mg, 23.0. Mu. Mol), (5-diphenylphosphanyl-9, 9-dimethylxanthen-4-yl) -diphenylphosphane (13.0 mg, 23.0. Mu. Mol) and cesium carbonate (151 mg, 460. Mu. Mol). The mixture was stirred under nitrogen at 80 ℃ for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were then washed with brine (25 ml×2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography ((petroleum ether: ethyl acetate=10:1 to 0:1) to give 6- [3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl) as a white solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]-N, N-dimethyl-pyridin-2-amine (50.0 mg,73.4umol, 28%). M/zES + [ M+H ]] ⁺ 682.2。

Step 2.6- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] -N, N-dimethyl-pyridin-2-amine

6- [3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxy) in trifluoroacetic acid (0.5 mL) Methyl) benzimidazol-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]A solution of N, N-dimethyl-pyridin-2-amine (40.0 mg,58.0 umol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 44% -74%,10 min) purification to give 6- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]-N, N-dimethyl-pyridin-2-amine (2.68 mg,4.86umol, 7.9%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.34-12.24(m,1H),9.35(s,1H),8.92(s,1H),8.45(s,1H),7.98-7.92(m,1H),7.60-7.42(m,1H),7.38-7.28(m,1H),7.25-7.16(m,1H),6.98-6.90(m,1H),5.84(d,J＝8.0Hz,1H),5.72(d,J＝8.0Hz,1H),5.53-5.49(m,1H),4.40(t,J＝8.0Hz,1H),4.28-4.23(m,2H),2.98(s,6H),2.50(s,3H)；m/z ES+[M+H] ⁺ 552.1。

EXAMPLE 17 Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [1- (2-pyridinyl) azetidin-3-yl ] pyrazol-4-yl ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [1- (2-pyridinyl) azetidin-3-yl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2-bromopyridine (40.0 mg,250 umol) and 2- [ [6- [3- [1- (azetidin-3-yl) pyrazol-4-yl ] in dioxane (3 mL)]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl ]Methoxy group]To a solution of ethyl-trimethyl-silane (130 mg, 230. Mu. Mol) was added tris (dibenzylideneacetone) dipalladium (21.0 mg, 23.0. Mu. Mol), (5-diphenylphosphanyl-9, 9-dimethylxanthen-4-yl) -diphenylphosphane (13.0 mg, 23.0. Mu. Mol) and cesium carbonate (150 mg, 460. Mu. Mol). The mixture was stirred under nitrogen at 80 ℃ for 12 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were treated with brine25ml×2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1 to 0:1) to give 2- [ [6- [ 5-chloro-3- [1- [1- (2-pyridinyl) azetidin-3-yl ] as a white solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (70.0 mg,110 mol, 34%). M/zES + [ M+H ]] ⁺ 639.3。

Step 2.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [1- (2-pyridinyl) azetidin-3-yl ] pyrazol-4-yl ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [1- (2-pyridinyl) azetidin-3-yl ] in trifluoroacetic acid (0.6 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl ]Methoxy group]A solution of ethyl-trimethyl-silane (60.0 mg,94.0 mmole) was stirred at 25℃for 0.5 h. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,10 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy) as a white solid]-2- [1- [1- (2-pyridyl) azetidin-3-yl]Pyrazol-4-yl]Quinoxaline (24.3 mg,47.8umol, 50%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.36(s,1H),8.93(s,1H),8.46(s,1H),8.15-8.11(m,1H),7.99(d,J＝9.2Hz,1H),7.64-7.57(m,2H),7.37(d,J＝9.2Hz,1H),7.30(d,J＝2.4Hz,1H),7.05(dd,J＝2.4,8.8Hz,1H),6.73(dd,J＝5.6,6.8Hz,1H),6.55(d,J＝8.4Hz,1H),5.61-5.51(m,1H),4.50(t,J＝8.4Hz,2H),4.34(dd,J＝5.6,8.8Hz,2H),2.57(s,3H)；m/z ES+[M+H] ⁺ 509.0。

EXAMPLE 18.5 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1, 2-thiazine 1, 1-dioxide

Step 1.5- (((tert-butyldiphenylsilyl) oxy) methyl) -1, 2-thiazine-2-carboxylic acid tert-butyl 1, 1-dioxide

To a solution of 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1, 2-thiazine 1, 1-dioxide (300 mg,743 umol) and 4-dimethylaminopyridine (181 mg,1.49 mmol) in dichloromethane (10 mL) was added dropwise di-tert-butyldicarbonate (324 mg,1.49 mmol) at 25 ℃. The mixture was stirred at 25℃for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give tert-butyl 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1, 2-thiazine-2-carboxylate 1, 1-dioxide (330 mg,65 umol, 88%) as a white oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.54(d,J＝7.6Hz,3H),7.43-7.27(m,6H),4.23(td,J＝3.6,14.0Hz,1H),3.63-3.40(m,3H),3.25(dd,J＝3.2,13.6Hz,1H),2.94(t,J＝12.8Hz,1H),2.47(s,1H),1.64(d,J＝11.6Hz,1H),1.45(s,9H),0.98(s,9H)。

Step 2.5- (hydroxymethyl) -1, 2-thiazine-2-carboxylic acid tert-butyl ester 1, 1-dioxide

A solution of 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1, 2-thiazine-2-carboxylic acid tert-butyl 1, 1-dioxide (270 mg, 536. Mu. Mol) in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1M in THF, 0.8 mL) was stirred at 25℃for 5 hours. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (30 mL x 3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 5- (hydroxymethyl) -1, 2-thiazine-2-carboxylate 1, 1-dioxide (150 mg, crude) as a colorless oil.

Step 3.5- ((p-toluenesulfonyloxy) methyl) -1, 2-thiazine-2-carboxylic acid tert-butyl ester 1, 1-dioxide

To a solution of tert-butyl 5- (hydroxymethyl) -1, 2-thiazine-2-carboxylate 1, 1-dioxide (150 mg, 560 umol) in dichloromethane (5 mL) was added 4-methylbenzenesulfonyl chloride (161 mg,848 umol) and triethylamine (171 mg,1.70 mmol). The mixture was stirred at 25℃for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give tert-butyl 5- ((p-toluenesulfonyloxy) methyl) -1, 2-thiazine-2-carboxylate 1, 1-dioxide (140 mg,333 um) as a colorless oil ol，59％)。 ¹ H NMR(400MHz,CDCl ₃ )δ7.79(d,J＝8.4Hz,2H),7.39(d,J＝8.0Hz,2H),4.30(td,J＝4.0,14.0Hz,1H),4.09-3.90(m,2H),3.73-3.51(m,1H),3.30-3.15(m,1H),3.01-2.84(m,1H),2.69(s,1H),2.48(s,3H),1.78(d,J＝14.0Hz,1H),1.52(s,9H)。

Step 4.5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1, 2-thiazine-2-carboxylic acid tert-butyl ester 1, 1-dioxide

A solution of 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (70.0 mg,138 umol), 5- ((p-toluenesulfonyloxy) methyl) -1, 2-thiazine-2-carboxylic acid tert-butyl ester 1, 1-dioxide (70.0 mg,166 umol), cesium carbonate (134 mg,414 umol) in N, N-dimethylformamide (1 mL) was stirred at 80℃for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (50 ml x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1, 2-thiazine-2-carboxylate 1, 1-dioxide (70.0 mg,92.0 mol, 67%) as a yellow oil.

Step 5.5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1, 2-thiazine 1, 1-dioxide

5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl methyl) -1, 2-thiazine-2-carboxylic acid tert-butyl ester 1, 1-dioxide (70 mg,92.9 umol) was stirred at 25 ℃ for 10min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -52%,8 min) purification to give 5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinazolinesOxin-2-yl) -1H-pyrazol-1-yl) methyl) -1, 2-thiazine 1, 1-dioxide (7.5 mg,14.2umol, 15%). ¹ H NMR(400MHz,CD ₃ OD)δ9.12(s,1H),8.57(s,1H),8.36(s,1H),7.87(d,J＝9.2Hz,1H),7.52(d,J＝8.6Hz,1H),7.33(d,J＝9.2Hz,1H),7.18(d,J＝2.2Hz,1H),7(dd,J＝2.4,8.4Hz,1H),4.39-4.20(m,2H),3.39-3.32(m,2H),3.17(d,J＝10.1Hz,1H),2.96-2.78(m,2H),2.57(s,3H),1.78-1.65(m,1H),1.48-1.25(m,1H)；m/z ES+[M+H] ⁺ 524.0。

EXAMPLE 19 Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [1- (2-pyridyl) -4-piperidinyl ] pyrazol-4-yl ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [1- (2-pyridinyl) -4-piperidinyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- [1- (4-piperidinyl) pyrazol-4-yl ] in dioxane (1.5 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl ]Methoxy group]To a solution of ethyl-trimethyl-silane (150 mg,254 mol) and 2-bromopyridine (40.2 mg,254 mol) were added methanesulfonyl (2-dicyclohexylphosphino-2, 6-di-isopropoxy-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (II) (21.3 mg,25.4 mol) and cesium carbonate (166 mg,508 mol). The mixture was degassed and purged 3 times with nitrogen and then stirred at 80 ℃ for 12 hours, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1 to 0/1) to give 2- [ [6- [ 5-chloro-3- [1- [1- (2-pyridyl) -4-piperidinyl ] as a yellow oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (100 mg,150 mol, 59%). M/zES + [ M+H ]] ⁺ 667.3。

Step 2.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [1- (2-pyridinyl) -4-piperidinyl ] pyrazol-4-yl ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- ] in trifluoroacetic acid (0.5 mL)1- (2-pyridyl) -4-piperidyl]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (65.0 mg,97.4 umol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Luna C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,10 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as an off-white solid]-2- [1- [1- (2-pyridyl) -4-piperidinyl]Pyrazol-4-yl]Quinoxaline (27.0 mg,50.3umol, 52%). ¹ H NMR(400MHz,CD ₃ OD)δ9.14(s,1H),8.62(s,1H),8.33(s,1H),8.07(dd,J＝1.2,5.2Hz,1H),7.90(d,J＝9.2Hz,1H),7.72-7.65(m,1H),7.62(d,J＝8.8Hz,1H),7.38(d,J＝9.2Hz,1H),7.23(d,J＝2.0Hz,1H),7.14(dd,J＝2.4,8.8Hz,1H),7.04(d,J＝8.8Hz,1H),6.75(t,J＝6.0Hz,1H),4.66-4.54(m,1H),4.42(br d,J＝13.6Hz,2H),3.23-3.11(m,2H),2.68(s,3H),2.33-2.24(m,2H),2.23-2.10(m,2H)；m/z ES+[M+H] ⁺ 537.0。

EXAMPLE 20 Synthesis of 8-chloro-2- (1- (1- (5-fluoropyridin-3-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- (1- (5-fluoropyridin-3-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [3- [1- (azetidin-3-yl) pyrazol-4-yl ] in dioxane (2 mL)]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (130 mg, 231. Mu. Mol) and 3-bromo-5-fluoro-pyridine (44.8 mg, 254. Mu. Mol) were added tris (dibenzylideneacetone) dipalladium (21.2 mg, 23.1. Mu. Mol), (5-diphenylphosphanyl-9, 9-dimethylxanthen-4-yl) -diphenylphosphane (13.4 mg, 23.1. Mu. Mol) and cesium carbonate (151 mg, 463. Mu. Mol). The mixture was degassed and purged 3 times with nitrogen atmosphere, and then under nitrogenStirring is carried out for 12 hours at 80℃under an atmosphere. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/methanol=1/0 to 20/1) to give 8-chloro-2- (1- (1- (5-fluoropyridin-3-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil ]Imidazol-6-yl) oxy) quinoxaline (30.0 mg,42.5umol, 18%). M/zES + [ M+H ]] ⁺ 657.2。

Step 2.8-chloro-2- (1- (1- (5-fluoropyridin-3-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-chloro-3- [1- [1- (5-fluoro-3-pyridinyl) azetidin-3-yl ] in trifluoroacetic acid (0.5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (30.0 mg,38.0 mmole) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 11% -41%,10 min) purification to give 8-chloro-2- (1- (1- (5-fluoropyridin-3-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) quinoxaline (24.5 mg,46.2umol, 99%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.35(s,1H),8.93(s,1H),8.48(s,1H),8.19(s,1H),7.99-7.91(m,2H),7.82(s,1H),7.51(d,J＝8.3Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.97-6.89(m,2H),5.64-5.56(m,1H),4.49(t,J＝8.0Hz,2H),4.31(dd,J＝5.5,8.2Hz,2H),2.48(s,3H)；m/z ES+[M+H] ⁺ 527.0。

EXAMPLE 21 Synthesis of 8-chloro-2- [1- [1- (5-fluoro-3-pyridinyl) -4-piperidinyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [1- (5-fluoro-3-pyridinyl) -4-piperidinyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- [1- (4-piperidinyl) pyrazol-4-yl ] in dioxane (2 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 399 umol) and 3-bromo-5-fluoro-pyridine (59.6 mg, 399 umol) were added cesium carbonate (221 mg,678 umol), tris (dibenzylideneacetone) dipalladium (31.0 mg,33.9 umol) and (5-diphenylphosphanyl-9, 9-dimethylxanthen-4-yl) -diphenylphosphane (19.6 mg,33.9 umol). The mixture was degassed and purged 3 times with nitrogen and then stirred at 80 ℃ for 16 hours, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (15 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to ethyl acetate/methanol=20/1) to give 2- [ [6- [ 5-chloro-3- [1- [1- (5-fluoro-3-pyridinyl) -4-piperidinyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (120 mg,175umol, 48%). M/zES + [ M+H ]] ⁺ 685.2。

Step 2.8-chloro-2- [1- [1- (5-fluoro-3-pyridinyl) -4-piperidinyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [1- (5-fluoro-3-pyridinyl) -4-piperidinyl ] in trifluoroacetic acid (0.5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (60.0 mg,87.6 umol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,7 min) purification to give 8-chloro-2- [1- [1- (5-fluoro-3-pyridinyl) -4-piperidinyl ] as an off-white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (24.2 mg,40.1umol, 39%). ¹ H NMR(400MHz,CD ₃ OD)δ9.20(s,1H),8.67(s,1H),8.38(s,1H),8.18(s,1H),7.95(d,J＝9.2Hz,1H),7.86(d,J＝2.0Hz,1H),7.63(d,J＝8.8Hz,1H),7.42(d,J＝9.2Hz,1H),7.29(td,J＝2.4,12.0Hz,1H),7.24(d,J＝2.0Hz,1H),7.18-7.13(m,1H),4.62-4.51(m,1H),4.03(d,J＝13.2Hz,2H),3.15-3.07(m,2H),2.69(s,3H),2.33-2.22(m,4H)；m/z ES+[M+H] ⁺ 555.0。

EXAMPLE 22 Synthesis of 1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) azetidin-3-ol

Step 1.1- (2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) azetidin-3-ol

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in methanol (1 mL) and tetrahydrofuran (1 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Triethylamine (96.5 mg,954 umol) and azetidin-3-ol (69.7 mg, 630 umol, HCl) were added to a solution of ethylmethanesulfonate (200 mg,318 umol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/methanol=10/1 to 1/1) to give 1- (2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) azetidin-3-ol (100 mg,124umol, 39%). M/zES + [ M+H ]] ⁺ 606.1。

Step 2.1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) azetidin-3-ol

1- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]A solution of azetidin-3-ol (80.0 mg,132 umol) was stirred at 20℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was subjected to SFC (column: daicel Chiralcel OD (250 mm. Times.30 mm. Times.10 um); mobile phase: [0.1% ammonium hydroxide/methanol) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 45% -45%,4.5min, total run 50 min) and preparative HPLC (column: waters Xridge 150 x 25mm x 5um; mobile phase: [ water (ammonium bicarbonate-acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 21% -51%,10 min) purification to give 1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo) d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) azetidin-3-ol (6.6 mg,13.4umol, 10%). ¹ H NMR(400MHz,CD ₃ OD)δ9.14(s,1H),8.56(s,1H),8.35(s,1H),7.89(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.17(d,J＝2.0Hz,1H),7(dd,J＝2.0,8.8Hz,1H),4.36-4.23(m,3H),3.68-3.55(m,2H),3.03(t,J＝6.0Hz,2H),2.92(d,J＝2.0Hz,2H),2.57(s,3H)；m/z ES+[M+H] ⁺ 476.0。

Example 23: synthesis of 8-chloro-2- [1- [ (1E) -3-fluorobut-1, 3-dienyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

(3, 3-Difluorocyclobutyl) methanesulfonate

To a solution of 3, 3-difluorocyclobutanol (100 mg,925 umol) in dichloromethane (2 mL) was added triethylamine (102 mg,1.02 mmol) and methanesulfonyl chloride (116 mg,1.02 mmol) at 0deg.C. The mixture was stirred at 0℃for 0.5 h. The reaction mixture was quenched by the addition of water (10 mL) at 0 ℃ and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (3, 3-difluorocyclobutyl) methanesulfonate (172 mg, crude) as a brown oil.

Step 2.2- [ [6- [ 5-chloro-3- [1- [ (1E) -3-fluorobut-1, 3-dienyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- (1H-pyrazole) in N, N-dimethylformamide (1.5 mL)-4-yl) quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (150 mg, 295. Mu. Mol) was added cesium carbonate (192 mg, 591. Mu. Mol), potassium iodide (9.82 mg, 59.1. Mu. Mol) and (3, 3-difluorocyclobutyl) methanesulfonate (82.6 mg, 447. Mu. Mol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column Phenomenex Synergi C18:150.25 mm.10 um; mobile phase: [ water (0.225% formic acid))Acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 46% -76%,10 min) to give 2- [ [6- [ 5-chloro-3- [1- [ (1E) -3-fluorobut-1, 3-dienyl ] as a white solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (120 mg,208umol, 70%). ¹ HNMR(400MHz,CDCl ₃ )δppm 9.09(s,1H),8.43(d,J＝4.8Hz,2H),7.97(d,J＝8.8Hz,1H),7.88-7.79(m,1H),7.42-7.34(m,2H),7.19(s,1H),7.17-7.10(m,1H),6.87-6.72(m,1H),5.49(s,2H),4.87(dd,J＝3.2,16.4Hz,1H),4.77-4.57(m,1H),3.55(t,J＝8.0Hz,2H),2.86(s,3H),0.90(t,J＝7.6Hz,2H),-0.05(s,9H)；m/z ES+[M+H] ⁺ 577.3。

Step 3.8-chloro-2- [1- [ (1E) -3-fluorobut-1, 3-dienyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 2- [ [6- [ 5-chloro-3- [1- [ (1E) -3-fluorobut-1, 3-dienyl ] in tetrahydrofuran (0.5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (90.0 mg, 155. Mu. Mol) was added tetrabutylammonium fluoride (1M in THF, 1.56 mL). The mixture was stirred at 80℃for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: welch Ultimate XB-CN 250 x 70 x 10um; mobile phase: [ heptane-ethanol (0.1% ammonium hydroxide)) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 30% -70%,15 min) and further purified by preparative HPLC (column: shim-pack C18 x 25 x 10um; mobile phase: [ water (0.225% formic acid))Acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,10 min) purification to give 8-chloro-2- [1- [ (1E) -3-fluorobut-1, 3-dienyl as an off-white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (26.1 mg,58.5umol, 36%). ¹ H NMR(400MHz,CDCl ₃ ):δppm 9.04(s,1H),8.43(s,1H),8.40(s,1H),7.90(d,J＝9.2Hz,1H),7.56(d,J＝8.8Hz,1H),7.38(d,J＝14.0Hz,1H),7.32(d,J＝9.2Hz,1H),7.26(d,J＝2.0Hz,1H),7.04(dd,J＝2.0,8.8Hz,1H),6.84-6.70(m,1H),4.86(dd,J＝3.2,16.4Hz,1H),4.76-4.57(m,1H),2.66(s,3H)；m/z ES+[M+H] ⁺ 447.0。

EXAMPLE 24 Synthesis of 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.3- (trifluoromethyl) cyclobutyl 4-methylbenzenesulfonate

To a solution of 3- (trifluoromethyl) cyclobutanol (50 mg, 317 umol) in dichloromethane (3 mL) were added 4-methylbenzenesulfonyl chloride (102 mg, 335 umol), triethylamine (72.2 mg, 714umol) and 4-dimethylaminopyridine (4.36 mg,35.7 umol). The mixture was stirred at 20℃for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=4:1) to give 3- (trifluoromethyl) cyclobutyl 4-methylbenzenesulfonate as a yellow oil (50.0 mg,170umol, 48%). ¹ H NMR(400MHz,CDCl ₃ )δ＝7.79(d,J＝8.4Hz,2H),7.36(d,J＝8.0Hz,2H),4.75(t,J＝7.2Hz,1H),2.47(s,3H),2.54-2.46(m,2H),2.36-2.26(m,2H)。

Step 2.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (70.0 mg,138 umol) was added cesium carbonate (135 mg,414 umol) and [3- (trifluoromethyl) cyclobutyl]4-Methylbenzenesulfonate (40.6 mg, 138. Mu. Mol). The mixture was stirred at 80℃for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). Combining the organic mattersThe layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) -2- (1- (3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline (80.0 mg, crude product). m/zES +H ⁺ 629.4。

Step 3.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline

2- [ [6- [ 5-chloro-3- [1- [3- (trifluoromethyl) cyclobutyl ] in trifluoroacetic acid (0.3 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (80 mg,127 umol) was stirred at 20℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C, 18, 250, 50mm 15um; mobile phase: [ water (0.2% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -52%,10 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) -2- (1- (3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline (51.8 mg,104umol, 82%). ¹ H NMR(400MHz,DMSO-d ₆ )δppm 9.35(s,1H),8.84(s,1H),8.45(s,1H),8.02(d,J＝9.2Hz,1H),7.69(d,J＝8.8Hz,1H),7.47-7.35(m,2H),7.15(dd,J＝2.0,8.8Hz,1H),5.30-5.13(m,1H),3.35(d,J＝4.8Hz,1H),2.96-2.87(m,2H),2.73-2.67(m,2H),2.65(s,3H)；m/z ES+[M+H] ⁺ 499.0。

Example 25: synthesis of 8-chloro-2- (1- ((1 s,3 s) -3- (3-methoxyazetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- ((1 r,3 r) -3- (3-methoxyazetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- (3- (3-methoxyazetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in methanol (2 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (150 mg,337 umol) and 3-methoxyazetidine hydrochloride (125 mg,1.01 mmol) were added diisopropylethylamine (131 mg,1.01 mmol) and titanium (IV) propan-2-ol (192 mg,674 umol). The mixture was stirred at 60℃for 2 hours. Sodium cyanoborohydride (21 mg,337 umol) was then added, and the reaction mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine (25 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 8-chloro-2- (1- (3- (3-methoxyazetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxaline (60.0 mg,112umol, 33%) M/zES + [ M+H] ⁺ 516.1。

Step 2.8-chloro-2- (1- ((1 s,3 s) -3- (3-methoxyazetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- ((1 r,3 r) -3- (3-methoxyazetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

8-chloro-2- [1- [3- (3-methoxyazetidin-1-yl) cyclobutyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline (60.0 mg,116 umol) was purified by SFC (basic conditions, column Daicel Chiralpak IE (50X 250mm,10 um); mobile phase [ hexane-ethanol (0.1% ammonium hydroxide ]; (B%: 80% -80%,30, 120 min)) to give 8-chloro-2- (1- ((1 s,3 s) -3- (3-methoxyazetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline (11.3 mg,18.4umol, 16%) and 8-chloro-2- (1- ((r, 3 r) -3- (3-methoxyazetidin-1-yl) cyclobutyl) -1H-pyrazol-6-yl) quinoxaline as white solids (11.3 mg,18.4 umol) and 8-chloro-2- (1- ((1 r,3 s) -3-methoxyazetidin-1-H-1-yl) imidazol-6-yl) quinoxaline (11.3 g).

¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.16(s,1H),8.63(s,1H),8.41(s,2H),7.90(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.35(d,J＝9.2Hz,1H),7.18(d,J＝2.4Hz,1H),7.01(dd,J＝2.4,8.8Hz,1H),4.79(s,1H),4.25-4.17(m,1H),4.07-4(m,2H),3.65(dd,J＝4.8,10.4Hz,2H),3.62-3.55(m,1H),3.34(s,3H),2.90-2.81(m,2H),2.70-2.65(m,2H),2.58(s,3H)；m/z ES+[M+H] ⁺ 516.0. ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.16-9.14(m,1H),8.61(s,1H),8.39(s,1H),7.89(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.18(d,J＝2.4Hz,1H),7.01(dd,J＝2.4,8.8Hz,1H),5.18-5.05(m,1H),4.21-4.13(m,1H),3.94-3.84(m,2H),3.76-3.65(m,1H),3.40(dd,J＝5.2,10.0Hz,2H),3.32(s,3H),2.85-2.75(m,2H),2.57(s,3H),2.56-2.49(m,2H)；m/z ES+[M+H] ⁺ 516.0。

Example 26: synthesis of (1S, 4S) -5- ((1 r, 3S) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane and (1S, 4S) -5- ((1 s, 3R) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane

(1S, 4S) -5- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutyl ] -2-oxa-5-azabicyclo [2.2.1] heptane

To 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in methanol (4 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutanone (200 mg,450 umol) and (1S, 4S) -2-oxa-5-azabicyclo [2.2.1]To a solution of heptane hydrochloride (180 mg,1.35 mmol) were added diisopropylethylamine (174 mg,1.35mmol,235 ul) and titanium (IV) propan-2-ol (256 mg,900 umol). The mixture was stirred at 60℃for 2 hours. Sodium cyanoborohydride (28 mg,450 umol) was then added and the reaction mixture was stirred at 25 ℃Mix for 2 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and then extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were washed with brine (25 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give (1S, 4S) -5- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a colorless oil]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutyl group]-2-oxa-5-azabicyclo [2.2.1]Heptane (38.0 mg,71.3umol, 16%). M/zES + [ M+H ]] ⁺ 528.1。

(1S, 4S) -5- ((1 r, 3S) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane and (1S, 4S) -5- ((1 s, 3R) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane

(1S, 4S) -5- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutyl ] -2-oxa-5-azabicyclo [2.2.1] heptane (54.0 mg,102 umol) was isolated by SFC (basic conditions, column Daicel Chiralpak IG (250 mm. Times.50 mm,10 um); mobile phase: [ hexane-ethanol (0.1% ammonium hydroxide) ]; (B%: 80% -80%,12 min) to give (1S, 4S) -5- ((1 r, 3S) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane (36.4 mg,66.9umol, 65%) and (1S, 4S) -5- ((1 s, 3R) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane (8.4 mg,14.6umol, 14%) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.42-12.20(m,1H),9.33(s,1H),8.80(s,1H),8.37(s,1H),7.95(d,J＝9.2Hz,1H),7.59-7.42(m,1H),7.38-7.27(m,1H),7.26-7.11(m,1H),6.99-6.89(m,1H),4.78-4.68(m,1H),4.38(s,1H),3.79(d,J＝7.2Hz,1H),3.54-3.49(m,2H),3.18-3.08(m,1H),2.77(d,J＝8.8Hz,1H),2.71-2.56(m,3H),2.49-2.47(m,3H),2.44-2.36(m,2H),1.72(d,J＝8.4Hz,1H),1.58(d,J＝10.0Hz,1H)；m/z ES+[M+H] ⁺ 528.0。

¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.48-12.17(m,1H),9.31(s,1H),8.80(s,1H),8.39(s,1H),7.95(dd,J＝3.6,8.8Hz,1H),7.58-7.44(m,1H),7.31(d,J＝10.4Hz,1H),7.26-7.13(m,1H),6.94(dd,J＝8.8,10.4Hz,1H),5.16-5.07(m,1H),4.38(s,1H),3.80(d,J＝7.6Hz,1H),3.56(s,1H),3.53(dd,J＝1.6,7.2Hz,1H),3.47-3.40(m,2H),2.76-2.71(m,1H),2.69-2.54(m,2H),2.49-2.47(m,3H),2.43-2.34(m,2H),1.76(d,J＝9.2Hz,1H),1.58(d,J＝9.2Hz,1H)；m/z ES+[M+H] ⁺ 528.0。

Example 27: synthesis of 8-chloro-2- [1- (3, 3-difluorocyclobutyl) pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- (3, 3-difluorocyclobutyl) pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (0.5 mL) at 0deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (20.0 mg,34.7 umol) was added bis (2-methoxyethyl) aminothiotrifluoride (76.9 mg,347 umol). The mixture was stirred under nitrogen at 25 ℃ for 1.5 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) at 0 ℃ and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by preparative HPLC (column: welch Ultimate XB-SiOH 250 x 50 x 10um; mobile phase: [ heptane-ethanol (0.1% ammonium hydroxide))]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -35%,15 min) to afford 2- [ [6- [ 5-chloro-3- [1- (3, 3-difluorocyclobutyl) pyrazol-4-yl ] as a yellow solid ]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (20.0 mg,33.6umol, 91%). M/zES + [ M+H ]] ⁺ 597.3。

Step 2.8-chloro-2- [1- (3, 3-difluorocyclobutyl) pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- (3, 3-difluorocyclobutyl) pyrazol-4-yl ] in trifluoroacetic acid (0.5 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (17.0 mg,28.4 umol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (column Phenomenex Synergi C18:150.25 mm.10 um; mobile phase: [ water (0.225% formic acid))Acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,10 min) purification to give 8-chloro-2- [1- (3, 3-difluorocyclobutyl) pyrazol-4-yl as a yellow solid]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (11.4 mg,24.5umol, 85%). ¹ H NMR(400MHz,CDCl ₃ )δppm 9.02(s,1H),8.35(s,1H),8.30(s,1H),7.89(d,J＝9.2Hz,1H),7.55(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.27-7.25(m,1H),7.03(dd,J＝2.4,8.8Hz,1H),4.90-4.78(m,1H),3.43-3.28(m,2H),3.27-3.13(m,2H),2.66(s,3H)；m/z ES+[M+H] ⁺ 467.0。

EXAMPLE 28 Synthesis of (1R, 4R) -5- ((1 r, 3R) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane and (1R, 4R) -5- ((1 s, 3S) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane

Step 1. (1R, 4R) -5- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane

To 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in methanol (2 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutanone (50.0 mg,112 u)mol) and (1R, 4R) -2-oxa-5-azabicyclo [2.2.1]Heptane; diisopropylethylamine (43.6 mg, 307 umol) and titanium (IV) propan-2-ol (63.9 mg,225 umol) were added to a solution of hydrochloride (45.7 mg,337 umol). The mixture was stirred at 60℃for 2 hours. Sodium cyanoborohydride (7.06 mg,112 umol) was then added, and the reaction mixture was stirred at 25 ℃ for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give (1R, 4R) -5- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-cyclobutyl) -2-oxa-5-azabicyclo [2.2.1 ]Heptane (38.0 mg,72.0umol, 21%). M/zES + [ M+H ]] ⁺ 528.3。

Step 2. (1R, 4R) -5- ((1 r, 3R) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane and (1R, 4R) -5- ((1 s, 3S) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane

The compound (1R, 4R) -5- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane (38.0 mg,72.0 umol) was separated by SFC (column: daicel Chiralpak IG (250 mm. Times.50 mm,10 um); mobile phase: [ hexane-EtOH (0.1% ammonium hydroxide) ]; (B%: 90% -90%,30 min) to give (1R, 4R) -5- ((1 r, 3R) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinolin-1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane (32.9 mg, 9-um), 78%) and (1R, 4R) -5- ((1 s, 3S) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) -2-oxa-5-azabicyclo [2.2.1] heptane (6.91 mg,12.3umol, 17%) as an off-white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.53-12.14(m,1H),9.33(s,1H),8.81(s,1H),8.38(s,1H),7.96(d,J＝8.8Hz,1H),7.52(d,J＝6.8Hz,1H),7.32(d,J＝8.8Hz,1H),7.22(s,1H),6.95(d,J＝8.0Hz,1H),4.82-4.68(m,1H),4.40(s,1H),3.81(d,J＝6.8Hz,1H),3.54(d,J＝4.0Hz,2H),3.17(s,1H),2.79(d,J＝10.0Hz,1H),2.67-2.56(m,3H),2.54-2.51(m,3H),2.46-2.35(m,2H),1.79-1.56(m,2H)；m/z ES+[M+H] ⁺ 528.0。

¹ H NMR(400MHz,CD ₃ OD)δ＝9.12(s,1H),8.61(s,1H),8.39(s,1H),7.87(d,J＝9.2Hz,1H),7.53(d,J＝8.4Hz,1H),7.33(d,J＝9.6Hz,1H),7.18(s,1H),7.01(d,J＝8.4Hz,1H),5.24-5.14(m,1H),4.59(s,1H),4.14-3.87(m,4H),3.76(d,J＝8.8Hz,1H),3.11-2.98(m,2H),2.92-2.72(m,4H),2.57(s,3H),2.11(d,J＝10.8Hz,1H),1.97(d,J＝10.6Hz,1H)；m/z ES+[M+H] ⁺ 528.0。

Example 29: synthesis of 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -N- (2-carboxamide-2-methylpropyl) acetamide

Step 1.2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -1- (5, 5-dimethyl-4H-imidazo l-3-yl) ethanone

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in N, N-dimethylamide (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of acetic acid (70.0 mg,124 umol), 4-dimethyl-1, 5-dihydroimidazole (15.8 mg,161 umol) and diisopropylethylamine (64.0 mg,495 umol) was added [ dimethylamino (triazolo [4,5-b ]]Pyridin-3-yloxy) methylene]-dimethylaminoonium; hexafluorophosphate (236 mg,619 umol). The mixture was stirred at 25℃for 5 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (50 ml x 2), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1- (5, 5-dimethyl-4H-imidazo l-3-yl) ethanone (105 mg, crude). M/zES + [ M+H ]] ⁺ 645.2。

Step 2.2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -N- (2-carboxamide-2-methylpropyl) acetamide

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1- (5, 5-dimethyl-4H-imidazo l-3-yl) ethanone (105 mg, 163. Mu. Mol) is stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo t to give a residue. The crude product was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -52%,10 min) and purified by preparative HPLC (column: phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -30%,10 min) re-purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as an off-white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-N- (2-carboxamide-2-methylpropyl) acetamide (6.58 mg,12.6umol, 7.6%). ¹ H NMR(400MHz,DMSO-d ₆ )δ12.85-11.67(m,1H),9.33(s,1H),8.74-8.62(m,1H),8.42-8.31(m,1H),8.29-8.20(m,1H),7.96(d,J＝9.2Hz,1H),7.92-7.86(m,1H),7.71(s,1H),7.56-7.45(m,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.95(dd,J＝2.4,8.8Hz,1H),5.06-4.87(m,2H),3.41(d,J＝6.0Hz,2H),2.49(s,3H),1.25-1.17(m,6H)；m/z ES+[M+H] ⁺ 533.0。

EXAMPLE 30 Synthesis of 8-chloro-2- (1- (3, 3-difluorocyclopentyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclopentanone

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in acetonitrile (4 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (300 mg,592 umol) was added scandium (III) triflate (29.1 mg,59.2 umol) and cyclopent-2-en-1-one (194 mg,2.37 mmol). The mixture was stirred at 25℃for 13 hours. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 50% -80% acetonitrile, 10 min) to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclopentanone (300 mg,510umol, 82%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(d,J＝3.6Hz,1H),8.83(s,1H),8.39(s,1H),7.96(dd,J＝0.8,9.2Hz,1H),7.69-7.57(m,1H),7.46-7.28(m,2H),7.09-6.99(m,1H),5.65-5.52(m,2H),5.29-5.21(m,1H),3.56-3.45(m,2H),2.90-2.66(m,2H),2.57(d,J＝6.4Hz,3H),2.55-2.52(m,1H),2.47-2.41(m,1H),2.39-2.28(m,2H),0.90-0.75(m,2H),-0.07--0.14(m,9H)；m/z ES+[M+H] ⁺ 589.3。

Step 2.8-chloro-2- (1- (3, 3-difluorocyclopentyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in dichloromethane (3 mL) at 0deg.C]To a solution of imidazol-6-yl) oxy-quinoxalin-2-yl) -1H-pyrazol-1-yl cyclopentanone (280 mg, 470 umol) was slowly added bis (2-methoxyethyl) amino sulfur trifluoride (210 mg,951 umol). The mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with saturated sodium bicarbonate (40 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, filtered and purified under reduced pressureConcentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 75% -80% acetonitrile, 5 min) to give 8-chloro-2- (1- (3, 3-difluorocyclopentyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as an orange oil]Imidazol-6-yl) oxy) quinoxaline (140 mg,230umol, 48%). M/zES + [ M+H ]] ⁺ 611.1。

Step 3.8-chloro-2- (1- (3, 3-difluorocyclopentyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

8-chloro-2- (1- (3, 3-difluorocyclopentyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxaline (60.0 mg,98.2 umol) was stirred at 25 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,10 min) purification to give 8-chloro-2- (1- (3, 3-difluorocyclopentyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) quinoxaline (27.7 mg,57.5umol, 59%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.34(s,1H),8.81(s,1H),8.42(s,1H),7.99(d,J＝9.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.40-7.29(m,2H),7.05(dd,J＝2.4,8.8Hz,1H),5.12(q,J＝7.6Hz,1H),2.86-2.75(m,1H),2.67(dd,J＝7.6,16.0Hz,1H),2.57(s,3H),2.45-2.36(m,2H),2.31-2.19(m,2H)；m/z ES+[M+H] ⁺ 481.0。

EXAMPLE 31 Synthesis of 2- (1- ((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.2- (1- ((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in tetrahydrofuran (2 mL) ]To a solution of imidazol-6-yl) oxy quinoxaline (90.0 mg,153 umol) was added oxetan-3-one (22.1 mg,306 umol) and the mixture was stirred at 25℃for 0.5 hours. Sodium triacetoxyborohydride (97.4 mg,459 umol) was then added to the mixture. The mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: methanol=10:1) to give 2- (1- ((3 s,4 s) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) quinoxaline (40.0 mg,61.5umol, 40%). M/zES + [ M+H ]] ⁺ 644.4。

Step 2.2- (1- ((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- (1- ((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in tetrahydrofuran (1 mL) ]To a solution of imidazol-6-yl) oxy quinoxaline (35.0 mg,54.4 umol) was added pyridine hydrofluoride (220 mg,2.22 mmol). The mixture was stirred at 80℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: unisil3-100C18 Ultra 150*50mm*3um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,10 min) purification to give 2- (1- ((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxaline (23.5 mg,44.8umol, 82%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.24(s,1H),8.83(s,1H),8.42(s,1H),7.85(d,J＝9.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.26(d,J＝9.2Hz,1H),7.10(d,J＝2.4Hz,1H),6.92(dd,J＝2.4,8.8Hz,1H),5.11-4.90(m,1H),4.60-4.55(m,2H),4.50-4.45(m,2H),3.62(s,1H),3.21(s,1H),2.81(d,J＝10.0Hz,1H),2.69(s,3H),2.51-2.50(m,1H),2.49-2.48(m,3H),2.17-2.04(m,4H)；m/z ES+[M+H] ⁺ 514.1。

Example 32: synthesis of 1- ((1 s,3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol and 1- ((1 r,3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol

Step 1.1- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol

To 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in methanol (2 mL) ]Quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (150 mg,340 umol) and azetidine-3-ol hydrochloride (111 mg,1.01 mmol) were added titanium (IV) propan-2-ol (192 mg,674 umol) and diisopropylethylamine (131 mg,1.01 mmol). The mixture was stirred at 60℃for 2 hours. Sodium cyanoborohydride (21.0 mg,337 umol) was then added, and the mixture was stirred at 25 ℃ for 2 hours. The reaction mixture was diluted with saturated sodium bicarbonate (20 mL) and then extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were washed with brine (25 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol (30.0 mg,60.0 mol, 18%). M/zES + [ M+H ]] ⁺ 502.3。

Step 2.1- ((1 s,3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol and 1- ((1 r,3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol

1- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutyl ] azetidin-3-ol (80.0 mg,160 umol) was isolated by SFC (basic conditions; column: daicel Chiralpak IG (250 mm. Times.50 mm,10 um); mobile phase: [ hexane-ethanol (0.1% ammonium hydroxide) ]; (B%: 40% -40%,22, 66 min) to give 1- ((1 s,3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol (39.5 mg,77.1umol, 48%) and 1- ((1 r,3 r) -3- (4- (8-chloro-7-methyl-1H-benzo [ 6-yl ] imidazol-1-yl) oxy) quinolin-1-yl) azetidin-3-ol as a white solid (18.5 mg,3 s) -3- ((1 r, 3.1-3-yl) oxy) quinoxalin-1-ol.

¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.40-12.10(m,1H),9.33(s,1H),8.77(s,1H),8.38(s,1H),7.95(d,J＝9.2Hz,1H),7.62-7.43(m,1H),7.39-7.28(m,1H),7.27-7.12(m,1H),6.94(d,J＝7.2Hz,1H),5.32(d,J＝6.8Hz,1H),4.75-4.64(m,1H),4.25-4.16(m,1H),3.44(t,J＝6.8Hz,2H),3.11-3(m,1H),2.90(t,J＝6.8Hz,2H),2.57-2.52(m,2H),2.49-2.47(m,3H),2.42-2.32(m,2H)；m/z ES+[M+H] ⁺ 502.0。

¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.53-12.09(m,1H),9.30(s,1H),8.77(s,1H),8.37(s,1H),7.95(d,J＝9.2Hz,1H),7.58-7.44(m,1H),7.31(d,J＝8.0Hz,1H),7.21(s,1H),6.94(d,J＝7.2Hz,1H),5.34(s,1H),5.14-5(m,1H),4.21(s,1H),3.55(s,2H),3.21-3.14(m,1H),2.75(s,2H),2.59-2.53(m,2H),2.49-2.45(m,3H),2.31-2.21(m,2H)；m/z ES+[M+H] ⁺ 502.0。

EXAMPLE 33 Synthesis of 1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one

Step 1.2- (2-oxopyrrolidin-1-yl) ethylmethanesulfonate

To a solution of 1- (2-hydroxyethyl) pyrrolidin-2-one (500 mg,3.87 mmol) in dichloromethane (5 mL) was added triethylamine (1.18 g,11.6 mmol) and methanesulfonyl chloride (668mg, 5.81 mmol). The mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (2-oxopyrrolidin-1-yl) ethylmethanesulfonate (700 mg, crude) as a yellow oil. ¹ H NMR(400MHz,DMSO-d ₆ )δ4.28(t,J＝5.2Hz,2H),3.49(t,J＝5.2Hz,2H),3.40(t,J＝7.2Hz,2H),3.18(s,3H),2.26-2.19(m,2H),1.97-1.89(m,2H)。

Step 2.1- (2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (2 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (200 mg, 390 umol) was added potassium acetate (164 mg,1.18 mmol) and 2- (2-oxopyrrolidin-1-yl) ethylmethanesulfonate (163 mg,789 umol). The mixture was stirred at 80℃for 12 hours. The reaction was then stirred at 100℃for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 80% -90% acetonitrile, 5 min) to give 1- (2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as an orange oil ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one (150 mg,243umol, 62%). M/zES + [ M+H ]] ⁺ 618.1。

Step 3.1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one

1- (2- (4- (8-chloro-7- ((2-)) in trifluoroacetic acid (1 mL)Methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one (50.0 mg,80.9 umol) was stirred at 25 ℃ for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 9% -39%,10 min) purification to give 1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo) d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-2-one (13.1 mg,26.9umol, 33%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.30(s,1H),8.72(s,1H),8.36(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝1.6Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.38(t,J＝6.0Hz,2H),3.65(t,J＝6.0Hz,2H),3.22(t,J＝7.2Hz,2H),2.48(s,3H),2.19-2.13(m,2H),1.87(q,J＝7.6Hz,2H)；m/z ES+[M+H] ⁺ 488.1。

EXAMPLE 34.Synthesis of 8-cyclopropyl-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-bromo-2- [1- [ (3, 3-difluorocyclobutyl) methyl in tetrahydrofuran (2 mL) at 0deg.C]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (100 mg,190 umol) was added sodium hydride (15.2 mg, 383 umol,60% in mineral oil). The mixture was stirred at 0℃for 30min. 2- (chloromethoxy) ethyl-trimethyl-silane (47.6 mg, 284 umol) was then added at 0deg.C. The mixture was stirred at 25℃for 1.5 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and purifiedConcentrating under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/4) to give 8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (30.0 mg,45.8umol, 24%). M/zES + [ M+H ]] ⁺ 657.2。

Step 2.8-cyclopropyl-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-bromo-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in dioxane (0.5 mL) and water (0.05 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (25.0 mg,38.1 mol) and cyclopropylboronic acid (32.8 mg, 383 mol) were added sodium carbonate (12.1 mg,114 mol) and methanesulfonyl (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (4.50 mg,5.72 mol). The mixture was stirred under nitrogen at 110 ℃ for 8 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 1/9) to give 8-cyclopropyl-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) quinoxaline (15.0 mg,19.9umol, 52%). M/zES + [ M+H ]] ⁺ 617.4。

Step 3.8-cyclopropyl-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-cyclopropyl-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in trifluoroacetic acid (0.5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (13.0 mg,17.3 umol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acidConditions; column: phenomenex Synergi C18, 150×25mm×10um; mobile phase: [ Water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 20% -50%,10 min) purification to give 8-cyclopropyl-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (3.7 mg,7.43umol, 43%). ¹ H NMR(400MHz,CD ₃ OD)δppm 9.06(s,1H),8.50(s,1H),8.27(s,1H),7.74(d,J＝9.2Hz,1H),7.48(d,J＝8.8Hz,1H),7.25(d,J＝9.2Hz,1H),7.03(d,J＝2.0Hz,1H),6.93(dd,J＝2.4,8.8Hz,1H),4.39(d,J＝6.8Hz,2H),2.92-2.81(m,1H),2.77-2.63(m,3H),2.55(s,3H),2.52-2.39(m,2H),1.65-1.58(m,2H),1.07-1.02(m,2H)；m/z ES+[M+H] ⁺ 487.1。

Example 35: synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [1- (oxetan-3-ylmethyl) azetidin-3-yl ] pyrazol-4-yl ] quinoxaline

Step 1.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [1- (oxetan-3-ylmethyl) azetidin-3-yl ] pyrazol-4-yl ] quinoxaline

To 2- [1- (azetidin-3-yl) pyrazol-4-yl in tetrahydrofuran (0.8 mL) and methanol (0.8 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ]Triethylamine (46.8 mg,463 mol) was added to a mixture of quinoxalines (100 mg,231 mol), followed by oxetan-3-ylmethyl mesylate (38.4 mg,231 mol). The reaction mixture was stirred at 80℃for 12 hours. The reaction mixture was quenched with water (3 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (column Phenomenex Synergi C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -24%,10 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a white solid]-2- [1- [1- (oxetan-3-ylmethyl) azetidin-3-yl]Pyrazole-4-yl]Quinoxaline (26.2 mg,51.2umol, 22%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.33(s,1H),8.84(s,1H),8.41(s,1H),8.19(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝2.4Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),5.20-5.05(m,1H),4.70-4.55(m,2H),4.29(t,J＝6.0Hz,2H),3.74(t,J＝7.6Hz,2H),3.49(t,J＝7.2Hz,2H),3.04-2.96(m,1H),2.83(d,J＝7.6Hz,2H),2.48(s,3H)；m/z ES+[M+H] ⁺ 502.0。

EXAMPLE 36 Synthesis of 2- [1- (2-azaspiro [3.3] heptan-6-yl) pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline and 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- (oxetan-3-yl) -2-azaspiro [3.3] heptan-6-yl ] pyrazol-4-yl ] quinoxaline

Step 1.6-methylsulfonyloxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester

To 6-hydroxy-2-azaspiro [3.3] in dichloromethane (3 mL)]To a solution of tert-butyl heptane-2-carboxylate (150 mg, 703. Mu. Mol) was added triethylamine (214 mg,2.11 mmol) and methanesulfonyl chloride (161 mg,1.41 mmol), and the mixture was stirred at 0℃for 4 hours. The reaction mixture was quenched with water (5 mL) at 0 ℃ and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with water (3×5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-methylsulfonyloxy-2-azaspiro [3.3] as a yellow oil]Heptane-2-carboxylic acid tert-butyl ester (220 mg,75 umol, 96%). M/zES + [ M-55 ]] ⁺ 236.1。

Step 2.6- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (5 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (50.0 mg,98.6 umol), 6-methylsulfonyloxy1-2-azaspiro [3.3]To a solution of tert-butyl heptane-2-carboxylate (43.1 mg, 148. Mu. Mol) was added potassium carbonate (54.5 mg, 390. Mu. Mol). The mixture was stirred at 100℃for 16 hours. The reaction mixture was quenched with water (50 mL) at 20 ℃ and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=1:1) to give 6- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-2-azaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester (80.0 mg,114umol, 90%). M/zES + [ M+H ]] ⁺ 702.5。

Step 3.2- [1- (2-azaspiro [3.3] heptan-6-yl) pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

6- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-2-azaspiro [3.3]A solution of tert-butyl heptane-2-carboxylate (80.0 mg, 114. Mu. Mol) was stirred at 20℃for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 3% -33%,10 min) to give 2- [1- (2-azaspiro [3.3] as a yellow solid]Heptane-6-yl) pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (15.4 mg,32.6umol, 36%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.22(s,1H),8.60(s,1H),8.40(s,1H),8.01(d,J＝9.2Hz,1H),7.78-7.74(m,1H),7.50(d,J＝9.2Hz,1H),7.35-7.28(m,2H),4.98-4.92(m,1H),4.24(d,J＝18.0Hz,4H),3.02-2.87(m,4H),2.84(s,3H)；m/z ES+[M+H] ⁺ 472.1。

Step 4.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- (oxetan-3-yl) -2-azaspiro [3.3] heptan-6-yl ] pyrazol-4-yl ] quinoxaline

To 2- [1- (2-azaspiro [3.3] in methanol (1 mL)]Heptane-6-yl) pyrazol-4-yl ]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (100).To a mixture of 0mg,212 umol) and oxetan-3-one (30.6 mg,424 umol) was added sodium cyanoborohydride (40.0 mg, 630 umol) and sodium acetate (87.9 mg,1.06 mmol). The mixture was stirred at 20℃for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 27% -57%,8 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]-2- [1- [2- (oxetan-3-yl) -2-azaspiro [3.3 ]]Heptan-6-yl]Pyrazol-4-yl]Quinoxaline (17.7 mg,32.0 mol, 15%). ¹ H NMR(400MHz,CD ₃ OD)δ9.11(d,J＝1.6Hz,1H),8.56(s,1H),8.34(s,1H),7.86(dd,J＝1.6,9.2Hz,1H),7.52(br d,J＝8.4Hz,1H),7.37-7.26(m,1H),7.17(s,1H),7(dd,J＝2.0,8.8Hz,1H),4.99-4.90(m,1H),4.73(t,J＝6.8Hz,2H),4.48(dd,J＝5.2,6.8Hz,2H),3.86-3.73(m,1H),3.48(s,2H),3.40(s,2H),2.79(d,J＝8.4Hz,4H),2.57(s,3H)；m/z ES+[M+H] ⁺ 528.1。

EXAMPLE 37.8 Synthesis of chloro-2- [1- [1- [ (1-fluorocyclopropyl) methyl ] azetidin-3-yl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

(1-fluorocyclopropyl) methyl methanesulfonate

To a mixture of (1-fluorocyclopropyl) methanol (500 mg,5.55 mmol) in dichloromethane (6 mL) was added triethylamine (1.12 g,11.1 mmol) followed by methanesulfonyl chloride (953 mg,8.32 mmol) at 0deg.C. The reaction mixture was stirred at 25 ℃ for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 1/1) to give (1-fluorocyclopropyl) methyl methanesulfonate (400 mg,2.38mmol, 42%) as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ＝4.55-4.41(m,2H),3.11(s,3H),1.31-1.15(m,2H),0.87(d,J＝7.6Hz,2H)。

Step 2.8-chloro-2- [1- [1- [ (1-fluorocyclopropyl) methyl ] azetidin-3-yl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 2- [1- (azetidin-3-yl) pyrazol-4-yl in tetrahydrofuran (1 mL) and methanol (1 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]A mixture of quinoxaline (100 mg, 231. Mu. Mol) and (1-fluorocyclopropyl) methyl mesylate (38.9 mg, 231. Mu. Mol) was added triethylamine (46.8 mg, 463. Mu. Mol), and the reaction mixture was stirred at 80℃for 12 hours. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Synergi C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -28%,10 min) purification to give 8-chloro-2- [1- [1- [ (1-fluorocyclopropyl) methyl ] as a white solid]Azetidin-3-yl]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (14.3 mg,28.2umol, 12%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.89-11.79(m,1H),9.33(s,1H),8.87(s,1H),8.42(s,1H),8.14(s,1H),7.96(d,J＝8.8Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),7-6.91(m,1H),5.24-5.14(m,1H),3.86(t,J＝7.6Hz,2H),3.61(s,2H),2.94-2.88(m,2H),2.49(s,3H),1.05-0.90(m,2H),0.75-0.63(m,2H)；m/z ES+[M+H] ⁺ 504.0。

EXAMPLE 38 Synthesis of 8-chloro-2- [1- [1- (2, 2-difluoroethyl) azetidin-3-yl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.8-chloro-2- [1- [1- (2, 2-difluoroethyl) azetidin-3-yl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 2- [1- (aza) in acetonitrile (1.5 mL)Cyclobutan-3-yl) pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a mixture of quinoxaline (100 mg,231 mol) and 2, 2-difluoroethyl triflate (49.5 mg,231 mol) were added potassium carbonate (96.0 mg,694 mol) and potassium iodide (3.84 mg,23.1 mol), and the reaction mixture was stirred at 70℃for 2 hours. The reaction mixture was extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (column: phenomenex Synergi C150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -31%,11 min) purification to give 8-chloro-2- [1- [1- (2, 2-difluoroethyl) azetidin-3-yl as a white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (25.2 mg,50.4umol, 22%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.55-12.11(m,1H),9.34(s,1H),8.94-8.81(m,1H),8.43(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.6Hz,1H),7.22(s,1H),7.05-6.85(m,1H),6.21-5.87(m,1H),5.26-5.13(m,1H),3.86(t,J＝7.6Hz,2H),3.67(t,J＝7.2Hz,2H),3.05-2.92(m,2H),2.49(s,3H)；m/zES+[M+H] ⁺ 496.0。

Example 39: synthesis of 2- [1- [ benzyloxy (cyclopropyl) methyl ] pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2-Benzyloxycyclobutanol

To a solution of 2-benzyloxycyclobutanone (800 mg,4.54 mmol) in methanol (8 mL) was added sodium borohydride (258 mg,6.81 mmol). The mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched by the addition of water (10 mL) at 0 ℃, then diluted with water (30 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (30 ml x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 3/1) to give 2-benzyloxycyclobutane as a colorless oilAlcohol (350 mg,1.96mmol, 43%). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.38-7.26(m,5H),5.29(d,J＝6.8Hz,1H),4.51-4.41(m,2H),3.86(m,1H),3.69(q,J＝7.6Hz,1H),1.93-1.83(m,2H),1.26-1.15(m,2H)。

(2-Benzyloxycyclobutyl) 4- (trifluoromethyl) benzenesulfonate

To a solution of 2-benzyloxycyclobutanol (410 mg,2.30 mmol) and 4- (trifluoromethyl) benzenesulfonyl chloride (1.13 g,4.60 mmol) in dichloromethane (4 mL) was added diisopropylethylamine (1.19 g,9.20mmol,1.6 mL) and 4-dimethylaminopyridine (56.2 mg,460 umol). The mixture was stirred at 25℃for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 10/1) to give (2-benzyloxycyclobutyl) 4- (trifluoromethyl) benzenesulfonate (400 mg, crude) as a white solid. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.13(d,J＝8.4Hz,2H),7.92(d,J＝8.0Hz,2H),7.37-7.21(m,5H),4.79-4.65(m,1H),4.44-4.25(m,2H),4.07-3.95(m,1H),2.11-1.97(m,2H),1.67-1.50(m,1H),1.48-1.39(m,1H)。

Step 3.2- [ [6- [3- [1- (2-benzyloxycyclobutyl) pyrazol-4-yl ] -5-chloro-quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (1.5 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (100 mg, 197umol) and (2-benzyloxycyclobutyl) 4- (trifluoromethyl) benzenesulfonate (229 mg,592 umol) was added potassium carbonate (81.8 mg,592 umol). The mixture was stirred at 80℃for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1 to 0/1) to give 2- [ [6- [3- [1- (2-benzyloxycyclobutyl) pyrazol-4-yl ] as a yellow solid]-5-chloro-quinoxaline-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (90.0 mg,135umol, 68%). M/zES + [ M+H ]] ⁺ 667.1。

Step 4.2- [1- [ benzyloxy (cyclopropyl) methyl ] pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 2- [ [6- [3- [1- (2-benzyloxycyclobutyl) pyrazol-4-yl ] in tetrahydrofuran (1 mL)]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (35.0 mg, 52.4. Mu. Mol) was added tetrabutylammonium fluoride (1M in THF, 105. Mu.L). The mixture was stirred at 40℃for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with brine (10 ml x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate/methanol=20:1) and then by preparative HPLC (column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 40% -70%,9 min) purification to give 2- [1- [ benzyloxy (cyclopropyl) methyl ] as a white solid]Pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (6.0 mg,11.2umol, 21%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(s,1H),8.97(s,1H),8.45(s,1H),7.98(d,J＝8.8Hz,1H),7.51(d,J＝8.8Hz,1H),7.45-7.28(m,6H),7.22(s,1H),6.95(d,J＝7.6Hz,1H),5.17-5.07(m,1H),4.53-4.40(m,2H),2.49-2.47(m,3H),1.70(d,J＝3.6Hz,1H),0.77-0.61(m,2H),0.58-0.39(m,2H)；m/z ES+[M+H] ⁺ 537.2。

EXAMPLE 40.2 Synthesis of- [1- (3-azabicyclo [3.2.1] oct-8-yl) pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.8-hydroxy-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester

To 8-oxo-3-azabicyclo [3.2.1] in methanol (5 mL)]Solution of tert-butyl octane-3-carboxylate (500 mg,2.22 mmol)Sodium borohydride (126 mg,3.33 mmol) was added. The mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched by addition of 2mL of water at 0 ℃, then diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 8-hydroxy-3-azabicyclo [3.2.1] as a white solid]Octane-3-carboxylic acid tert-butyl ester (440 mg,1.94mmol, 87%). ¹ H NMR(400MHz,CD ₃ OD)δ3.97(t,J＝5.2Hz,1H),3.58(d,J＝12.4Hz,2H),3.40(d,J＝12.4Hz,1H),3.33(dd,J＝1.6,3.2Hz,1H),2.03-1.91(m,2H),1.81-1.70(m,2H),1.57-1.51(m,2H),1.48(s,9H)。

Step 2.8- (trifluoromethylsulfonyloxy) -3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester

8-hydroxy-3-azabicyclo [3.2.1] in dichloromethane (2 mL) at-78deg.C]To a mixture of tert-butyl octane-3-carboxylate (200 mg,880 mmol) and pyridine (696 mg,8.80 mmol) was added dropwise trifluoromethylsulfonyl trifluoromethanesulfonate (497 mg,1.76 mmol). The mixture was slowly warmed to 0 ℃ and stirred at 0 ℃ for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate (5 mL) and extracted with dichloromethane (3 mL x 3). The combined organic layers were washed with brine (3 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 20/1) to give 8- (trifluoromethylsulfonyloxy) -3-azabicyclo [3.2.1] as a colorless oil ]Tert-butyl octane-3-carboxylate (230 mg,640 mol, 73%). ¹ H NMR(400MHz,CDCl ₃ )δ5.04(t,J＝5.2Hz,1H),3.85(d,J＝12.8Hz,1H),3.70(d,J＝12.8Hz,1H),3.31(d,J＝13.2Hz,1H),3.21(d,J＝13.2Hz,1H),2.43-2.26(m,2H),1.81-1.66(m,4H),1.47(s,9H)。

Step 3.8- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane(150 mg, 256 umol) and 8- (trifluoromethylsulfonyloxy) -3-azabicyclo [3.2.1]To a solution of tert-butyl octane-3-carboxylate (128 mg,355 umol) was added cesium carbonate (193 mg,592 umol). The mixture was stirred at 80℃for 16 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 ml×3). The combined organic layers were washed with brine (3 ml×3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give 8- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a colorless oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-3-azabicyclo [3.2.1]Tert-butyl octane-3-carboxylate (90.0 mg,126umol, 43%). M/zES + [ M+H ] ] ⁺ 716.3。

Step 4.2- [1- (3-azabicyclo [3.2.1] oct-8-yl) pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

8- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-3-azabicyclo [3.2.1]A mixture of tert-butyl octane-3-carboxylate (90.0 mg, 126. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,7 min) purification to give 2- [1- (3-azabicyclo [ 3.2.1) as a white solid]Oct-8-yl) pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (34.6 mg,71.0 mol, 57%). ¹ H NMR(400MHz,CD ₃ OD)δ9.23(s,1H),8.69(s,1H),8.39(s,1H),7.98(d,J＝9.2Hz,1H),7.68(d,J＝8.8Hz,1H),7.45(d,J＝9.2Hz,1H),7.28(d,J＝1.2Hz,1H),7.21(d,J＝8.4Hz,1H),3.46(d,J＝3.6Hz,4H),3.33-3.32(m,1H),3.27(s,2H),2.74(s,3H),2.07(s,2H),1.98-1.85(m,2H)；m/zES+[M+H] ⁺ 486.1。

EXAMPLE 41.8 Synthesis of chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2- (trifluoromethyl) -1H-benzo [ d ] imidazol-5-yl) oxy) quinoxaline

Step 1N-tert-Butoxycarbonyl-N- [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-nitro-phenyl ] carbamic acid tert-butyl ester

To 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl in N, N-dimethylformamide (3 mL) ]Pyrazol-4-yl]To a solution of quinoxalin-6-ol (250 mg, 719 umol) were added potassium carbonate (197mg, 1.43 mmol) and tert-butyl N-tert-butoxycarbonyl-N- (5-fluoro-2-nitro-phenyl) carbamate (508 mg,1.43 mmol). The mixture was stirred at 80℃for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give N-tert-butoxycarbonyl-N- [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-nitro-phenyl]Tert-butyl carbamate (380 mg, 540 umol, 76%). M/zES + [ M+H ]] ⁺ 687.5。

Step 2N- [ 2-amino-5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-phenyl ] -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

To N-tert-butoxycarbonyl-N- [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in ethanol (5 mL) and water (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-nitro-phenyl]To a solution of tert-butyl carbamate (330 mg,480 mmol) was added iron powder (134 mg,2.40 mmol) and ammonium chloride (257 mg,4.80 mmol). The mixture was stirred at 60℃for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give N- [ 2-amino-5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow oil ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-phenyl]-tert-butyl N-tert-butoxycarbonyl-carbamate (200 mg, crude). M/zES + [ M+H ]] ⁺ 657.1。

Step 3.4- ((5-chloro-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) oxy) benzene-1, 2-diamine

To N- [ 2-amino-5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in dichloromethane (1.5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-phenyl]To a solution of tert-butyl N-tert-butoxycarbonyl-carbamate (200 mg,304 umol) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 20℃for 20min. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 4- ((5-chloro-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) benzene-1, 2-diamine (100 mg,212umol, 70%) as a yellow solid. M/z ES+ [ M+H ]] ⁺ 457.0。

Step 4.8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2- (trifluoromethyl) -1H-benzo [ d ] imidazol-5-yl) oxy) quinoxaline

A solution of 4- ((5-chloro-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) benzene-1, 2-diamine (50 mg,109 umol) in trifluoroacetic acid (1 mL) was stirred at 60℃for 6 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Phenomenex Luna C, 18, 250, 50mm 15um; mobile phase: [ water (0.2% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 50% -80%,10 min) purification to give 8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2- (trifluoromethyl) -1H-benzo [ d) as a yellow solid]Imidazol-5-yl) oxy) quinoxaline (38.5 mg,71.9umol, 66%). ¹ H NMR(400MHz,CD ₃ OD)δ＝9.19(s,1H),8.61(s,1H),8.37(s,1H),7.97(d,J＝8.8Hz,1H),7.78(d,J＝8.8Hz,1H),7.45(d,J＝9.6Hz,1H),7.32-7.21(m,2H),4.40(d,J＝6.8Hz,2H),2.79-2.64(m,3H),2.57-2.43(m,2H)；m/z ES+[M+H] ⁺ 535.0。

EXAMPLE 42 Synthesis of (1S, 4S) -5- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] ethyl ] -2-oxa-5-azabicyclo [2.2.1] heptane

Step 1.2- [ [6- [ 5-chloro-3- [1- [2- [ (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl ] ethyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in acetonitrile (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl methanesulfonate (300 mg,476 umol) and (1 s,4 s) -2-oxa-5-azabicyclo [2.2.1]To a solution of heptane hydrochloride (193 mg,1.43 mmol) was added sodium bicarbonate (200 mg,2.38 mmol). The mixture was stirred at 80℃for 12 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate=0:1) to give 2- [ [6- [ 5-chloro-3- [1- [2- [ (1 s,4 s) -2-oxa-5-azabicyclo [2.2.1] as a yellow solid ]Heptan-5-yl]Ethyl group]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (100 mg,158 mol, 30%). M/zES + [ M+H ]] ⁺ 632.3。

(1S, 4S) -5- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] ethyl ] -2-oxa-5-azabicyclo [2.2.1] heptane

2- [ [6- [ 5-chloro-3- [1- [2- [ (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] in trifluoroacetic acid (1 mL)]Heptan-5-yl]Ethyl group]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (90.0 mg, 142. Mu. Mol) was stirred at 25℃for 6 hours. The mixture was concentrated in vacuo and the residue was purified by prep HPLC (column Phenomenex Synergi C18 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -29%,11 min) and re-purified by preparative TLC (dichloromethane: methanol=10:1) to give (1 s,4 s) -5- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]-2-oxa-5-azabicyclo [2.2.1]Heptane (8.2 mg,16.4umol, 10%). ¹ H NMR(400MHz,CD ₃ OD)δppm 9.16(s,1H),8.61(s,1H),8.37(s,1H),7.90(d,J＝9.2Hz,1H),7.53(d,J＝8.4Hz,1H),7.35(d,J＝9.6Hz,1H),7.17(s,1H),7.01(dd,J＝2.0,8.8Hz,1H),4.59(s,1H),4.44-4.32(m,3H),4(d,J＝8.0Hz,1H),3.62(dd,J＝2.0,8.0Hz,1H),3.52(s,1H),3.23-3.08(m,2H),2.89(dd,J＝1.6,10.0Hz,1H),2.60(s,1H),2.57(s,3H),1.87(d,J＝10.0Hz,1H),1.73(d,J＝10.0Hz,1H)；m/z ES+[M+H] ⁺ 502.0。

EXAMPLE 43 Synthesis of 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] -1- (3, 3-difluoroazetidin-1-yl) ethanone

Step 1.2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] acetic acid ethyl ester

To 2- [1- (azetidin-3-yl) pyrazol-4-yl in dichloromethane (1.5 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a mixture of quinoxaline (100 mg,231 umol) was added diisopropylethylamine (74.8 mg,578 umol) and ethyl 2-bromoacetate (31.7 mg,189 umol), and the reaction mixture was stirred at 40℃for 1 hour. The reaction mixture was concentrated in vacuo to give 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]Ethyl acetate (100 mg,193umol, 83%). M/zES + [ M+H ]] ⁺ 518.4。

Step 2.2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] acetic acid

To 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in tetrahydrofuran (1 mL) and water (1 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]To a mixture of ethyl acetate (100 mg, 193. Mu. Mol) was added lithium hydroxide monohydrate (40.5 mg, 965. Mu. Mol), and the reaction mixture was stirred at 25℃for 1 hour. The reaction mixture was quenched with 1N HCl solution to a pH of about 3. The mixture was purified by preparative HPLC (column: phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -28%,10 min) direct purification toObtaining 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]Acetic acid (50.0 mg,102umol, 52%). M/zES + [ M+H ]] ⁺ 490.3。

Step 3.2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] -1- (3, 3-difluoroazetidin-1-yl) ethanone

To 3, 3-difluoroazetidine hydrochloride (10.5 mg,81.6 umol) and 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in dichloromethane (1 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]Diisopropylethylamine (31.6 mg,244 umol) was added to a mixture of acetic acid (40.0 mg,81.6 umol), and the reaction mixture was stirred at 25℃for 10min. Then 3- (ethyliminomethyleneamino) propyl-dimethylaminoonium is added; chloride (23.4 mg, 122. Mu. Mol) and 1-hydroxybenzotriazole (16.5 mg, 122. Mu. Mol), and the reaction mixture was stirred at 40℃for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: phenomenex Synergi C150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -29%,11 min) purification to give 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]-1- (3, 3-difluoroazetidin-1-yl) ethanone (17.5 mg,30.7umol, 37%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.57-12.09(m,1H),9.34(s,1H),8.87(s,1H),8.43(s,1H),8.28(s,1H),7.96(d,J＝9.2Hz,1H),7.59-7.42(m,1H),7.39-7.09(m,2H),6.98-6.75(m,1H),5.18(t,J＝6.4Hz,1H),4.70-4.61(m,2H),4.34-4.24(m,2H),3.85(t,J＝7.6Hz,2H),3.59(t,J＝8.0Hz,2H),3.42-3.38(m,2H),2.55-2.46(m,3H)；m/zES+[M+H] ⁺ 565.1。

EXAMPLE 44 Synthesis of 8-chloro-2- [1- (1-methylazetidin-3-yl) pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.8-chloro-2- [1- (1-methylazetidin-3-yl) pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 2- [1- (azetidin-3-yl) pyrazol-4-yl in tetrahydrofuran (1.5 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (50.0 mg,116 umol), formaldehyde (69.5 mg,2.32mmol,37% aqueous solution) and diisopropylethylamine (74.8 mg,579 umol) was added sodium triacetoxyborohydride (49.1 mg,232 umol). The mixture was stirred at 25℃for 3 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (50 ml x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC (column: phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -29%,10 min) purification to give 8-chloro-2- [1- (1-methylazetidin-3-yl) pyrazol-4-yl as a yellow gum]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (26.9 mg,60.3umol, 52%). ¹ H NMR(400MHz,CD ₃ OD)δ＝9.16(s,1H),8.64(s,1H),8.53(s,1H),8.33(s,1H),7.91(d,J＝9.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.37(d,J＝9.2Hz,1H),7.19(d,J＝2.0Hz,1H),7.02(dd,J＝2.0,8.8Hz,1H),5.52-5.40(m,1H),4.69-4.61(m,2H),4.54-4.48(m,2H),3.05(s,3H),2.58(s,3H)；m/zES+[M+H] ⁺ 446.0。

EXAMPLE 45.3 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) thietane 1, 1-dioxide

Step 1 Thiocyclobutan-3-ylmethyl 4-methylbenzenesulfonate

To thia in dichloromethane (1 mL) at 0deg.CTo a solution of cyclobutan-3-yl-methanol (30.0 mg, 287. Mu. Mol) and triethylamine (87.4 mg, 863. Mu. Mol) was added 4-methylbenzenesulfonyl chloride (82.3 mg, 431. Mu. Mol). The mixture was stirred at 25℃for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=3:1) to give thietan-3-ylmethyl 4-methylbenzenesulfonate (60.0 mg,232 mol, 80%) as a yellow oil. ¹ HNMR(400MHz,CDCl ₃ )δ＝7.73(d,J＝8.0Hz,2H),7.30(d,J＝8.4Hz,2H),4.03(d,J＝6.8Hz,2H),3.55-3.32(m,1H),3.11(t,J＝8.8Hz,2H),2.86(dd,J＝6.4,9.6Hz,2H),2.39(s,3H)。

Step 2.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (thietan-3-ylmethyl) -1H-pyrazol-4-yl) quinoxaline

8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (1 mL) ]A solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (100 mg, 197umol), thietan-3-ylmethyl 4-methylbenzenesulfonate (50.9 mg, 197umol) and cesium carbonate (128 mg, 390 umol) was stirred at 80℃for 3 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (50 ml x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1 to 0/1) to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) -2- (1- (thietan-3-ylmethyl) -1H-pyrazol-4-yl) quinoxaline (100 mg,168umol, 85%). M/zES + [ M+H ]] ⁺ 593.2。

Step 3.3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) thietane 1, 1-dioxide

To 2- [ [6- [ 5-chloro-3- [1- (thietan-3-ylmethyl) pyrazol-4-yl ] in dichloromethane (1 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (100 mg, 168) umol) was added with 3-chloroperoxybenzoic acid (116 mg,505 umol). The mixture was stirred at 25℃for 16 hours. The mixture was poured into saturated sodium sulfite solution (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to give 3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl thietane 1, 1-dioxide (80.0 mg,127umol, 75%). M/zES + [ M+H ]] ⁺ 625.2。

Step 4.3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) thietane 1, 1-dioxide

3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) thietane 1, 1-dioxide (80 mg,127 umol) was stirred at 25 ℃ for 10min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,7 min) and purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 25% -55%,7 min) re-purification to give 3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl thietane 1, 1-dioxide (8.9 mg,17.0umol, 14%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.16-9.12(m,1H),8.65-8.62(m,1H),8.38-8.35(m,1H),7.92-7.86(m,1H),7.53(d,J＝8.8Hz,1H),7.37-7.33(m,1H),7.19(s,1H),7.02(d,J＝8.8Hz,1H),4.57(d,J＝7.6Hz,2H),4.30-4.24(m,2H),4.11-4.06(m,2H),3.20(m,1H),2.58(s,3H)；m/zES+[M+H] ⁺ 495.0。

EXAMPLE 46.8 Synthesis of chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -7- [ (4-fluoro-2-methyl-1H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.3- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-fluoro-6-nitro-aniline

To 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl in N, N-dimethylformamide (3 mL)]Pyrazol-4-yl]To a solution of quinoxalin-6-ol (150 mg,427 umol) was added potassium carbonate (177 mg,1.28 mmol) and 2, 3-difluoro-6-nitro-aniline (105 mg,603 umol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 3- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl as a yellow solid ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-fluoro-6-nitro-aniline (180 mg, 317 umol, 66%). M/zES + [ M+H ]] ⁺ 505.0。

Step 2.4- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-3-fluoro-benzene-1, 2-diamine

To 3- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in ethanol (2 mL) and water (0.4 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]To a solution of oxy-2-fluoro-6-nitro-aniline (150 mg, 294 mol) was added iron powder (82.9 mg,1.49 mmol) and ammonium chloride (79.4 mg,1.49 mmol). The mixture was stirred at 60℃for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 4- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-3-fluoro-benzene-1, 2-diamine (180 mg, crude). M/zES + [ M+H ]] ⁺ 475.2。

Step 3.8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -7- [ (4-fluoro-2-methyl-1H-benzimidazol-5-yl) oxy ] quinoxaline

To a solution of 1, 1-trimethoxyethane (189 mg,1.58 mmol) in MeOH (3 mL) was added sulfamic acid (61.3 mg,631 umol) and 4- [ 5-chloro-3- [1- ](3, 3-Difluorocyclobutyl) methyl]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-3-fluoro-benzene-1, 2-diamine (150 mg,315. Umol). The mixture was stirred at 25℃for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Synergi C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 29% -59%,10 min) purification to give 8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]-7- [ (4-fluoro-2-methyl-1H-benzimidazol-5-yl) oxy]Quinoxaline (101 mg,203umol, 62%). ¹ H NMR(400MHz,DMSO-d ₆ )δ12.81-12.56(m,1H),9.31(s,1H),8.77(s,1H),8.39(s,1H),7.94(d,J＝9.2Hz,1H),7.49-6.99(m,3H),4.39(d,J＝6.0Hz,2H),2.76-2.63(m,3H),2.56(s,1H),2.53(s,3H),2.49-2.44(m,1H)；m/z ES+[M+H] ⁺ 499.0。

Example 47: synthesis of 8-chloro-2- [1- [1- (1-methylazetidin-3-yl) azetidin-3-yl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.3- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] azetidine-1-carboxylic acid tert-butyl ester

2- [1- (azetidin-3-yl) pyrazol-4-yl ] in tetrahydrofuran (1 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]A mixture of quinoxaline (100 mg, 231. Mu. Mol), tert-butyl 3-oxo-azetidine-1-carboxylate (51.5 mg, 301. Mu. Mol), sodium triacetoxyborohydride (147 mg, 694. Mu. Mol) was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 ml×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 35% -65%,9 min) purification to give 3- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazole-1-yl]Azetidin-1-yl]Azetidine-1-carboxylic acid tert-butyl ester (50.0 mg,85.3umol, 37%). M/zES + [ M+1 ]] ⁺ 587.4。

Step 2.2- [1- [1- (azetidin-3-yl) azetidin-3-yl ] pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 3- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in dichloromethane (5 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]To a solution of tert-butyl azetidine-1-carboxylate (50 mg, 85.1. Mu. Mol) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure to give 2- [1- [1- (azetidin-3-yl) azetidin-3-yl ] as a yellow solid]Pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (40.0 mg, crude). M/zES + [ M+1 ]] ⁺ 487.2。

Step 3.8-chloro-2- [1- [1- (1-methylazetidin-3-yl) azetidin-3-yl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 2- [1- [1- (azetidin-3-yl) azetidin-3-yl in methanol (2 mL) ]Pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (35.0 mg,71.8 umol) were added formaldehyde (43.1 mg,1.44mmol,37% aqueous solution) and sodium triacetoxyborohydride (76.1 mg, 399 umol). The mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 ml×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 24% -54%,10 min) purification to give 8-chloro-2- [1- [1- (1-methylazetidin-3-yl) azetidin-3-yl as a white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (24.3 mg,48.6umol, 67%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.34(s,1H),8.85(s,1H),8.42(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝1.6Hz,1H),6.95-+6.82(m,1H),5.20-5.10(m,1H),3.70(t,J＝7.6Hz,2H),3.58(t,J＝7.2Hz,2H),3.39-3.38(m,1H),3.27-3.24(m,2H),2.95(t,J＝6.4Hz,2H),2.48(s,3H),2.21(s,3H)；m/zES+[M+1] ⁺ 501.1。

Example 48: synthesis of 2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -8- (prop-1-en-2-yl) quinoxaline

Step 1.8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (5 mL) ]Imidazol-6-yl) oxy) quinoxaline (430 mg, 650 umol) was stirred at 25 ℃ for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (300 mg, crude). M/zES + [ M+H ]] ⁺ 527.1。

Step 2.2- (1- ((3, 3-Difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -8- (prop-1-en-2-yl) quinoxaline

To 8-bromo-2- [1- [ (3, 3-difluorocyclobutyl) methyl in dioxane (2 mL) and water (0.2 mL)]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (100 mg,190 umol) and potassium trifluoro (prop-1-en-2-yl) borate (282 mg,1.90 mmol) were added sodium carbonate (60.5 mg,571 umol) and methanesulfonyl (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (22.5 mg,28.6 umol). The mixture was stirred under nitrogen at 110 ℃ for 2 hours. The reaction mixture was poured into water (20 mL) and ethyl acetate The ester (15 mL. Times.3) was extracted. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 19% -49%,10 min) purification to give 2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -8- (prop-1-en-2-yl) quinoxaline (17.8 mg,35.8umol, 18.8%). ¹ H NMR(400MHz,CD ₃ OD)δ＝9.08(s,1H),8.49(s,1H),8.26(s,1H),7.88(d,J＝9.2Hz,1H),7.48(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.07(d,J＝2.0Hz,1H),6.95(dd,J＝2.4,8.8Hz,1H),5.47(s,1H),5.05(s,1H),4.38(d,J＝6.8Hz,2H),2.82-2.62(m,3H),2.57(s,3H),2.54-2.40(m,2H),2.24(s,3H)；m/z ES+[M+H] ⁺ 487.1。

Example 49: synthesis of 3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -1-methyl-cyclobutanol

Step 1.3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -1-methyl-cyclobutanol

A solution of 3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] cyclobutanone (100 mg,170 umol) in tetrahydrofuran (1 mL) was degassed

And purged 3 times with nitrogen. Then methyl magnesium bromide (3M in THF, 170. Mu.L) was added dropwise at 0deg.C. The mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3×3 mL). The combined organic layers were washed with brine (3×3 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, ethyl acetate: methanol=10:1) to give 3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylmethyl) as a white solid Silanylethoxymethyl) benzimidazol-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-1-methyl-cyclobutanol (35.0 mg,57.2umol, 33%). M/zES + [ M+H ]] ⁺ 605.2。

Step 2.3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -1-methyl-cyclobutanol

3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (2.16 g,18.9 mmol)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of 1-methyl-cyclobutanol (35.0 mg, 57.8. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC (column Phenomenex Gemini-NX 18C 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,7 min) purification to give 3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-1-methyl-cyclobutanol (18.0 mg,37.5umol, 64%). ¹ H NMR(400MHz,CD ₃ OD)δppm 9.16(s,1H),8.57-8.54(m,1H),8.35(s,1H),7.91(d,J＝9.2Hz,1H),7.56(d,J＝8.8Hz,1H),7.36(d,J＝9.2Hz,1H),7.20(d,J＝2.4Hz,1H),7.04(dd,J＝2.4,8.8Hz,1H),4.31(d,J＝7.2Hz,2H),2.61(s,3H),2.47(t,J＝7.6Hz,1H),2.24-2.10(m,2H),2.02-1.90(m,2H),1.36(s,2H),1.35(s,1H)；m/z ES+[M+H] ⁺ 475.1。

Example 50.5 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-methyl-1, 2-thiazine 1, 1-dioxide

Step 1.5- (((tert-butyldiphenylsilyl) oxy) methyl) -2-methyl-1, 2-thiazine 1, 1-dioxide

To tert-butyl- [ (1, 1-dioxothiazinan-5-yl) methoxy in tetrahydrofuran (20 mL)]To a solution of diphenyl-silane (1 g,2.48 mmol) was added potassium carbonate (1.03 g,7.43 mmol) and methyl iodide (1.76 g,12.4 mmol)) The mixture was stirred at 60℃for 30 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 5- (((tert-butyldiphenylsilyl) oxy) methyl) -2-methyl-1, 2-thiazine 1, 1-dioxide (1.30 g, crude) as a yellow oil. M/zES + [ M+H ]] ⁺ 418.2。

Step 2.5- (hydroxymethyl) -2-methyl-1, 2-thiazine 1, 1-dioxide

Tert-butyl- [ (2-methyl-1, 1-dioxo-thiazinan-5-yl) methoxy group in aqueous sodium hydroxide (5M, 10 mL)]A solution of diphenyl-silane (500 mg,1.20 mmol) was stirred at 40℃for 16 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×30 mL). The aqueous layer was acidified to pH < 5 with concentrated hydrochloric acid (12M) and then extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 5- (hydroxymethyl) -2-methyl-1, 2-thiazinan 1, 1-dioxide (500 mg, crude) as a yellow oil. M/zES + [ M+H ] ] ⁺ 179.9。

(2-methyl-1, 1-dioxido-1, 2-thiazinan-5-yl) methyl 4-methylbenzenesulfonate

To a solution of 5- (hydroxymethyl) -2-methyl-1, 2-thiazine 1, 1-dioxide (500 mg, crude) in dichloromethane (5 mL) was added 4-methylbenzenesulfonyl chloride (239 mg,1.26 mmol) and triethylamine (254 mg,2.51 mmol), and the mixture was stirred at 25 ℃ for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give (2-methyl-1, 1-dioxido-1, 2-thiazinan-5-yl) methyl 4-methylbenzenesulfonate (100 mg,299umol, 35%) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.71(d,J＝8.4Hz,2H),7.31(d,J＝8.0Hz,2H),3.90(d,J＝5.2Hz,2H),3.51-3.36(m,1H),3.12-3.03(m,1H),2.95(dd,J＝3.2,13.2Hz,1H),2.72(s,3H),2.67(d,J＝13.2Hz,1H),2.62-2.49(m,1H),2.40(s,3H),1.63-1.54(m,3H)。

Step 4.5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-methyl-1, 2-thiazinan 1, 1-dioxide

8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (1 mL)]Imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (100 mg, 197umol), (2-methyl-1, 1-dioxido-1, 2-thiazinan-5-yl) methyl 4-methylbenzenesulfonate (80.0 mg,240 umol), cesium carbonate (192 mg,591 umol) was stirred at 80℃for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was washed with brine (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-methyl-1, 2-thiazinan 1, 1-dioxide (130 mg, crude product). M/zES + [ M+H ]] ⁺ 668.2。

Step 5.5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-methyl-1, 2-thiazinan 1, 1-dioxide

5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (2 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-methyl-1, 2-thiazinan 1, 1-dioxide (130 mg, crude) was stirred at 25 ℃ for 0.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,7 min) purification to give 5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-methyl-1, 2-thiazine 1, 1-dioxide (74.9 mg,139umol, 71%). ¹ H NMR(400MHz,CD ₃ OD)δ9.15(s,1H),8.56(s,1H),8.34(s,1H),8.02-7.87(m,1H),7.75(d,J＝8.0Hz,1H),7.46(d,J＝6.0Hz,1H),7.33(s,2H),4.40-4.23(m,2H),3.59-3.38(m,1H),3.25(s,1H),3.11-2.85(m,3H),2.84(s,3H),2.79(s,3H),1.80-1.46(m,2H)；m/z ES+[M+H] ⁺ 538.0。

Example 51.Synthesis of 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutyronitrile

Step 1.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanoic acid ethyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (14 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (700 mg,1.38 mmol) and ethyl 3-methylbut-2-enoate (265 mg,2.07mmol, 288. Mu.L) was added cesium carbonate (900 mg,2.76 mmol) and the mixture stirred at 25℃for 48 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 1/9) to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanoic acid ethyl ester (340 mg,45 umol, 32%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.38-9.36(m,1H),8.79(s,1H),8.34(s,1H),7.96(d,J＝9.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.44(d,J＝2.4Hz,1H),7.34-7.30(m,1H),7.01(dd,J＝2.4,8.8Hz,1H),5.56-5.52(m,2H),3.96(q,J＝7.2Hz,2H),3.51-3.46(m,2H),3(s,2H),2.57-2.54(m,3H),1.73(s,6H),1.07(t,J＝7.2Hz,3H),0.81-0.75(m,2H),-0.12--0.16(m,9H)。

Step 2.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanoic acid

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in methanol (2.5 mL), tetrahydrofuran (2.5 mL) and water (2.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-3-methyl groupTo a solution of ethyl butyrate (270 mg,361 umol) was added lithium hydroxide monohydrate (45.5 mg,1.08 mmol). The mixture was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo. The residue was adjusted to ph=5 with aqueous citric acid, then filtered and concentrated in vacuo to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanoic acid (150 mg, crude product). M/zES + [ M+H ]] ⁺ 607.3。

Step 3.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanamide

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in N, N-dimethylformamide (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of 3-methyl-butyric acid (150 mg, 247. Mu.mol) and ammonium chloride (132 mg,2.47 mmol) were added diisopropylethylamine (95.8 mg, 741. Mu.L) and [ dimethylamino (triazolo [4, 5-b) ]Pyridin-3-yloxy) methylene]-dimethyl-ammonium; hexafluorophosphate (141 mg,371 umol) and the mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3X 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanamide (180 mg, crude). M/zES + [ M+H ]] ⁺ 606.3。

Step 4.3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanamide

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 3-methyl-butyramide (50.0 mg, 82.5. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C18, 150×25mm×10um; mobile phase: [ Water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,10 min) purification to give 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanamide (17.8 mg,37.4umol, 45%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.36(s,1H),8.75(s,1H),8.35(s,1H),7.96(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.33-7.27(m,2H),7.23(s,1H),6.97(d,J＝8.8Hz,1H),6.82(s,1H),2.74(s,2H),2.49-2.48(m,3H),1.73(s,6H)；m/z ES+[M+H] ⁺ 476.1。

Step 5.4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) quinuclidine

To 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in acetonitrile (0.5 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]To a solution of 3-methyl-butyramide (8 mg, 16.8. Mu. Mol) was added methoxycarbonyl- (triethylamino) sulfonyl-aza compound (8.01 mg, 33.6. Mu. Mol), and the mixture was stirred at 25℃for 1 hour. The reaction mixture was filtered and concentrated in vacuo to give a mixture. The residue was purified by preparative HPLC (neutral; column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,10 min) purification to give 4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl quinuclidine (10.0 mg,16.6umol, 98%). M/zES + [ M+H ]] ⁺ 595.0。

Step 6.3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanenitrile

To N- [6- [ 5-chloro-3- [1- (2-cyano-1, 1-dimethyl-ethyl) pyrazol-4-yl ] in dimethyl sulfoxide (0.5 mL) ]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]To a solution of methyl sulfonylcarbamate (8 mg,13.4 umol) was added potassium carbonate (3.72 mg,26.9 umol), and the mixture was stirred at 25℃for 2 hours. The reaction mixture was filtered and concentrated in vacuo and the residue was purified by prep HPLC (neutral conditions; column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM ammonium bicarbonate)) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,10 min) purification to give 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanenitrile (3.3 mg,6.80umol, 50%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.38(s,1H),8.89(s,1H),8.44(s,1H),7.97(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.95(dd,J＝2.4,8.8Hz,1H),3.32-3.31(m,2H),2.49-2.48(m,3H),1.75(s,6H)；m/z ES+[M+H] ⁺ 458.0。

EXAMPLE 52.Synthesis of 2- (1- (2-oxabicyclo [2.2.1] heptan-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.4-hydroxycyclopentane-1, 2-dicarboxylic acid dimethyl ester

To a solution of dimethyl 4-oxocyclopentane-1, 2-dicarboxylate (17.5 g,87.4 mmol) in methanol (200 mL) was added sodium borohydride (3.64 g,96.2 mmol) in portions at 0deg.C. The mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with brine (100 mL) at 0 ℃ and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give dimethyl 4-hydroxycyclopentane-1, 2-dicarboxylate (10.0 g,49.5mmol, 56%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ4.50-4.32(m,1H),3.72(d,J＝4.8Hz,6H),3.47-3.36(m,1H),3.28-3.19(m,1H),2.32-2.08(m,3H),2.06-1.88(m,2H)。

Step 2.4- (benzyloxy) cyclopentane-1, 2-dicarboxylic acid dimethyl ester

To a solution of dimethyl 4-hydroxycyclopentane-1, 2-dicarboxylate (2 g,9.89 mmol) in N, N-dimethylformamide (20 mL) at 0deg.C was added sodium hydride (390 mg,9.89mmol,60% in mineral oil) in portions and the mixture was stirred at 20deg.C for 0.5 h. Then slowly addBenzyl bromide (1.69 g,9.89mmol,1.17 mL) was added and the resulting mixture was stirred at 20deg.C for 0.5 h. The reaction mixture was quenched with water (100 mL) at 0deg.C, then extracted with ethyl acetate (3X 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to give dimethyl 4- (benzyloxy) cyclopentane-1, 2-dicarboxylate (1 g,3.42mmol, 35%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.33-7.19(m,5H),4.47-4.37(m,2H),4.07-3.99(m,1H),3.69-3.59(m,6H),3.47-3.36(m,1H),3.17-3.06(m,1H),2.29-2.11(m,3H),1.96-1.84(m,1H)；m/z ES+[M+H] ⁺ 293.1。

(4- (benzyloxy) cyclopentane-1, 2-diyl) dimethanol

To a solution of dimethyl 4-benzyloxycyclopentane-1, 2-dicarboxylate (1 g,3.42 mmol) in tetrahydrofuran (10 mL) at 0deg.C was added lithium aluminum hydride (493 mg,13.0 mmol) in portions, and the mixture was stirred under nitrogen at 20deg.C for 12 hours. The reaction mixture was quenched with water (0.5 mL), 10% aqueous sodium hydroxide (0.5 mL) and water (1.5 mL) in this order at 0 ℃ and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (4- (benzyloxy) cyclopentane-1, 2-diyl) dimethanol (800 mg, crude) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.38-7.27(m,5H),4.45(d,J＝1.2Hz,2H),4.07-3.95(m,1H),3.79-3.68(m,2H),3.49(t,J＝9.6Hz,1H),3.37(t,J＝9.6Hz,1H),3.12(s,2H),2.23-2.15(m,1H),2.12-2.03(m,1H),2.03-1.95(m,1H),1.94-1.83(m,1H),1.53-1.45(m,1H),1.44-1.35(m,1H)；m/z ES+[M+H] ⁺ 237.2。

(4- (benzyloxy) cyclopentane-1, 2-diyl) bis (methylene) bis (4-methylbenzenesulfonate)

To [ 4-benzyloxy-2- (hydroxymethyl) cyclopentyl in pyridine (2 mL)]To a solution of methanol (100 mg,423 umol) was added 4-methylbenzenesulfonyl chloride (242 mg,1.27 mmol), and the mixture was stirred at 25℃for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10 to 5/1) to give a colorless oil(4- (benzyloxy) cyclopentane-1, 2-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (150 mg, 262. Mu. Mol, 62%). ¹ HNMR(400MHz,CDCl ₃ )δ7.68(dd,J＝8.4,13.2Hz,4H),7.31-7.14(m,9H),4.33-4.19(m,2H),3.94-3.84(m,5H),2.37(d,J＝12.4Hz,6H),2.16-2.02(m,1H),1.99-1.84(m,3H),1.57-1.38(m,3H)；m/z ES+[M+18] ⁺ 562.4。

(4-hydroxycyclopentane-1, 2-diyl) bis (methylene) bis (4-methylbenzenesulfonate)

To [ 4-benzyloxy-2- (p-toluenesulfonyloxymethyl) cyclopentyl ] in dichloromethane (1 mL)]To a solution of methyl 4-methylbenzenesulfonate (140 mg, 255 umol) was added boron trichloride (1 mL). The mixture was stirred at 20℃for 0.5 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give (4-hydroxycyclopentane-1, 2-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (80.0 mg,176umol, 68%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.77(dd,J＝2.0,8.4Hz,4H),7.36(dd,J＝4.0,8.0Hz,4H),4.39-4.20(m,1H),4.04-3.88(m,4H),2.47(d,J＝2.0Hz,6H),2.31-2.16(m,1H),2.13-1.95(m,3H),1.84-1.75(m,1H),1.58(dd,J＝4.8,9.6Hz,1H),1.43(d,J＝2.0Hz,1H)；m/z ES+[M+18] ⁺ 471.9。

Step 6.2-oxabicyclo [2.2.1] heptane-5-ylmethyl 4-methylbenzenesulfonate

To [ 4-hydroxy-2- (p-toluenesulfonyloxymethyl) cyclopentyl ] in anhydrous tetrahydrofuran (1 mL)]Sodium hydride (14.1 mg,352 mol,60% in mineral oil) was added to a solution of methyl 4-methylbenzenesulfonate (80.0 mg,176 mol), and the mixture was stirred at 0℃for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (5 mL) at 0 ℃ and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) to give 2-oxabicyclo [2.2.1] as a yellow oil]Heptan-5-ylMethyl 4-methylbenzenesulfonate (45.0 mg,159umol, 91%). ¹ H NMR(400MHz,CDCl ₃ )δ7.80(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),4.30(s,1H),3.88-3.79(m,2H),3.67(dd,J＝2.8,7.2Hz,1H),3.47(d,J＝7.2Hz,1H),2.47(s,3H),2.15-2.08(m,1H),1.86-1.77(m,1H),1.64-1.55(m,2H),1.43(d,J＝10.8Hz,1H),1.06(dd,J＝4.4,13.2Hz,1H)。

Step 7.2- (1- (2-oxabicyclo [2.2.1] heptan-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Potassium carbonate (54.5 mg, 390 umol) and 2-oxabicyclo [2.2.1 were added to a solution of ethyl-trimethyl-silane (100 mg, 197umol) ]Heptan-5-ylmethyl 4-methylbenzenesulfonate (44.6 mg,158 mol) and the mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (1- (2-oxabicyclo [ 2.2.1) as a black solid]Heptane-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (120 mg, crude). M/zES + [ M+H ]] ⁺ 617.2。

Step 8.2- (1- (2-oxabicyclo [2.2.1] heptan-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-chloro-3- [1- (2-oxabicyclo [2.2.1] in trifluoroacetic acid (0.5 mL)]Heptane-5-ylmethyl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (70.0 mg,113 umol) was stirred at 20℃for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25 mm. Times.10 um; mobile phase: [ water (0.2% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 14% -44%,10 min) purification to give 2- (1- (2-oxabicyclo [ 2.2.1) as an off-white solid]Heptan-5-ylmethyl1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxaline (22.9 mg,45.7umol, 40%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.29(d,J＝3.6Hz,1H),8.75(s,1H),8.37(s,1H),7.93(s,1H),7.53(s,1H),7.40-7.12(m,2H),6.96(s,1H),4.33-4.06(m,3H),3.55-3.32(m,2H),2.55-2.51(m,3H),2.31(s,2H),1.67(s,2H),1.55-1.42(m,1H),1.27(d,J＝0.8Hz,1H)；m/z ES+[M+H] ⁺ 487.1。

Example 53: synthesis of 2- [1- [3- (azetidin-1-yl) cyclobutyl ] pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- (1- (3- (azetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -8-chloro-7- ((1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in methanol (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Titanium tetraisopropoxide (98.8 mg,348 mol) and diisopropylethylamine (67.4 mg,522 mol) were added to a solution of cyclobutanone (100 mg,174 mol) and azetidine (48.8 mg,522 mol), and the mixture was stirred at 60℃for 2 hours. Sodium cyanoborohydride (10.9 mg,174 mol) was then added, and the mixture was stirred at 25℃for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and then filtered. The filtrate was extracted with ethyl acetate (3X 50 mL). The combined organic layers were washed with brine (3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 2- (1- (3- (azetidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) -8-chloro-7- ((1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a white solid ]Imidazol-6-yl) oxy) quinoxaline (30.0 mg,48.7umol, 28%). M/zES + [ M+H ]] ⁺ 616.3。

Step 2.2- [1- [3- (azetidin-1-yl) cyclobutyl ] pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [3- [1- [3- (azetidin-1-yl) cyclobutyl ] in trifluoroacetic acid (0.5 mL)]Pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (25.0 mg,40.6 umol) was stirred at 25℃for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was taken up in preparative HPL (formic acid conditions; column: unisil 3-100C18 Ultra 150*50mm*3um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 3% -33%,10 min) purifying the residue to give 2- [1- [3- (azetidin-1-yl) cyclobutyl as a white solid]Pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (12.4 mg,23.9umol, 60%). ¹ HNMR(400MHz,DMSO-d ₆ )δ＝9.35-9.30(m,1H),8.87-8.79(m,1H),8.42(d,J＝2.4Hz,1H),8.15(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝1.2,8.4Hz,1H),5.22-4.78(m,1H),3.82(t,J＝8.0Hz,3H),3.69(t,J＝7.6Hz,2H),2.81-2.58(m,4H),2.49-2.48(m,3H),2.30-2.13(m,2H)；m/z ES+[M+H] ⁺ 486.1。

Example 54: synthesis of 8-chloro-2- [1- [3- (3, 3-difluoroazetidin-1-yl) cyclobutyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [3- (3, 3-difluoroazetidin-1-yl) cyclobutyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in methanol (1.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (100 mg, 170. Mu. Mol) and 3, 3-difluoroazetidine (68.0 mg, 520. Mu. Mol) were added diisopropylethylamine (67.0 mg, 520. Mu. Mol) and titanium tetraisopropoxide (99.0 mg, 350. Mu. Mol), and the mixture was heated at 60 ℃Stirring is carried out for 2 hours. Sodium cyanoborohydride (11.0 mg,170 umol) was then added. The mixture was stirred at 40℃for 12 hours. The reaction mixture was then filtered. The filtrate was washed with water (20 mL) and extracted with ethyl acetate (2X 10 mL). The combined organic layers were washed with saturated sodium bicarbonate (2×10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 2- [ [6- [ 5-chloro-3- [1- [3- (3, 3-difluoroazetidin-1-yl) cyclobutyl ] as a white solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (40.0 mg,61.3umol, 36%). M/zES + [ M+H ]] ⁺ 652.2。

Step 2.8-chloro-2- [1- [3- (3, 3-difluoroazetidin-1-yl) cyclobutyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [3- (3, 3-difluoroazetidin-1-yl) cyclobutyl ] in trifluoroacetic acid (0.2 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (30.0 mg,46.0 mmole) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 35% -65%,10 min) purifying the residue to give 8-chloro-2- [1- [3- (3, 3-difluoroazetidin-1-yl) cyclobutyl as a white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (13.7 mg,26.2umol, 56%). ¹ HNMR(400MHz,DMSO-d ₆ )δ＝12.62-11.89(m,1H),9.34-9.29(m,1H),8.81-8.76(m,1H),8.39(s,1H),7.95(d,J＝9.2Hz,1H),7.50(d,J＝9.6Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝1.6Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),5.15-4.67(m,1H),3.69-3.60(m,4H),3.25-3.17(m,1H),2.63-2.57(m,2H),2.49(s,3H),2.43-2.32(m,2H)；m/zES+[M+H] ⁺ 522.1。

Example 55: synthesis of 1- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] cyclopropane

Step 1.1- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] cyclopropane

2- [ [6- [ 5-chloro-3- [1- [ (1-tetrahydropyran-2-yloxycyclopropyl) methyl ] in trifluoroacetic acid (2 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl ]Methoxy group]A solution of ethyl-trimethyl-silane (190 mg, 287. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC (column Phenomenex Synergi C18:150:25 mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 8% -38%,10 min) purification to give 1- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Cyclopropyl alcohol (74.6 mg,167umol, 58%). ¹ HNMR(400MHz,DMSO-d ₆ )δ＝9.40(s,1H),8.69(s,1H),8.37(s,1H),8.03(d,J＝9.2Hz,1H),7.75(d,J＝8.8Hz,1H),7.46-7.42(m,2H),7.23(dd,J＝2.0,8.8Hz,1H),5.90-5.42(m,1H),4.30(s,2H),2.71(s,3H),0.79-0.68(m,4H)；m/z ES+[M+H] ⁺ 447.0。

Example 56: synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [ 3-methyl-1- (4-piperidinyl) pyrazol-4-yl ] quinoxaline and 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [ 5-methyl-1- (4-piperidinyl) pyrazol-4-yl ] quinoxaline

Step 1.4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] -3-methyl-pyrazol-1-yl ] piperidine-1-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (5-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (3 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Solution of ethyl-trimethyl-silane (200 mg,383 umol)Cesium carbonate (625 mg,1.92 mmol) and tert-butyl 4- (p-toluenesulfonyloxy) piperidine-1-carboxylate (409 mg,1.15 mmol) were added. The mixture was stirred at 100℃for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by reverse phase HPLC (0.1% formic acid conditions) to give 4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]-3-methyl-pyrazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester (100 mg,142umol, 36%). M/zES + [ M+H ]] ⁺ 704.2。

Step 2.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [ 3-methyl-1- (4-piperidinyl) pyrazol-4-yl ] quinoxaline

4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]-3-methyl-pyrazol-1-yl]A solution of tert-butyl piperidine-1-carboxylate (90.0 mg, 127. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,7 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy) as a white solid]-2- [ 3-methyl-1- (4-piperidinyl) pyrazol-4-yl]Quinoxaline (60.0 mg,126umol, 99%). M/zES + [ M+H ]] ⁺ 474.2。

Step 3.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [ 3-methyl-1- (4-piperidinyl) pyrazol-4-yl ] quinoxaline and 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [ 5-methyl-1- (4-piperidinyl) pyrazol-4-yl ] quinoxaline

8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [ 3-methyl-1- (4-piperidinyl) pyrazol-4-yl ] quinoxaline (50.0 mg,105 umol) was isolated by SFC (column: daicel ChiralPak IG (250 x 30mm,10 um); mobile phase: [0.1% ammonium hydroxide/ethanol ]; (B%: 70% -70%,5.4min, total run 60 min), then purified again by preparative HPLC (column: phenomenex Gemini-NX C18 x 75 x 30 mm; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 5% -35%,7 min) to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [ 3-methyl-1- (4-piperidinyl) pyrazol-4-yl ] quinoxaline (11.3 mg,23.8umol, 22%) and 8-chloro-7- [ (2-methyl-5-yl) pyrazol-4-yl ] quinoxaline as a white solid (11.3 mg,23.8umol, 22%) and as a white solid- [ 2-chloro-7- [ (0.225% formic acid) -acetonitrile ]; (B%: (7.35% methyl-35% methyl-3-piperidinyl) quinoxaline).

¹ H NMR(400MHz,CD ₃ OD)δ9.12(s,1H),8.59(s,1H),8.48(s,1H),7.89(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.18(d,J＝2.4Hz,1H),7.03-6.98(m,1H),4.64-4.51(m,1H),3.60(d,J＝13.2Hz,2H),3.29-3.19(m,2H),2.79(s,3H),2.57(s,3H),2.46-2.25(m,4H)；m/z ES+[M+H] ⁺ 474.1。

¹ H NMR(400MHz,CD ₃ OD)δ9.15(s,1H),8.33(s,2H),7.89(d,J＝9.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.19(d,J＝2.4Hz,1H),7.02-7(m,1H),4.82-4.72(m,1H),3.63(d,J＝13.2Hz,2H),3.36-3.32(m,1H),3.30-3.25(m,1H),3.01(s,3H),2.59(s,3H),2.50-2.35(m,2H),2.25(d,J＝11.6Hz,2H)；m/z ES+[M+H] ⁺ 474.1。

Example 57: synthesis of 8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) quinoxaline

Step 1N-tert-Butoxycarbonyl-N- [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-3-fluoro-2-nitro-phenyl ] carbamic acid tert-butyl ester

To 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl in N, N-dimethylformamide (3 mL)]Pyrazol-4-yl]To a solution of quinoxalin-6-ol (200 mg,570 umol) were added potassium carbonate (236 mg,1.71 mmol) and tert-butyl N- (3, 5-difluoro-2-nitro-phenyl) carbamate (320 mg,855 umol). The mixture was stirred at 80℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 5/1) to give N-t-butoxycarbonyl-N- [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ]]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-3-fluoro-2-nitro-phenyl]Tert-butyl carbamate (120 mg,170umol, 30%). M/zES + [ M+H ]] ⁺ 705.2。

Step 2.5- ((5-chloro-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) oxy) -3-fluoro-2-nitroaniline

To N-tert-butoxycarbonyl-N- [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in dichloromethane (0.9 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-3-fluoro-2-nitro-phenyl]To a solution of tert-butyl carbamate (100 mg,142 umol) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at 20℃for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 5- ((5-chloro-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) -3-fluoro-2-nitroaniline (90 mg, crude, trifluoroacetate) as a yellow oil. M/zES + [ M+H ]] ⁺ 505.0。

Step 3.8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) quinoxaline

To 5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in ethanol (5 mL) and water (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]To a solution of oxy-3-fluoro-2-nitro-aniline (80 mg,129 mol, trifluoroacetate salt) was added iron powder (36.1 mg, 640 mol) and ammonium chloride (69.2 mg,1.29 mmol). The mixture was stirred at 60℃for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25 mm. Times.10 um; mobile phase: [ water (0.2% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 28% -58%,10 min) purification to give 8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-5-yl) oxy) quinoxaline (29.0 mg,58.1umol, 45%). ¹ H NMR(400MHz,CD ₃ OD)δ9.19(s,1H),8.61(s,1H),8.37(s,1H),7.96(d,J＝8.8Hz,1H),7.44(d,J＝9.2Hz,1H),6.96(s,1H),6.82(d,J＝10.8Hz,1H),4.41(d,J＝6.8Hz,2H),2.89-2.66(m,3H),2.62-2.43(m,5H)；m/zES+[M+H] ⁺ 499.0。

Example 58: synthesis of 2- [ [6- [3- [1- [2- (azetidin-1-yl) ethyl ] pyrazol-4-yl ] -5-chloro-quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

Step 1.4- (3- (methoxycarbonyl) -4-nitrophenyl) hexahydropyrrolo [3,2-b ] pyrrole-1 (2H) -carboxylic acid tert-butyl ester

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in isopropanol (8 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of ethylmethanesulfonate (200 mg,318 umol) was added azetidine (60.0 mg,1.05 mmol), and the mixture was stirred at 80℃for 2.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 2- [ [6- [3- [1- [2- (azetidin-1-yl) ethyl ] as a yellow solid]Pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group ]Ethyl-trimethyl-silane (35.0 mg,59.3umol, 19%). M/z ES+ [ M+H ]] ⁺ 590.2。

Step 2.2- [1- [2- (azetidin-1-yl) ethyl ] pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [3- [1- [2- (azetidin-1-yl) ethyl ] in trifluoroacetic acid (2 mL)]Pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (30.0 mg, 50.8. Mu. Mol) was stirred at 25℃for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 2- [1- [2- (azetidin-1-yl) ethyl as a yellow gum]Pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (11.8 mg,24.4umol, 48%). ¹ H NMR(400MHz,CD ₃ OD)δ9.13(s,1H),8.56(s,1H),8.36(s,1H),7.88(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.18(d,J＝2.0Hz,1H),7.03-6.97(m,1H),4.30(t,J＝6.0Hz,2H),3.39(t,J＝7.2Hz,4H),3.11(t,J＝6.0Hz,2H),2.57(s,3H),2.15(t,J＝7.2Hz,2H)；m/z ES+[M+H] ⁺ 460.1。

EXAMPLE 59.Synthesis of 1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-3-ol

Step 1.1- (2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-3-ol

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in acetonitrile (3 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of ethyl methanesulfonate (0.2 g, 317. Mu. Mol), pyrrolidin-3-ol (83.0 mg, 953. Mu. Mol), sodium bicarbonate (186 mg,2.23 mmol) was stirred at 80℃for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 1- (2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-3-ol (50 mg,80.6umol, 25%). M/zES + [ M+H ]] ⁺ 620.2。

Step 2.1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-3-ol

1- (2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ]) in trifluoroacetic acid (45.9 mg,403 umol)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-3-ol (50 mg,80.6 umol) was stirred at 25 ℃ for 4H. The mixture was concentrated in vacuo and the residue was purified by prep HPLC (column: waters Xbridge150 x 25mm x 5um; mobile phase: [ water (ammonium bicarbonate) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 19% -49%,8 min) purification to give 1- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo) d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-3-ol (8.0 mg,16.3umol, 20%). ¹ H NMR(400MHz,DMSO-d ₆ )δ12.41-12.12(m,1H),9.30(s,1H),8.72(s,1H),8.35(s,1H),7.95(d,J＝8.0Hz,1H),7.60-7.43(m,1H),7.39-7.11(m,2H),6.94(t,J＝9.6Hz,1H),4.69(d,J＝4.4Hz,1H),4.33(t,J＝6.4Hz,2H),4.20-4.14(m,1H),2.90(t,J＝6.4Hz,2H),2.81-2.73(m,1H),2.68-2.52(m,2H),2.50(s,3H),2.38-2.33(m,1H),1.99-1.90(m,1H),1.58-1.48(m,1H)；m/z ES+[M+H] ⁺ 490.1。

Example 60: synthesis of 8-chloro-2- [1- [2- (3-methoxypyrrolidin-1-yl) ethyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [2- (3-methoxypyrrolidin-1-yl) ethyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in acetonitrile (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Sodium bicarbonate (134 mg,1.59 mmol) was added to a solution of ethyl methanesulfonate (200 mg,318 mol) and 3-methoxypyrrolidine (131 mg,954 mol), and the mixture was stirred at 80℃for 12 hours. The reaction mixture was filtered and concentrated in vacuo, and the residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 2- [ [6- [ 5-chloro-3- [1- [2- (3-methoxypyrrolidin-1-yl) ethyl ] as a yellow solid ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (45.0 mg,70.9umol, 22%). M/z ES+ [ M+H ]] ⁺ 634.3。

Step 2.8-chloro-2- [1- [2- (3-methoxypyrrolidin-1-yl) ethyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [2- (3-methoxypyrrolidin-1-yl) ethyl ] in trifluoroacetic acid (1.6 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (39.0 mg, 61.5. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC (column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 28% -58%,10 min) and purified by preparative HPLC (column: waters Xridge 150 x 25mm x 5um; mobile phase: [ water (0.05% ammonium hydroxide v/v) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 21% -51%,9 min) re-purification to give 8-chloro-2- [1- [2- (3-methoxypyrrolidin-1-yl) ethyl ] as an off-white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (1.5 mg,3.02umol, 4%). ¹ HNMR(400MHz,DMSO-d ₆ )δ＝9.35(s,1H),8.79(s,1H),8.47(s,1H),7.98(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.22(s,1H),7-6.92(m,1H),4.62(d,J＝4.4Hz,2H),4.15-3.99(m,1H),3.72-3.44(m,2H),3.30-3.29(m,2H),3.23(s,3H),3.18-2.95(m,2H),2.49-2.49(m,3H),2.24-1.79(m,2H)；m/z ES+[M+H] ⁺ 504.1。

Example 61: synthesis of 8-chloro-2- [1- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in acetonitrile (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of ethyl methanesulfonate (200 mg,318 mol) and 3, 3-difluoropyrrolidine hydrochloride (137 mg,954 mol) was added sodium bicarbonate (134 mg,1.59 mmol), and the mixture was stirred at 80℃for 12 hours. The reaction mixture was filteredAnd concentrated in vacuo, and the residue purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 2- [ [6- [ 5-chloro-3- [1- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (41.0 mg,64.0 mol, 20%). M/zES + [ M+H ]] ⁺ 640.2。

Step 2.8-chloro-2- [1- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] in trifluoroacetic acid (1.6 mL) ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methylbenzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (41.0 mg,64.0 mmole) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC (column Phenomenex Synergi C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,10 min) and re-purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 8-chloro-2- [1- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl as a white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (2.5 mg,4.88umol, 7%). ¹ HNMR(400MHz,CD ₃ OD)δ＝9.15(s,1H),8.61(s,1H),8.36(s,1H),7.90(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.18(s,1H),7.01(dd,J＝2.0,8.8Hz,1H),4.40(t,J＝6.4Hz,2H),3.04(t,J＝6.4Hz,2H),2.97(t,J＝13.2Hz,2H),2.83(t,J＝7.2Hz,2H),2.57(s,3H),2.32-2.18(m,2H)；m/z ES+[M+H] ⁺ 510.1。

Example 62: synthesis of 8-chloro-2- [1- [2- (3, 3-difluoroazetidin-1-yl) ethyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [2- (3, 3-difluoroazetidin-1-yl) ethyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in acetonitrile (3 mL)]Oxy-quinoxalin-2-yl ]Pyrazol-1-yl]To a solution of ethyl methanesulfonate (200 mg,318 mol) and 3, 3-difluoroazetidine hydrochloride (124 mg,954 mol) was added sodium bicarbonate (134 mg,1.59 mmol), and the mixture was stirred at 80℃for 12 hours. The reaction mixture was filtered and concentrated in vacuo, and the residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 2- [ [6- [ 5-chloro-3- [1- [2- (3, 3-difluoroazetidin-1-yl) ethyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (37.0 mg,59.1umol, 19%). M/zES + [ M+H ]] ⁺ 626.2。

Step 2.8-chloro-2- [1- [2- (3, 3-difluoroazetidin-1-yl) ethyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [2- (3, 3-difluoroazetidin-1-yl) ethyl ] in trifluoroacetic acid (1.6 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (37.0 mg, 59.1. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (column Phenomenex Synergi C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,10 min) and re-purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 8-chloro-2- [1- [2- (3, 3-difluoroazetidin-1-yl) ethyl ] as a white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (7.4 mg,14.9umol, 25%). ¹ H NMR(400MHz,CD ₃ OD)δ＝9.13(s,1H),8.57(s,1H),8.35(s,1H),7.88(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.18(d,J＝1.6Hz,1H),7(dd,J＝2.4,8.8Hz,1H),4.32(t,J＝6.0Hz,2H),3.61(t,J＝12.0Hz,4H),3.13(t,J＝6.0Hz,2H),2.57(s,3H)；m/z ES+[M+H] ⁺ 496.0。

Example 63: synthesis of 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutanol

Step 1.3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutanol

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in ethanol (2 mL) at 0deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (170 mg,300 umol) was added sodium borohydride (11.0 mg,300 umol), and the mixture was stirred at 0℃for 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) at 0 ℃, then diluted with water (20 mL), and extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with water (2X 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutylalcohol (180 mg, crude). M/zES + [ M+H ]] ⁺ 577.1。

Step 2.3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutanol

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of cyclobutanol (170 mg,300 umol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions, column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -52%,10 min) purification to give 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutylalcohol (5.9 mg,13.3umol, 4.3%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.38-12.19(m,1H),9.32(d,J＝3.2Hz,1H),8.80-8.76(m,1H),8.38(s,1H),7.96(dd,J＝4.8,9.2Hz,1H),7.57-7.46(m,1H),7.37-7.27(m,1H),7.26-7.15(m,1H),7.01-6.89(m,1H),5.37-5.26(m,1H),4.57-4.47(m,1H),4.06-3.95(m,1H),2.86-2.75(m,2H),2.49-2.47(m,3H),2.46-2.38(m,2H)；m/z ES+[M+H] ⁺ 447.0。

Example 64: synthesis of 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -1-methyl-cyclobutanol

Step 1.3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -1-methyl-cyclobutanol

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in tetrahydrofuran (3 mL) at 0deg.C ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (100 mg, 170. Mu.L) was added methyl magnesium bromide (3M in THF, 170. Mu.L). The mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) at 0 ℃, then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a white solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1-methyl-cyclobutanol (40.0 mg,67.7umol, 32%). M/zES + [ M+H ]] ⁺ 591.1。

Step 2.3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -1-methyl-cyclobutanol

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1-methyl-cyclobutanol (30.0 mg,51.0 mol) was stirred at 25℃for 0.5 hours. Mixing the reaction The compound was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 27% -57%,10 min) purification to give 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-1-methyl-cyclobutanol (15.0 mg,32.5umol, 64%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.33(s,1H),8.77(s,1H),8.38(s,1H),7.96(d,J＝9.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.24(s,1H),6.97(d,J＝8.4Hz,1H),5.32(s,1H),4.66(s,1H),2.69-2.53(m,5H),2.49-2.49(m,3H),1.35(s,3H)；m/z ES+[M+H] ⁺ 461.0。

Example 65: synthesis of 4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethylpiperidine-1-carboxamide

Step 1.4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethylpiperidine-1-carboxamide

To a solution of 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (50.0 mg,84.7 umol) in dichloromethane (1 mL) was added triethylamine (25.7 mg,254 umol) and dimethylcarbamoyl chloride (18.2 mg,169 umol) at 0 ℃. The mixture was stirred at 25℃for 1 hour. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethylpiperidine-1-carboxamide (50.0 mg,75.6umol, 89%) as a yellow oil.

Step 2.4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethylpiperidine-1-carboxamide

4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of-N, N-dimethyl-piperidine-1-carboxamide (50.0 mg,75.6 umol) was stirred at 25℃for 0.5 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25 mm. Times.10 um; mobile phase: [ water (0.2% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 14% -44%,10 min) purification to give 4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethylpiperidine-1-carboxamide (13.4 mg,25.2umol, 32%). ¹ H NMR(400MHz,CD ₃ OD)δ9.26-9.10(m,1H),8.71-8.58(m,1H),8.44-8.30(m,1H),8.13(s,1H),8.03-7.85(m,1H),7.62(d,J＝8.8Hz,1H),7.46-7.35(m,1H),7.24(d,J＝2.0Hz,1H),7.13(dd,J＝2.4,8.8Hz,1H),4.61-4.43(m,1H),3.86(d,J＝12.8Hz,2H),3.04(t,J＝11.6Hz,2H),2.92(s,6H),2.68(s,3H),2.29-2.09(m,4H)；m/z ES+[M+H] ⁺ 531.1。

Example 66: synthesis of 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -2, 2-dimethyl-propanenitrile and 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -2, 2-dimethyl-propanamide

(2-cyano-2-methyl-propyl) methanesulfonate

To a solution of 3-hydroxy-2, 2-dimethyl-propane nitrile (200 mg,2.02 mmol) in ethyl acetate (3 mL) was added methanesulfonyl chloride (277 mg,3.03 mmol) and triethylamine (612 mg,6.05 mmol) at 0deg.C, and the mixture was stirred at 25deg.C for 2 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3×3 mL). The combined organic layers were washed with brine (3×3 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil (2-cyano-2-methyl-propyl) methanesulfonate (310 mg,1.75mmol, 86%) as a product. ¹ H NMR(400MHz,CDCl ₃ )δ4.12(s,2H),3.12(s,3H),1.44(s,6H)。

Step 2.3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -2, 2-dimethyl-propanenitrile

To (2-cyano-2-methyl-propyl) methanesulfonate (76.9 mg, 414 umol) and 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl in N, N-dimethylformamide (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (100 mg, 197umol) was added potassium carbonate (54.5 mg, 390 umol) and potassium iodide (32.7 mg, 197umol). The mixture was stirred at 100℃for 48 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3×3 mL). The combined organic layers were washed with brine (3×3 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-2, 2-dimethyl-propane nitrile (100 mg, crude). M/zES + [ M+H ]] ⁺ 588.2。

Step 3.3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -2, 2-dimethyl-propanenitrile and 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -2, 2-dimethyl-propanamide

A solution of 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -2, 2-dimethyl-propanenitrile (90.0 mg,153 umol) in trifluoroacetic acid (1 mL) was stirred at 25℃for 1 hour. The reaction mixture was filtered and concentrated in vacuo to give a residue, and the residue was purified by preparative HPLC (column: phenomenex Gemini-NX 18X 30mm X3 um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 12% -42%,7 min) to give 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -2, 2-dimethyl-propanenitrile (11.6 mg,25.1umol, 16%) and 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -2, 2-dimethyl-propanamide (9.9 mg,20.7umol, 13%) as an off-white solid.

¹ H NMR(400MHz,CD ₃ OD)δ9.20(s,1H),8.68(s,1H),8.41(s,1H),8.23-8.17(m,1H),7.93(d,J＝9.2Hz,1H),7.57(d,J＝8.8Hz,1H),7.39(d,J＝9.2Hz,1H),7.21(d,J＝2.4Hz,1H),7.07(dd,J＝2.4,8.8Hz,1H),4.47(s,2H),2.62(s,3H),1.47(s,6H)；m/z ES+[M+H] ⁺ 458.0。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.49-12.02(m,1H),9.31(s,1H),8.55(s,1H),8.36(s,1H),8.16(s,1H),7.95(d,J＝9.2Hz,1H),7.59-7.43(m,1H),7.31(d,J＝9.2Hz,1H),7.28-7.14(m,2H),7.07(s,1H),6.94(d,J＝8.8Hz,1H),4.35(s,2H),2.49(s,3H),1.14(s,6H)；m/z ES+[M+H] ⁺ 476.1。

Example 67: synthesis of 2- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] morpholine and 2- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -4-methyl-morpholine

Step 1.2- (methylsulfonyloxymethyl) morpholine-4-carboxylic acid tert-butyl ester

To a solution of tert-butyl 2- (hydroxymethyl) morpholine-4-carboxylate (1 g,4.60 mmol) in dichloromethane (10 mL) was added triethylamine (1.40 g,13.8 mmol) followed by methanesulfonyl chloride (1.05 g,9.21 mmol) at 0deg.C. The mixture was stirred at 25℃for 1 hour. The reaction mixture was diluted with water (50 mL) at 20 ℃ and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2- (methylsulfonyloxymethyl) morpholine-4-carboxylate (1.55 g, crude) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ＝4.24(d,J＝4.8Hz,2H),4.04-3.80(m,3H),3.74-3.66(m,1H),3.59-3.51(m,1H),3.07(s,3H),3.03-2.71(m,2H),1.47(s,9H)。

Step 2.2- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] morpholine-4-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (4 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Potassium carbonate (164 mg,1.18 mmol) was added to a solution of ethyl-trimethylsilane (200 mg, 390 umol) and tert-butyl 2- (methylsulfonyloxymethyl) morpholine-4-carboxylate (175 mg,592 umol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 2- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Morpholine-4-carboxylic acid tert-butyl ester (315 mg, crude). M/zES + [ M+H ]] ⁺ 706.4。

Step 3.2- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] morpholine

2- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of morpholine-4-carboxylic acid tert-butyl ester (500 mg, 706. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC (column Phenomenex Synergi C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 2- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Morpholine (227 mg,477umol, 68%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.32(s,1H),8.65(s,1H),8.39(s,1H),8.22(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝2.4Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.43-4.28(m,2H),4.01(dd,J＝4.4,6.0Hz,1H),3.90(dd,J＝2.4,12.0Hz,1H),3.65-3.51(m,1H),3.14(d,J＝12.0Hz,1H),2.98(d,J＝12.4Hz,1H),2.89-2.77(m,1H),2.69(t,J＝11.6Hz,1H),2.49(s,3H)；m/z ES+[M+H] ⁺ 476.1

Step 4.2- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -4-methyl-morpholine

To 2- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in N, N-dimethylformamide (2 mL)]Quinoxalin-2-yl]Pyrazol-1-yl ]Methyl group]To a solution of morpholine (150 mg,315 umol) was added paraformaldehyde (189 mg,6.30 mmol) and formic acid (15.1 mg,315 umol). The mixture was stirred at 60℃for 1.5 hours. The reaction mixture was filtered and concentrated in vacuo, and the residue was purified by prep HPLC (column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 25% -55%,10 min) purification to give 2- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-4-methyl-morpholine (15.2 mg,31.0 mol, 9%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.32(s,1H),8.66(s,1H),8.39(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.34(d,J＝5.6Hz,2H),4.38-4.31(m,1H),3.99-3.84(m,2H),3.53(t,J＝10.8Hz,1H),3-2.69(m,2H),2.49(s,3H),2.33(s,3H),2.27-1.94(m,2H)；m/z ES+[M+H] ⁺ 490.1。

Example 68: synthesis of 8-chloro-2- (1- ((3S, 4S) -3-fluoro-1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- ((3S, 4S) -3-fluoro-1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-chloro-2- (1- ((3 s,4 s) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) in N, N-dimethylformamide (1 mL)]Imidazol-6-yl) oxy) quinoxaline (50.0 mg,10To a 5. Mu. Mol solution were added diisopropylethylamine (27.0 mg, 209. Mu. Mol) and 2, 2-trifluoroethyl triflate (29.1 mg, 126. Mu. Mol), and the mixture was stirred at 25℃for 2 hours. The reaction mixture was quenched with water (0.5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 45% -75%,8 min) purification to give 8-chloro-2- (1- ((3S, 4S) -3-fluoro-1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (10.4 mg,18.0umol, 17%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.85(s,1H),8.43(s,1H),7.98(d,J＝9.2Hz,1H),7.58(d,J＝8.8Hz,1H),7.36(d,J＝9.2Hz,1H),7.28(d,J＝1.6Hz,1H),7.03(dd,J＝2.4,8.8Hz,1H),5.07-4.88(m,1H),4.61-4.51(m,1H),3.41(q,J＝10.0Hz,3H),3.01(d,J＝11.6Hz,1H),2.70-2.61(m,1H),2.56(s,3H),2.18-2.05(m,2H)；m/z ES+[M+H] ⁺ 560.1。

Example 69: (E) Synthesis of-4- ((3S, 4S) -4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) but-3-en-2-one

(E) -4- ((3S, 4S) -4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) but-3-en-2-one

To 8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) in dichloromethane (1 mL)]To a solution of imidazol-6-yl) oxy quinoxaline (50.0 mg,105 mol), 3-hydroxy cyclobutanone (13.5 mg,157 mol) was added triethylamine (12.7 mg,126 mol) and sodium triacetoxyborohydride (24.4 mg,115 mol), and the mixture was stirred at 25℃for 13 hours. The reaction mixture was quenched with methanol (0.2 mL) at 25 ℃ and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM ammonium bicarbonate) ) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 27% -57%,10 min) purification to give (E) -4- ((3S, 4S) -4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-fluoropiperidin-1-yl) but-3-en-2-one (16.4 mg,28.5umol, 27%). ¹ H NMR(400MHz,CD ₃ OD)δ9.16(s,1H),8.67(s,1H),8.41(s,1H),7.90(d,J＝10.0Hz,1H),7.66(d,J＝12.8Hz,1H),7.53(d,J＝8.0Hz,1H),7.35(d,J＝8.8Hz,1H),7.18(s,1H),7.01(d,J＝8.0Hz,1H),5.42(d,J＝12.4Hz,1H),5.09-4.96(m,1H),4.77-4.54(m,2H),4.22-4.11(m,1H),3.89-3.78(m,1H),3.45-3.34(m,1H),2.57(s,3H),2.39-2.24(m,2H),2.15(s,3H)；m/z ES+[M+H] ⁺ 546.1。

EXAMPLE 70 Synthesis of azetidin-1-yl (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methanone

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in dichloromethane (1 mL)]Imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (100 mg,169 umol), triethylamine (51.4 mg,508 umol) was added to a solution of 4-nitrophenyl chloroformate (68.3 mg,338 umol), and the mixture was stirred at 25℃for 1 hour. The mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1 to 0/1) to give 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a colorless oil ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid 4-nitrophenyl ester (80.0 mg,105umol, 62%). M/zES + [ M+H ]] ⁺ 755.4。

Step 2. Azetidin-1-yl (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methanone

4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in tetrahydrofuran (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid 4-nitrophenyl ester (80.0 mg,105 mol), azetidine (19.8 mg,211 mol), triethylamine (32.1 mg,317 mol) were stirred at 60℃for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give azetidin-1-yl (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl methanone (70.0 mg,103umol, 98%). M/zES + [ M+H ] ] ⁺ 673.4。

Step 3 azetidin-1-yl (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methanone

Azetidin-1-yl (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl methanone (70.0 mg,103 umol) was stirred at 25 ℃ for 10min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,7 min) purification to give azetidin-1-yl (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ]) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl methanone (20.5 mg,37.7umol, 36%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.31(s,1H),8.78(s,1H),8.35(s,1H),8.23(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝7.6Hz,1H),7.30(d,J＝8.4Hz,1H),7.21(s,1H),6.94(d,J＝8.4Hz,1H),4.52(s,1H),3.98-3.81(m,6H),2.91(t,J＝12.8Hz,2H),2.49-2.46(m,3H),2.23-2.01(m,4H),1.95-1.76(m,2H)；m/z ES+[M+H] ⁺ 543.1。

Example 71: synthesis of 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutanone

Step 1.3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] cyclobutanone

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.3 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of cyclobutanone (30.0 mg,52.2 umol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 9% -39%,10 min) purification to give 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow gum]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutanone (12.5 mg,27.5umol, 52%). ¹ HNMR(400MHz,DMSO-d ₆ )δ＝9.33(s,1H),8.95(s,1H),8.45(s,1H),7.96(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.23(d,J＝2.0Hz,1H),6.96(dd,J＝2.4,8.8Hz,1H),5.41-5.31(m,1H),3.70-3.64(m,4H),2.50(s,3H)；m/z ES+[M+H] ⁺ 445.0。

Example 72: synthesis of 8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilane) in trifluoroacetic acid (1 mL)Group) ethoxy) methyl) -1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxaline (55.0 mg,83.9 umol) was stirred at 25 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 16% -46%,10 min) purification to give 8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxaline (22.2 mg,42.3umol, 50%). ¹ H NMR(400MHz,CD ₃ OD)δppm＝9.13(s,1H),8.60(s,1H),8.35(s,1H),7.94(d,J＝9.2Hz,1H),7.59(d,J＝8.7Hz,1H),7.35(d,J＝9.2Hz,1H),7.22(d,J＝1.6Hz,1H),7.10(dd,J＝1.6,8.8Hz,1H),4.40(d,J＝6.8Hz,2H),2.83-2.66(m,3H),2.65(s,3H),2.56-2.42(m,2H)；m/z ES+[M+H] ⁺ 525.0。

Example 73: synthesis of 3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) morpholine and 3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -4-methylmorpholine

Step 1.3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) morpholine-4-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in toluene (5 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (300 mg,591 umol), tert-butyl 3- (hydroxymethyl) morpholine-4-carboxylate (154 mg,709 umol) was added diisopropyl azodicarboxylate (178 mg,887 umol) and triphenylphosphine (232 mg,887 umol), and the mixture was stirred under nitrogen at 60℃for 12 hours. The reaction mixture was quenched with water (20 mL) at 25℃and extracted with ethyl acetate (3X 100 mL). The combined organic layers were washed with brine (3×10 mL), dried over sodium sulfate, filtered, and purified in vacuo Concentrating under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl methyl) morpholine-4-carboxylic acid tert-butyl ester (150 mg,212umol, 35%). M/zES + [ M+H ]] ⁺ 706.3。

Step 2.3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) morpholine

3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (7.70 g,67.5 mmol)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of tert-butyl morpholine-4-carboxylate (150 mg, 42.4. Mu. Mol) was stirred at 25℃for 3 hours. The mixture was concentrated in vacuo and the residue was purified by prep HPLC (column: waters Xbridge150 x 25mM x 5um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 19% -49%,8 min) purification to give 3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl morpholine (120 mg,252umol, 80%). ¹ H NMR(400MHz,CD ₃ OD)δ9.13(s,1H),8.56(s,1H),8.37(s,1H),7.88(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.18(s,1H),7.07-6.94(m,1H),4.31-4.18(m,2H),3.85-3.74(m,2H),3.60-3.50(m,1H),3.33(d,J＝6.8Hz,2H),2.99-2.82(m,2H),2.57(s,3H)；m/z ES+[M+H] ⁺ 476.1。

Step 3.3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -4-methylmorpholine

3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in N, N-dimethylformamide (2 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of morpholine (70.0 mg,118 mmol), formic acid (114 mg,2.37 mmol) and paraformaldehyde (71.2 mg,2.37 mmol) was stirred at 60℃for 16 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 23% -53%,9 min) purification toObtaining 3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -4-methylmorpholine (16.0 mg,32.7umol, 27%). ¹ H NMR(400MHz,DMSO-d ₆ )δ12.42-12.18(m,1H),9.31(s,1H),8.72(s,1H),8.37(s,1H),7.96(d,J＝9.2Hz,1H),7.66-7.42(m,1H),7.39-7.11(m,2H),6.94(t,J＝9.6Hz,1H),4.53-4.44(m,1H),4.31-4.22(m,1H),3.66(d,J＝11.2Hz,1H),3.59-3.53(m,1H),3.46(t,J＝9.2Hz,1H),3.30-3.22(m,1H),2.70(d,J＝12.0Hz,1H),2.59-2.56(m,1H),2.49-2.49(m,3H),2.37(s,3H),2.28-2.19(m,1H)；m/z ES+[M+H] ⁺ 490.1。

Example 74: synthesis of 8-chloro-2- [1- [ (1-fluorocyclopropyl) methyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [ (1-fluorocyclopropyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A mixture of ethyl-trimethyl-silane (70.0 mg, 138. Mu. Mol), (1-fluorocyclopropyl) methyl methanesulfonate (23.2 mg, 138. Mu. Mol) and potassium carbonate (57.2 mg, 414. Mu. Mol) was stirred under a nitrogen atmosphere at 80℃for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=0:1) to give 2- [ [6- [ 5-chloro-3- [1- [ (1-fluorocyclopropyl) methyl ] as a yellow solid ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (70.0 mg,120 mol, 87%). M/zES + [ M+1 ]] ⁺ 579.2。

Step 2.8-chloro-2- [1- [ (1-fluorocyclopropyl) methyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [ (1-fluorocyclopropyl) methyl ] in trifluoroacetic acid (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A mixture of ethyl-trimethyl-silane (65.0 mg,112 umol) was stirred at 25℃for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,7 min) purification to give 8-chloro-2- [1- [ (1-fluorocyclopropyl) methyl ] as a white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (44.0 mg,98.0 mol, 85%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.35-12.17(m,1H),9.35(s,1H),8.76(s,1H),8.41(s,1H),7.96(d,J＝9.2Hz,1H),7.50(s,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.96-6.92(m,1H),4.68(d,J＝22.4Hz,2H),2.50(s,3H),1.17-1(m,4H)；m/zES+[M+H] ⁺ 449.0。

Example 75: synthesis of (1R, 4R) -5- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] ethyl ] -2-oxa-5-azabicyclo [2.2.1] heptane

Step 1.2- [ [6- [ 5-chloro-3- [1- [2- [ (1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl ] ethyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in acetonitrile (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl methanesulfonate (300 mg, 470 umol) and (1 r,4 r) -2-oxa-5-azabicyclo [2.2.1]Heptane; to a mixture of hydrochloride (193 mg,1.43 mmol) was added sodium bicarbonate (200 mg,2.38 mmol) and the reaction mixture was stirred at 80℃for 12 hours. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (2X 50 mL). For combined organic layersBrine (2×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate=0:1) to give 2- [ [6- [ 5-chloro-3- [1- [2- [ (1 r,4 r) -2-oxa-5-azabicyclo [2.2.1] as a yellow solid]Heptan-5-yl]Ethyl group]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (60.0 mg,94.9umol, 19%). M/zES + [ M+H ] ] ⁺ 632.5。

(1R, 4R) -5- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] ethyl ] -2-oxa-5-azabicyclo [2.2.1] heptane

2- [ [6- [ 5-chloro-3- [1- [2- [ (1R, 4R) -2-oxa-5-azabicyclo [2.2.1] in trifluoroacetic acid (1 mL)]Heptan-5-yl]Ethyl group]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (50.0 mg,79.0 mmole) was stirred at 25℃for 30min. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC (column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 24% -54%,10 min) purification to give (1R, 4R) -5- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]-2-oxa-5-azabicyclo [2.2.1]Heptane (1.5 mg,2.93umol, 3%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.44-12.09(m,1H),9.31(s,1H),8.71(br s,1H),8.36(br s,1H),8.04-7.85(m,1H),7.57-7.44(m,1H),7.38-7.27(m,1H),7.27-7.13(m,1H),7-6.86(m,1H),4.35-4.23(m,2H),3.84-3.80(m,1H),3.51-3.46(m,2H),3.12-2.89(m,2H),2.85-2.76(m,1H),2.49-2.47(m,3H),2.45-2.32(m,1H),1.76-1.68(m,1H),1.60-1.53(m,1H),1.24(s,1H)；m/z ES+[M+H] ⁺ 502.1。

Example 76: synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- (1-tetrahydropyran-4-ylazetidin-3-yl) pyrazol-4-yl ] quinoxaline

Step 1.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- (1-tetrahydropyran-4-ylazetidin-3-yl) pyrazol-4-yl ] quinoxaline

To 2- [1- (azetidin-3-yl) pyrazol-4-yl in tetrahydrofuran (2 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (80.0 mg,185 umol) and tetrahydropyran-4-one (24.1 mg,241 umol) were added diisopropylethylamine (120 mg, 226 umol, 161) and sodium triacetoxyborohydride (78.5 mg,371 umol), and the mixture was stirred at 25℃for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by preparative HPLC (column Phenomenex Synergi C18:150×25mm×10um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow solid]-2- [1- (1-tetrahydropyran-4-ylazetidin-3-yl) pyrazol-4-yl]Quinoxaline (28.7 mg,55.7umol, 30%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.33(s,1H),8.86(s,1H),8.41(s,1H),8.17(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝8.8Hz,1H),7.22(s,1H),6.95(d,J＝8.0Hz,1H),5.14(s,1H),3.86-3.81(m,2H),3.76(s,2H),3.49(s,2H),3.37-3.27(m,2H),2.50(s,3H),2.48-2.43(m,1H),1.69-1.64(m,2H),1.26-1.14(m,2H)；m/z ES+[M+H] ⁺ 516.0。

Example 77: synthesis of 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] acetonitrile

Step 1.2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] acetonitrile

2- [1- (azetidin-3-yl) pyrazol-4-yl ] in acetonitrile (2 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]A mixture of quinoxaline (30 mg,69.4 mol), 2-bromoacetonitrile (6.67 mg,55.5 mol), potassium carbonate (20.5 mg,148 mol) was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -5 min) and then purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 25% -55%,7 min) to give 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]Acetonitrile (2.7 mg,5.69umol, 8%). ¹ H NMR(400MHz,CD ₃ OD)δ＝9.17(s,1H),8.72(s,1H),8.41(s,1H),7.90(d,J＝9.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.35(d,J＝9.2Hz,1H),7.19(d,J＝2.0Hz,1H),7.04-7.01(m,1H),5.19(t,J＝6.4Hz,1H),4.66-4.58(m,1H),4.01-3.94(m,2H),3.91-3.83(m,2H),3.75(s,2H),2.59(s,3H)；m/z ES+[M+H] ⁺ 471.0。

Example 78: synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [1- (oxetan-3-yl) azetidin-3-yl ] pyrazol-4-yl ] quinoxaline

Step 1.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [1- (oxetan-3-yl) azetidin-3-yl ] pyrazol-4-yl ] quinoxaline

To 2- [1- (azetidin-3-yl) pyrazol-4-yl in tetrahydrofuran (3 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (50.0 mg,115 mol) was added oxetan-3-one (16.7 mg,231 mol), and the mixture was stirred at 25℃for 0.5 hours. Sodium triacetoxyborohydride (73.6 mg, 277 umol) was then added at 0deg.C. The mixture was stirred at 25℃for 6 hours. The reaction mixture was diluted with water (10 mL) and taken up in ethyl acetate @3X 30 mL) of the extract. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -52%,9 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy) as a white solid]-2- [1- [1- (oxetan-3-yl) azetidin-3-yl]Pyrazol-4-yl]Quinoxaline (26.9 mg,55.2umol, 47%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.41-12.13(m,1H),9.34(s,1H),8.87(s,1H),8.43(s,1H),7.96(d,J＝9.2Hz,1H),7.60-7.42(m,1H),7.39-7.11(m,2H),6.94(d,J＝8.0Hz,1H),5.22(t,J＝6.8Hz,1H),4.63(t,J＝6.8Hz,2H),4.47(t,J＝5.6Hz,2H),3.90-3.77(m,1H),3.79(t,J＝7.2Hz,2H),3.64(t,J＝6.8Hz,2H),2.54-2.51(m,3H)；m/z ES+[M+H] ⁺ 488.1。

Example 79: synthesis of 1- (azetidin-1-yl) -2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] ethanone

Step 1.1- (azetidin-1-yl) -2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] ethanone

To 2- [1- (azetidin-3-yl) pyrazol-4-yl in 1-methylpyrrolidin-2-one (2 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (50.0 mg,115 umol) was added potassium carbonate (48.0 mg,347 umol) and 1- (azetidin-1-yl) -2-chloro-ethanone (15.1 mg,113 umol). The mixture was stirred at 25℃for 6 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,7 min) purification to give 1- (azetidin-1-yl) -2- [3- [4- [ 8-chloro-7- [ (2-methyl) as a white solid-3H-benzimidazol-5-yl) oxy]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]Ethanone (10.2 mg,19.3umol, 16%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.41-12.13(m,1H),9.33(s,1H),8.87(s,1H),8.41(s,1H),7.96(d,J＝9.2Hz,1H),7.60-7.42(m,1H),7.39-7.11(m,2H),6.94(d,J＝8.0Hz,1H),5.16(t,J＝6.8Hz,1H),4.15(t,J＝7.6Hz,2H),3.89-3.79(m,4H),3.58(t,J＝7.2Hz,2H),3.20(s,2H),2.53-2.51(m,3H),2.23-2.16(m,2H)；m/z ES+[M+H] ⁺ 529.1。

Example 80: synthesis of 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] -1- (3-hydroxyazetidin-1-yl) ethanone

Step 1.2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] azetidin-1-yl ] -1- (3-hydroxyazetidin-1-yl) ethanone

To 2- [1- (azetidin-3-yl) pyrazol-4-yl in 1-methylpyrrolidin-2-one (2 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (50.0 mg,115 umol) were added potassium carbonate (48.0 mg,347 umol) and 2-chloro-1- (3-hydroxyazetidin-1-yl) ethanone (15.5 mg,104 umol). The mixture was stirred at 25℃for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 16% -46%,9 min) purification to give 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Azetidin-1-yl]-1- (3-hydroxyazetidin-1-yl) ethanone (16.6 mg,30.5umol, 26%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.43-12.15(m,1H),9.34(s,1H),8.87(s,1H),8.42(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝7.7Hz,1H),7.37-7.14(m,2H),6.95-6.93(m,1H),5.73(d,J＝1.8Hz,1H),5.16(t,J＝6.8Hz,1H),4.45(s,1H),4.32(t,J＝7.6Hz,1H),4.05-4.01(m,1H),3.89-3.80(m,1H),3.83(t,J＝7.6Hz,2H),3.57(t,J＝6.8Hz,3H),3.22(s,2H),2.52-2.51(m,3H)；m/z ES+[M+H] ⁺ 545.1。

EXAMPLE 81 Synthesis of (1R, 3 r) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol and (1S, 3 s) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol

Step 1. (1R, 3 r) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol and (1S, 3 s) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol

3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol (650 mg,1.37 mmol) was isolated by SFC (column: daicel Chiralpak IG (250 mm. 30mm,10 um)), mobile phase: [0.1% ammonium hydroxide, methanol ]; (B%: 60% -60%,4.6 min) to give (1R, 3 r) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol (60.9 mg,127 mol, 9.3%) and (1S, 3 s) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-1-methylcyclobutanol) 1-methylcyclobutanol (60 mg, 127.3%) as a green solid.

¹ H NMR(400MHz,CD ₃ OD)δ＝9.15(s,1H),8.55(s,1H),8.33(s,1H),7.89(d,J＝9.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.18(d,J＝2.0Hz,1H),7.02(dd,J＝2.4,8.8Hz,1H),4.30(d,J＝7.6Hz,2H),3.04-2.91(m,1H),2.58(s,3H),2.24-2.14(m,2H),2.01-1.94(m,2H),1.33(s,3H)；m/z ES+[M+H] ⁺ 475.0。

¹ H NMR(400MHz,CD ₃ OD)δ＝9.16(s,1H),8.54(s,1H),8.33(s,1H),7.92(d,J＝9.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.39(d,J＝9.2Hz,1H),7.22(d,J＝2.0Hz,1H),7.11(dd,J＝2.4,8.8Hz,1H),4.30(d,J＝7.2Hz,2H),2.66(s,3H),2.51-2.40(m,1H),2.20-2.14(m,2H),2.01-1.89(m,2H),1.35(s,3H)；m/z ES+[M+H] ⁺ 475.0。

EXAMPLE 82.Synthesis of 2- (1- (4-azaspiro [2.5] oct-7-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.7-hydroxy-4-azaspiro [2.5] octane-4-carboxylic acid tert-butyl ester

To 7-oxo-4-azaspiro [2.5] in methanol (1 mL) at 0deg.C]To a solution of tert-butyl octane-4-carboxylate (100 mg, 444. Mu. Mol) was added sodium borohydride (25.2 mg, 666. Mu. Mol) in portions. The mixture was stirred at 20℃for 1 hour. After completion, the mixture was quenched with saturated ammonium chloride solution (10 mL), diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give 7-hydroxy-4-azaspiro [2.5] as a colorless oil]Tert-butyl octane-4-carboxylate (90.0 mg, 396. Mu. Mol, 89%). ¹ H NMR(400MHz,CDCl ₃ )δ4.05-3.89(m,2H),3.05-2.90(m,1H),2-1.87(m,1H),1.82-1.71(m,1H),1.47(s,9H),1.46-1.38(m,2H),1.22-1.12(m,1H),0.88-0.79(m,1H),0.66-0.53(m,1H),0.50-0.41(m,1H)。

Step 2.7- ((methylsulfonyl) oxy) -4-azaspiro [2.5] octane-4-carboxylic acid tert-butyl ester

To 7-hydroxy-4-azaspiro [2.5] in dichloromethane (2 mL) at 0deg.C]To a solution of tert-butyl octane-4-carboxylate (90.0 mg, 396. Mu. Mol) and triethylamine (120 mg,1.19 mmol) was added methanesulfonyl chloride (68.0 mg, 594. Mu. Mol), and the mixture was stirred at 20℃for 0.5 hours. After completion, the mixture was washed with dichloromethane (20mL) and washed with water (15 mL x 3). The organic layer was dried over sodium sulfate and concentrated in vacuo to give 7-methylsulfonyloxy-4-azaspiro [2.5] as a colorless oil ]Tert-butyl octane-4-carboxylate (120 mg, 393. Mu. Mol, 99%). ¹ H NMR(400MHz,CDCl ₃ )δ5.03-4.92(m,1H),3.99-3.80(m,1H),3.15-3.07(m,1H),3.03(s,3H),2.12-1.91(m,2H),1.81-1.62(m,2H),1.47(s,9H),1.46-1.38(m,1H),1.20-1.09(m,1H),0.91-0.81(m,1H),0.77-0.65(m,1H),0.61-0.52(m,1H)。

Step 3.7- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -4-azaspiro [2.5] octane-4-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in dimethyl sulfoxide (3 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (120 mg, 237. Mu. Mol) and 7-methylsulfonyloxy-4-azaspiro [2.5]]Potassium carbonate (65.4 mg, 473. Mu. Mol) was added to a mixture of tert-butyl octane-4-carboxylate (108 mg, 355. Mu. Mol), and the mixture was stirred at 80℃for 2 hours. After completion, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give 7- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-4-azaspiro [2.5]]Tert-butyl octane-4-carboxylate (120 mg, 168. Mu. Mol, 70%). M/zES + [ M+H ] ] ⁺ 716.3。

Step 4.2- (1- (4-azaspiro [2.5] oct-7-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

7- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-4-azaspiro [2.5]]A solution of tert-butyl octane-4-carboxylate (120 mg, 167. Mu. Mol) was stirred at 20℃for 1 hour. After completion, the mixture was concentrated in vacuo, andthe residue was purified by preparative HPLC [ column: waters Xbridge150 x 25mm x 5um; mobile phase: [ Water (ammonium bicarbonate-acetonitrile)]；(B％：29％-59％，9min]Purification to give 2- [1- (4-azaspiro [2.5] as a yellow solid]Oct-7-yl) pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (43.8 mg,88.0 mu mol, 52%). ¹ H NMR(400MHz,DMSO-d ₆ )δ12.59-12.10(m,1H),9.32(s,1H),8.75(s,1H),8.36(s,1H),7.96(d,J＝9.2Hz,1H),7.62-7.42(m,1H),7.38-7.14(m,2H),6.95(d,J＝7.6Hz,1H),4.59-4.46(m,1H),3.10-3.01(m,1H),2.80-2.69(m,1H),2.49(s,3H),2.36-2.28(m,1H),2.16-2.06(m,1H),1.98-1.87(m,1H),1.57-1.48(m,1H),0.68-0.59(m,1H),0.55-0.42(m,3H)；m/z ES+[M+H] ⁺ 486.1。

EXAMPLE 83 Synthesis of (1R, 3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol and (1S, 3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol

(1R, 3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol and (1S, 3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol

3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol (250 mg, 559. Mu. Mol) was isolated by SFC (column: daicel Chiralpak IF (250 mm. Times.30 mm,10 um); mobile phase: [ hexane-EtOH (0.1% ammonium hydroxide) ]; (B%: 35% -35%,17 min) to give (1R, 3 r) -3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl) cyclobutanol (102 mg, 207. Mu. Mol, 37%) as an off-white solid and (1S, 3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol as an off-white solid (2.8 mg, 2.8.1%).

¹ H NMR(400MHz,DMSO-d6)δ12.45-12.15(m,1H),9.33(d,J＝4.0Hz,1H),8.78(s,1H),8.38(s,1H),7.96(dd,J＝5.2,9.2Hz,1H),7.60-7.42(m,1H),7.40-7.12(m,2H),6.95(dd,J＝8.8,11.2Hz,1H),5.36(d,J＝6.8Hz,1H),4.62-4.44(m,1H),4.09-3.91(m,1H),2.89-2.75(m,2H),2.49(s,3H),2.46-2.39(m,2H)；m/z ES+[M+H] ⁺ 447.0。

¹ H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.80(s,1H),8.39(s,1H),8.35(s,2H),7.97(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.22(s,1H),6.95(dd,J＝2.4,8.6Hz,1H),5.15-5(m,1H),4.53(s,1H),2.78-2.69(m,2H),2.48-2.46(m,3H),2.45-2.41(m,2H)；m/z ES+[M+H] ⁺ 447.0。

EXAMPLE 84.Synthesis of 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

Step 1.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in tetrahydrofuran (3 mL) at 0deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl ]To a solution of cyclobutanone (100 mg, 170. Mu. Mol) was added methylmagnesium bromide (3M in THF, 170. Mu.L). The mixture was stirred at 0 ℃ for 1 hour. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) at 0 ℃, then diluted with water (50 mL), and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine (25 ml×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a white solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1-methyl-cyclobutanol (40 mg, 67.8. Mu. Mol, 32%). m-zES+[M+H] ⁺ 591.1。

Step 2.3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A mixture of 1-methyl-cyclobutanol (30.0 mg, 51.0. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 27% -57%,10 min) purification to give 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-1-methyl-cyclobutanol (15 mg,33 μmol, 64%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝9.33(s,1H),8.77(s,1H),8.38(s,1H),7.96(d,J＝9.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.24(s,1H),6.97(d,J＝8.4Hz,1H),5.32(s,1H),4.66(s,1H),2.69-2.53(m,5H),2.49-2.49(m,3H),1.35(s,3H)；m/z ES+[M+H] ⁺ 461.0。

EXAMPLE 85.Synthesis of 3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -6- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-5-amine

Step 1.7-bromo-2- (1H-pyrazol-4-yl) quinoxaline

To a solution of 7-bromo-2- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxaline (5.2 g,14.5 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (20 mL). The mixture was stirred at 20℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline (5 g, crude) as a black solid. M/zES + [ M+H ]] ⁺ 274.7。

Step 2.7-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxaline

To a solution of 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline (2.3 g,8.36 mmol) in N, N-dimethylformamide (40 mL) was added potassium carbonate (2.31 g,16.7 mmol) and (3, 3-difluorocyclobutyl) methyl methanesulfonate (1.67 g,8.36 mmol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate= 5/1 to 1/1)) to give a residue. The residue was triturated with petroleum ether:ethyl acetate (20:1, 60 mL) at 20deg.C for 30min to give 7-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxaline (800 mg,2.12mmol, 12%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.43-9.31(m,1H),8.73(s,1H),8.34(s,1H),8.20(d,J＝2.0Hz,1H),7.99(d,J＝8.8Hz,1H),7.88(dd,J＝2.0,8.8Hz,1H),4.37(d,J＝6.0Hz,2H),3.30(s,1H),2.77-2.57(m,4H)；m/zES+[M+H] ⁺ 378.8。

Step 3.3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol

7-bromo-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] in dioxane (10 mL) and water (2 mL)]Pyrazol-4-yl]A mixture of quinoxaline (600 mg,1.58 mmol), tris (dibenzylideneacetone) dipalladium (145 mg,158 umol), 2-di-tert-butylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl (67.2 mg,158 umol) and potassium hydroxide (88 mg,15.8 mmol) was degassed and purged 3 times with nitrogen, and the mixture was stirred under nitrogen atmosphere at 100℃for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate= 5/1 to 1/1) to give 3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol (400 mg,1.27mmol, 68%) as a yellow solid. M/zES + [ M+H ]] ⁺ 317.1。

Step 4.3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -5-iodo-quinoxalin-6-ol

To chloroform in3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in (10 mL)]Pyrazol-4-yl]To a solution of quinoxalin-6-ol (900 mg,2.85 mmol) was added nickel chloride (365 mg,2.85 mmol), triethylamine (287 mg,2.85 mmol) and N-iodosuccinimide (1.28 g,5.69 mmol). The mixture was stirred at 60℃for 2 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a red solid ]Pyrazol-4-yl]-5-iodo-quinoxalin-6-ol (1.10 g,2.43mmol, 85%). M/z ES+ [ M+H ]] ⁺ 442.9。

Step 5N-tert-Butoxycarbonyl-N- [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -5-iodo-quinoxalin-6-yl ] oxy-2-nitro-phenyl ] carbamic acid tert-butyl ester

To 3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in N, N-dimethylformamide (10 mL)]Pyrazol-4-yl]To a solution of 5-iodo-quinoxalin-6-ol (1 g,2.26 mmol) was added potassium carbonate (937 mg,6.78 mmol) and tert-butyl N-tert-butoxycarbonyl-N- (5-fluoro-2-nitro-phenyl) carbamate (1.05 g,2.94 mmol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (water (0.1% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 40% -60%,7 min) purification to give N-tert-butoxycarbonyl-N- [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]Oxy-2-nitro-phenyl]Tert-butyl carbamate (1.20 g,1.32mmol, 58%). ¹ H NMR(400MHz,CDCl ₃ )δ9.03(s,1H),8.28(d,J＝8.0Hz,2H),8.19-8.06(m,2H),7.41(d,J＝9.2Hz,1H),7.02(d,J＝8.8Hz,1H),6.90(s,1H),4.37(d,J＝6.8Hz,2H),2.87-2.69(m,3H),2.56-2.39(m,2H),1.50-1.36(m,18H)。

Step 6.5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -5-iodo-quinoxalin-6-yl ] oxy-2-nitro-aniline

To N-tert-butoxycarbonyl-N- [ in dioxane (5 mL)5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ]]Pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]Oxy-2-nitro-phenyl]To a solution of tert-butyl carbamate (1 g,1.28 mmol) was added hydrochloric acid/dioxane (4 m,10 ml). The mixture was stirred at 40℃for 12 hours. The reaction mixture was concentrated under reduced pressure to give 5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]Oxy-2-nitro-aniline (1 g, crude). M/zES + [ M+H ]] ⁺ 579.1。

Step 7.4- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -5-iodo-quinoxalin-6-yl ] oxybenzene-1, 2-diamine

To 5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in ethanol (10 mL) and water (1 mL)]Pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]To a solution of oxy-2-nitro-aniline (900 mg,1.56 mmol) was added iron powder (695 mg,12.4 mmol) and ammonium chloride (665 mg,12.4 mmol). The mixture was stirred at 60℃for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]Oxybenzene-1, 2-diamine (1 g, crude). M/zES + [ M+H ]] ⁺ 549.1。

Step 8.2- [1- [ (3, 3-Difluorocyclobutyl) methyl ] pyrazol-4-yl ] -8-iodo-7- [ (2-methyl-1H-benzimidazol-5-yl) oxy ] quinoxaline

4- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] into methanol (10 mL)]Pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]To a solution of oxybenzene-1, 2-diamine (900 mg,1.64 mmol) and 1, 1-trimethoxyethane (986 mg,8.21 mmol) was added sulfamic acid (318 mg,3.28 mmol), and the mixture was stirred at 20℃for 1 hour. The mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate: methanol=10:1) to give 2- [1- [ (3, 3-difluorocyclobutyl) methyl as a yellow solid]Pyrazol-4-yl]-8-iodo-7- [ (2-methyl-1H-benzimidazol-5-yl) oxy]Quinoxaline (600 mg,1.05mmol, 63%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.23(s,1H),8.74(s,1H),8.3(s,1H),8.02(d,J＝8.8Hz,1H),7.59(d,J＝8.8Hz,1H),7.28(d,J＝8.8Hz,1H),7.24(d,J＝2.0Hz,1H),7.03-6.97(m,1H),4.41(d,J＝6.0Hz,2H),2.75-2.65(m,4H),2.57(s,3H),2.56-2.54(m,1H)。

Step 9.2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -5-iodo-quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [1- [ (3, 3-difluorocyclobutyl) methyl in tetrahydrofuran (10 mL) at 0deg.C]Pyrazol-4-yl]-8-iodo-7- [ (2-methyl-1H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (500 mg,873 umol) was added sodium hydride (52.4 mg,1.31mmol,60% in mineral oil) and the mixture was stirred at 0 ℃ for 0.5 h. A solution of 2- (chloromethoxy) ethyl-trimethylsilane (189 mg,1.14 mmol) in tetrahydrofuran (2 mL) was then added dropwise and the mixture stirred at 0deg.C for 1 hr. The mixture was quenched with saturated ammonium chloride solution (10 mL), washed with water (60 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo, and the residue was purified by column chromatography (100% ethyl acetate) to give 2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid ]Pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (550 mg,782umol, 89%). M/zES + [ M+H ]] ⁺ 703.0。

Step 10.3- (1- ((3, 3-Difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -N- (di-phenylmethylene) -6- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-5-amine

To 2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in t-amyl alcohol (0.5 mL) under nitrogen]Pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (50.0 mg, 71.2. Mu. Mol), diphenylmethane imine (25.8 mg, 142. Mu. Mol) and cesium carbonate (69.6 mg, 213. Mu. Mol) was added XantPhos Pd G4 (6.85 mg, 7.12. Mu. Mol), and the mixture was stirred at 90℃for 16 hours. After completion, the mixture was filtered and the filtrate concentrated in vacuo and the residue was purified by preparative TLC (100% ethyl acetate) to give N- [3- [1- [ (3, 3-difluorocyclobutyl) methyl as a yellow solid]Pyrazol-4-yl]-6- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazole-5-yl]Oxy-quinoxalin-5-yl]-1, 1-diphenyl-methanimine (50 mg, 42.0. Mu. Mol, 59%). M/zES + [ M+H ] ] ⁺ 756.3。

Step 11.3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -6- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-5-amine

A mixture of N- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -6- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-5-yl ] -1, 1-diphenyl-methanimine (50.0 mg, 66.1. Mu. Mol) in hydrogen chloride/dioxane (4M, 0.1 mL) was stirred at 20℃for 30min. After completion, the mixture was concentrated in vacuo to give 3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -6- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-5-amine (40 mg, crude) as a yellow solid, which was used directly in the next step.

Step 12.3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -6- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-5-amine

3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in trifluoroacetic acid (0.2 mL)]Pyrazol-4-yl]-6- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]A solution of oxy-quinoxalin-5-amine (40.0 mg, 67.6. Mu. Mol) was stirred at 20℃for 10min. After completion, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC [ column: phenomnex C18 75 x 30mm x 3um; mobile phase: [ Water (formic acid) -acetonitrile ]；(B％：15％-45％，7min]Purified and then re-purified by preparative TLC (dichloromethane: methanol=10:1) to give 3- [1- [ (3, 3-difluorocyclobutyl) methyl as a yellow solid]Pyrazol-4-yl]-6- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxalin-5-amine (2 mg, 4.11. Mu. Mol, 6%). ¹ H NMR(400MHz,CD ₃ OD)δ9.09(s,1H),8.61(s,1H),8.38(s,1H),7.48(d,J＝8.8Hz,1H),7.30(d,J＝0.8Hz,2H),7.10(s,1H),7.02(dd,J＝2.4,8.8Hz,1H),4.40(d,J＝6.8Hz,2H),2.81-2.65(m,3H),2.56(s,3H),2.54-2.44(m,2H)；m/z ES+[M+H] ⁺ 462.0。

EXAMPLE 86 Synthesis of 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1 r,3 r) -3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline

(1S, 3 s) -3- (trifluoromethyl) cyclobutyl 4-methylbenzenesulfonate

To a solution of 3- (trifluoromethyl) cyclobutanol (50.0 mg, 317 umol) in dichloromethane (3 mL) were added triethylamine (72.7 mg, 428 umol), 4-dimethylaminopyridine (5.0 mg,40.9 umol) and 4-methylbenzenesulfonyl chloride (170 mg,892 umol). The mixture was stirred at 25℃for 12 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate=5:1) to give (1 s,3 s) -3- (trifluoromethyl) cyclobutyl 4-methylbenzenesulfonate (50 mg,170umol, 48%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.89-7.74(m,2H),7.36(d,J＝8.0Hz,2H),4.82-4.67(m,1H),2.53-2.42(m,6H),2.37-2.24(m,2H)。

Step 2.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1 r,3 r) -3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline

To a solution of (1S, 3 s) -3- (trifluoromethyl) cyclobutyl 4-methylbenzenesulfonate (20 mg,68 umol) in N, N-dimethylformamide (1.2 mL) was added cesium carbonate (50 mg,153 umol) and 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (35 mg,69 umol). The mixture was stirred at 80℃for 6 hours. After completion, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) -2- (1- ((1 r,3 r) -3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline (62 mg, crude). M/zES + [ M+H ]] ⁺ 629.0。

Step 3.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1 r,3 r) -3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline

8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (1.2 mL)]Imidazol-6-yl) oxy) -2- (1- ((1 r,3 r) -3- (trifluoromethyl) cyclobutyl) -1H-pyrazol-4-yl) quinoxaline (60 mg,95.4 umol) was stirred at 25℃for 2 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25.mu.m.150.mu.m; mobile phase: [ water (formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 19% -49%,10 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow solid]-2- [1- [3- (trifluoromethyl) cyclobutyl ]]Pyrazol-4-yl]Quinoxaline (23.9 mg,48umol, 50%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.36(s,1H),8.82(s,1H),8.43(s,1H),8.02(d,J＝9.2Hz,1H),7.71(d,J＝8.8Hz,1H),7.46-7.37(m,2H),7.22-7.15(m,1H),5.04(t,J＝8.4Hz,1H),3.54-3.40(m,1H),3.25-3.07(m,2H),2.71(d,J＝8.4Hz,2H),2.68(s,3H)；m/z ES+[M+H] ⁺ 499.0。

Example 87.synthesis of 8-chloro-2- (1- (4, 4-difluoro-1-methylcyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- (4-fluoro-1-methylcyclohex-3-en-1-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.2- (8- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1, 4-dioxaspiro [4.5] decan-8-yl) acetic acid ethyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in acetonitrile (40 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (4 g,7.89 mmol) was added 2- (1, 4-dioxaspiro [ 4.5)]Decane-8-subunit) acetic acid ethyl ester(2.14 g,9.47 mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (1.44 g,9.47 mmol) and the mixture was stirred at 60℃for 30 hours. After completion, the mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL x 2). The organic layer was dried over sodium sulfate and concentrated in vacuo, and the residue was purified by column chromatography (100% ethyl acetate) to give 2- [8- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1, 4-dioxaspiro [4.5]]Decan-8-yl]Ethyl acetate (4.20 g,5.73mmol, 72%). M/zES + [ M+H ]] ⁺ 733.3。

Step 2.2- (8- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1, 4-dioxaspiro [4.5] decan-8-yl) acetaldehyde

To 2- [8- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in dichloromethane (100 mL) at-70deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1, 4-dioxaspiro [4.5]]Decan-8-yl]To a solution of ethyl acetate (1.5 g,2.05 mmol) was added dropwise diisobutylaluminum hydride (1M, 10.2 mL), and the mixture was stirred at-70℃for 2 hours. After completion, the mixture was slowly quenched with methanol (50 mL) at-70 ℃, then slowly warmed to 20 ℃, and stirred at 20 ℃ for 1 hour. The mixture was then filtered. The filtrate was dried and concentrated in vacuo to give 2- [8- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1, 4-dioxaspiro [4.5]]Decan-8-yl ]Acetaldehyde (1.40 g, crude), which was used directly in the next step. M/zES + [ M+H ]] ⁺ 689.1。

Step 3.8-chloro-2- (1- (8-methyl-1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [8- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in toluene (30 mL) under nitrogen]Oxy-quinoxaline-2-base group]Pyrazol-1-yl]-1, 4-dioxaspiro [4.5]]Decan-8-yl]Rh (PPh) was added to a solution of acetaldehyde (1.4 g,2.03 mmol) ₃ ) ₃ Cl (1.69 g,1.83 mmol) and the mixture was stirred at 120℃for 16 h. After completion, the mixture was concentrated in vacuo and the residue was purified by column chromatography (100% ethyl acetate) and then triturated with methanol (30 mL). The mixture was filtered and the filtrate concentrated in vacuo and the residue was purified by preparative HPLC [ column: phenomenex Synergi Max-RP 250 x 50mm x 10um; mobile phase: [ Water (formic acid) -acetonitrile]；(B％：37％-67％，21min]Purification to give 2- [ [6- [ 5-chloro-3- [1- (8-methyl-1, 4-dioxaspiro [4.5] as a yellow solid]Decan-8-yl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl ]Methoxy group]Ethyl-trimethyl-silane (610 mg,813 μmol, 40%). M/zES + [ M+H ]] ⁺ 661.3。

Step 4.4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -4-methylcyclohexanone

2- [ [6- [ 5-chloro-3- [1- (8-methyl-1, 4-dioxaspiro [4.5 ] in formic acid (5 mL) and dichloromethane (5 mL)]Decan-8-yl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (560 mg, 847. Mu. Mol) was stirred at 20℃for 16 hours. After completion, the mixture was washed with saturated aqueous sodium bicarbonate (40 mL) and extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by column chromatography (100% ethyl acetate) to give 4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-4-methyl-cyclohexanone (310 mg, 490. Mu. Mol, 57%). M/zES + [ M+H ]] ⁺ 617.3。

Step 5.8-chloro-2- (1- (4, 4-difluoro-1-methylcyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

At 0 ℃, the direction is at two4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in chloromethane (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of-4-methyl-cyclohexanone (150 mg, 243. Mu. Mol) was added dropwise diethylaminosulfur trifluoride (78.4 mg, 486. Mu. Mol), and the mixture was stirred at 35℃for 2 hours. After completion, the mixture was poured into saturated aqueous sodium bicarbonate (40 mL) and extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with brine (30 mL), dried and concentrated in vacuo, and the residue was purified by preparative TLC (100% ethyl acetate) to give 2- [ [6- [ 5-chloro-3- [1- (4, 4-difluoro-1-methyl-cyclohexyl) pyrazol-4-yl ] as a yellow solid]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (70 mg,98.4 μmol, 40%). M/zES + [ M+H ]] ⁺ 639.2。

Step 6.8-chloro-2- (1- (4, 4-difluoro-1-methylcyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- (4-fluoro-1-methylcyclohex-3-en-1-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

A solution of 2- [ [6- [ 5-chloro-3- [1- (4, 4-difluoro-1-methyl-cyclohexyl) pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane (160 mg,250 μmol) in trifluoroacetic acid (3 mL) was stirred at 20℃for 1 hour. After completion, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC [ column: phenomnex C18 75 x 30mm x 3um; mobile phase: [ water (formic acid) -acetonitrile ]; (B%: 32% -42%,7min ] purification to give 8-chloro-2- [1- (4, 4-difluoro-1-methyl-cyclohexyl) pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline (51.4 mg, 98.6. Mu. Mol, 39%) as a yellow solid and 8-chloro-2- [1- (4-fluoro-1-methyl-cyclohex-3-en-1-yl) pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline (23.4 mg, 47.8. Mu. Mol, 19%) as an off-white solid.

¹ H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.98(s,1H),8.39(s,1H),8.06(d,J＝9.2Hz,1H),7.78(d,J＝8.8Hz,1H),7.50-7.43(m,2H),7.25(dd,J＝2.4,8.8Hz,1H),2.74(s,3H),2.70-2.62(m,2H),2.15-2(m,4H),1.95-1.78(m,2H),1.55(s,3H)；m/z ES+[M+H] ⁺ 509.0。

¹ H NMR(400MHz,DMSO-d6)δ12.51-12.12(m,1H),9.36(s,1H),8.83(s,1H),8.38(s,1H),7.97(d,J＝9.1Hz,1H),7.52(d,J＝6.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.95(dd,J＝2.0,8.8Hz,1H),5.34-5.24(m,1H),3.07-2.96(m,1H),2.61-2.52(m,2H),2.50(s,3H),2.32-2.25(m,1H),2.20-2.07(m,2H),1.58(s,3H)；m/z ES+[M+H] ⁺ 489.0。

EXAMPLE 88 Synthesis of (1S, 3 s) -3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol and (1R, 3 r) -3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

Step 1.3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

To 3- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in anhydrous tetrahydrofuran (3 mL) at 0deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (110 mg, 185. Mu. Mol) was added methyl magnesium bromide (3M in THF, 185. Mu.L). The mixture was stirred at 0 ℃ for 2 hours. After completion, the mixture was quenched with saturated ammonium chloride (20 mL) at 0 ℃, then diluted with water (20 mL), and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/4) to give 3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol (170 mg,240 μmol, 65%). M/zES + [ M+H ]] ⁺ 609.3。

Step 2.3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

3- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1-methyl-cyclobutanol (140 mg, 198. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 19% -49%,10 min) purification to give 3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol (70.0 mg,146 μmol, 74%). M/zES + [ M+H ]] ⁺ 479.1。

(1S, 3 s) -3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol and (1R, 3 r) -3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol (70.0 mg, 146. Mu. Mol) was isolated by SFC (basic conditions; column: daicel Chiralpak AD (250 mm. Mu. 30mm,10 um), mobile phase: [0.1% ammonium hydroxide/methanol ]; (B%: 45% -45%,3.6min, total run for 50 min) to give (1S, 3 s) -3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol (44.5 mg, 92.9. Mu. Mol), 64%) and (1R, 3 r) -3- (4- (8-chloro-7-methyl-7-imidazol-6-yl) oxy) quinoxalin-2-yl) quinoxalin-1H-pyrazol-1-yl) as white solids (1R, 3 s) -3- (8-chloro-7-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) as white solids.

¹ H NMR(400MHz,DMSO-d6)δppm＝9.31(s,1H),8.76(s,1H),8.38(s,1H),7.93(d,J＝9.3Hz,1H),7.33(d,J＝7.9Hz,1H),7.22(d,J＝8.9Hz,1H),7.09(t,J＝7.7Hz,1H),5.32(s,1H),4.65(t,J＝8.2Hz,1H),2.65-2.54(m,4H),2.53(s,3H),1.35(s,3H).m/z ES+[M+H] ⁺ 478.9。

¹ H NMR(400MHz,DMSO-d6)δppm＝9.30(s,1H),8.80(s,1H),8.37(s,1H),7.94(d,J＝9.2Hz,1H),7.32(d,J＝8.6Hz,1H),7.21(d,J＝9.0Hz,1H),7.10(t,J＝7.4Hz,1H),5.13(s,1H),5.11-5.04(m,1H),2.53(s,7H),1.36(s,3H).m/z ES+[M+H] ⁺ 478.9。

EXAMPLE 89 Synthesis of (1S, 3 s) -3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol and (1R, 3 r) -3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol

Step 1.8-chloro-2- (1- ((3, 3-dimethoxycyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (5 mL)]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (270 mg, 514. Mu. Mol) and (3, 3-dimethoxycyclobutyl) methyl methanesulfonate (138 mg, 617. Mu. Mol) were added potassium carbonate (142 mg,1.03 mmol) and potassium iodide (85.4 mg, 514. Mu. Mol). The mixture was stirred at 100℃for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 0/1) to give 8-chloro-2- (1- ((3, 3-dimethoxycyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) quinoxaline (280 mg,416 μmol, 81%). M/zES + [ M+H ]] ⁺ 653.3。

Step 2.3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanone

2- [ [6- [ 5-chloro-3- [1- [ (3, 3-dimethoxycyclobutyl) methyl ] in dichloromethane (2.5 mL) and formic acid (2.5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (260 mg, 398. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1 to 0/1) to give 3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl cyclobutanone (230 mg,364 μmol, 91%). M/zES + [ M+H ]] ⁺ 607.3。

Step 3.3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol

To 3- [ [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in anhydrous tetrahydrofuran (5 mL) at 0deg.C ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of cyclobutanone (210 mg, 346. Mu. Mol) was added methylmagnesium bromide (3M in THF, 346. Mu.L). The mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) at 0 ℃, then diluted with water (20 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=20:1) to give 3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxaline-2-Phenyl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol (65.0 mg, 83.4. Mu. Mol, 24%). M/zES + [ M+H ]] ⁺ 623.3。

Step 4.3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol

3- [ [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of 1-methyl-cyclobutanol (65.0 mg, 83.4. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 21% -51%,10 min) purification to give 3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ]) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -1-methylcyclobutanol (30.0 mg,59.0 μmol, 71%). M/zES + [ M+H ]] ⁺ 493.2。

(1S, 3 s) -3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol and (1R, 3 r) -3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol

3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol (30.0. Mu. Mol) was isolated by SFC (column: daicel Chiralpak IE (250 mm. Mu. 30mm, 10. Mu.); mobile phase: [ hexane-EtOH (0.1% ammonium hydroxide) ], (B%: 55% -55%,15 min) to give (1S, 3 s) -3- ((4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol (5.4 mg, 11.0. Mu. Mol) and (1R, 3 r) -3- ((4- (8-chloro-7-methyl-6-yl) oxy) quinoxalin-2-yl) quinoxalin-1H-pyrazol-1-yl) methyl) -1-methylcyclobutanol as an off-white solid (5.4 mg, 18%) and (1R, 3 r) -3- ((8-chloro-7-methyl-6-methyl-1-yl) quinoxalin-2-yl) methyl ] quinoxalin-1-yl) as brown solid, 84%).

¹ H NMR(400MHz,CD ₃ OD)δppm＝9.13(s,1H),8.55(s,1H),8.33(s,1H),7.86(d,J＝9.2Hz,1H),7.33(d,J＝8.4Hz,1H),7.23(d,J＝9.2Hz,1H),7.09(dd,J＝7.2,8.6Hz,1H),4.31(d,J＝7.2Hz,2H),3.02-2.93(m,1H),2.60(s,3H),2.23-2.16(m,2H),2.03-1.96(m,2H),1.34(s,3H).m/z ES+[M+H] ⁺ 492.9。

¹ H NMR(400MHz,CD ₃ OD)δppm＝9.13(s,1H),8.55(s,1H),8.33(s,1H),7.86(d,J＝9.3Hz,1H),7.33(d,J＝8.6Hz,1H),7.23(d,J＝9.3Hz,1H),7.09(dd,J＝7.3,8.5Hz,1H),4.31(d,J＝7.6Hz,2H),3.02-2.93(m,1H),2.60(s,3H),2.23-2.16(m,2H),2.03-1.96(m,2H),1.34(s,3H).m/z ES+[M+H] ⁺ 492.9。

EXAMPLE 90 Synthesis of 2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3, 3-difluoropyrrolidin-1-yl) ethanone

Step 1.2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) acetic acid

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in anhydrous tetrahydrofuran (6 mL)]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (130 mg, 248. Mu. Mol) was added sodium hydride (29.7 mg,743umol,60% in mineral oil). The mixture was stirred at 25℃for 0.5 h. 2-Bromoacetic acid (51.6 mg, 371. Mu. Mol, 26.7. Mu.L) was then added. The mixture was stirred at 60℃for 1 hour. After completion, the mixture was quenched with water (2 mL) at 25 ℃ and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and then acidified by saturated aqueous citric acid until pH about 6. The mixture was then filtered and the filter cake was collected to give 2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl acetic acid (140 mg, crude product). ¹ HNMR(400MHz,DMSO-d6)δ9.34(s,1H),8.70(s,1H),8.38(s,1H),7.95(d,J＝8.8Hz,1H),7.57-7.43(m,1H),7.31-7.12(m,2H),5.63(d,J＝10.4Hz,2H),5.05(s,2H),3.60-3.56(m,2H),2.61(d,J＝7.2Hz,3H),0.91-0.82(m,2H),0.07(s,9H)；m/z ES+[M+H] ⁺ 583.2。

Step 2.2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3, 3-difluoropyrrolidin-1-yl) ethanone

To 2- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Diisopropylethylamine (86.5 mg, 669. Mu. Mol, 117. Mu.L) was added to a solution of acetic acid (130 mg, 223. Mu. Mol) and 3, 3-difluoropyrrolidine hydrochloride (48.0 mg, 334. Mu. Mol). EDCI (64.1 mg, 334. Mu. Mol) and HOBt (45.2 mg, 334. Mu. Mol) were then added. The mixture was stirred at 25℃for 12 hours. After completion, the mixture was poured into water (20 mL) and extracted with dichloromethane (15 ml×3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3, 3-difluoropyrrolidin-1-yl) ethanone (160 mg, crude). M/zES + [ M+H ]] ⁺ 672.4。

Step 3.2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3, 3-difluoropyrrolidin-1-yl) ethanone

2- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1- (3, 3-difluoropyrrolidin-1-yl) ethanone (150 mg, 223. Mu. Mol) was stirred at 25℃for 0.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 20% -50%,10 min) purification to give 2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) Oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3, 3-difluoropyrrolidin-1-yl) ethanone (33.8 mg,62.3 μmol, 28%). ¹ H NMR(400MHz,DMSO-d6):δppm＝9.33(s,1H),8.65(d,J＝4.4Hz,1H),8.39(s,1H),7.95(d,J＝9.2Hz,1H),7.34(d,J＝8.8Hz,1H),7.23(d,J＝9.2Hz,1H),7.10(t,J＝8.0Hz,1H),5.31-5.21(m,2H),4.10(t,J＝13.2Hz,1H),3.89-3.77(m,2H),3.63-3.59(m,1H),2.63-2.55(m,1H),2.53(s,3H),2.45(d,J＝7.6Hz,1H)；m/z ES+[M+H] ⁺ 542.0。

EXAMPLE 91.1 Synthesis of- ((4- (8- (cyclopent-1-en-1-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclopropane

Step 1.8- (cyclopent-1-en-1-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) methyl) -1H-pyrazol-4-yl) quinoxaline

8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in water (0.4 mL) and cyclopentylmethyl ether (2 mL) ]Imidazol-6-yl) oxy) -2- (1- ((1- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) methyl) -1H-pyrazol-4-yl) quinoxaline (150 mg, 227. Mu. Mol), 2- (cyclopent-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (88.1 mg, 454. Mu. Mol), [2- (2-aminophenyl) phenyl)]Palladium (1+); bis (1-adamantyl) -butyl-phosphane; a mixture of methanesulfonate (16.5 mg, 22.7. Mu. Mol), cesium carbonate (222 mg, 681. Mu. Mol) was degassed and purged 3 times with nitrogen, and the mixture was then stirred under a nitrogen atmosphere at 80℃for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether: ethyl acetate=1:3) to give 8- (cyclopent-1-en-1-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) -2- (1- ((1- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) methyl) -1H-pyrazol-4-yl) quinoxaline (120 mg, 173. Mu. Mol, 76%)。m/zES+[M+H] ⁺ 693.4。

Step 2.1- ((4- (8- (cyclopent-1-en-1-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclopropane

8- (cyclopent-1-en-1-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (0.5 mL) ]The solution of imidazol-6-yl) oxy) -2- (1- ((1- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) methyl) -1H-pyrazol-4-yl) quinoxaline (120 mg,173 μmol) was stirred at 25 ℃ for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 14% -44%,10 min) purification to give 1- ((4- (8- (cyclopent-1-en-1-yl) -7- ((2-methyl-1H-benzo [ d)) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl cyclopropane (44.3 mg,90.8 μmol, 52%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.26(s,1H),8.57(s,1H),8.23(s,1H),7.92(d,J＝9.2Hz,1H),7.55(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.13(d,J＝2.0Hz,1H),6.96(dd,J＝2.4,8.8Hz,1H),6.04(t,J＝2.0Hz,1H),5.72-5.50(m,1H),4.28(s,2H),2.86(dt,J＝2.0,7.4Hz,2H),2.57(s,3H),2.55-2.51(m,2H),1.96(q,J＝7.6Hz,2H),0.78-0.74(m,2H),0.72-0.68(m,2H)；m/z ES+[M+H] ⁺ 479.0。

Example 92.8 Synthesis of chloro-2- (1- ((4, 4-difluorocyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

(4, 4-Difluorocyclohexyl) methyl methanesulfonate

To a solution of (4, 4-difluorocyclohexyl) methanol (300 mg,2 mmol) and triethylamine (436 mg,4.31 mmol) in dichloromethane (5 mL) at 0 ℃ was added methanesulfonyl chloride (298 mg,2.58 mmol), and the mixture was stirred at 0 ℃ for 1 hour. The mixture was quenched with water (5 mL) and extracted with dichloromethane (8 mL. Times.3)The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give (4, 4-difluorocyclohexyl) methyl methanesulfonate (490 mg, crude) as a pale red solid. ¹ H NMR(400MHz,CDCl ₃ )δ＝4.09(d,J＝6.0Hz,2H),3.05-3.01(m,3H),2.22-2.08(m,2H),1.93-1.84(m,3H),1.80-1.65(m,2H),1.45-1.36(m,2H)。

Step 2.8-chloro-2- (1- ((4, 4-difluorocyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To (4, 4-difluorocyclohexyl) methyl methanesulfonate (100 mg,438 umol) and 2- [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (6 mL)]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (230 mg,438 mmole) was added potassium carbonate (180 mg,1.30 mmole). The mixture was stirred at 80℃for 3 hours. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (25 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 2- [ [6- [ 5-chloro-3- [1- [ (4, 4-difluorocyclohexyl) methyl ] as a yellow oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (310 mg, crude). M/zES + [ M+H ]] ⁺ 657.3。

Step 3.8-chloro-2- (1- ((4, 4-difluorocyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-chloro-3- [1- [ (4, 4-difluorocyclohexyl) methyl ] in trifluoroacetic acid (3 mL) ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (300 mg, 458 umol) was stirred at 25℃for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25.mu.m.150.mu.m; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 35% -65%,10 min) purification to give 8-chloro-2- [1- [ (4, 4-difluorocyclohexyl) methyl ] as a yellow solid]Pyrazol-4-yl]-7- [ (4-fluoro-2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (206 mg,390umol, 85%). ¹ H NMR(400MHz,CD ₃ OD)δ9.20(s,1H),8.59(s,1H),8.37(s,1H),7.95(d,J＝9.2Hz,1H),7.55-7.51(m,1H),7.38(d,J＝9.2Hz,1H),7.35-7.28(m,1H),4.20(d,J＝7.2Hz,2H),2.83(s,3H),2.87-2.80(m,1H),2.14-2.03(m,3H),1.92-1.79(m,2H),1.77-1.73(m,2H),1.46-1.36(m,2H)；m/z ES+[M+H] ⁺ 526.9。

EXAMPLE 93 Synthesis of (1R, 3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol and (1S, 3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (50 mL) ]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (3.50 g,6.90 mmol) and 2-bromo-5, 8-dioxaspiro [3.4 ]]To a solution of octane (2.13 g,11.0 mmol) was added potassium carbonate (2.86 g,20.7 mmol) and potassium iodide (115 mg, 690. Mu. Mol). The mixture was stirred at 100℃for 12 hours. After completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with brine (25 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=100:1 to 10:1) to give 2- (1- (5, 8-dioxaspiro [ 3.4) as a yellow solid]Oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (3.5 g,5.43mmol, 79%). M/zES + [ M+H ]] ⁺ 619.1。

Step 2.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanone

To 2- [ [6- [ 5-chloro-3- [1- (5, 8-dioxaspiro [3.4 ]) in dichloromethane (18 mL) and water (1 mL)]Oct-2-yl) pyrazol-4-yl ]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (3.5 g,5.65 mmol) was added formic acid (42.7 g,928mmol,35 mL). The mixture was stirred at 40℃for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 ml) and then basified with saturated aqueous sodium bicarbonate until ph=8-9. The mixture was extracted with ethyl acetate (100 mL. Times.2). The combined organic layers were washed with brine (50 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane: methanol=100:1 to 50:1) to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl cyclobutanone (2.5 g,4.26mmol, 75%). M/zES + [ M+H ]] ⁺ 575.3。

Step 3.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in anhydrous tetrahydrofuran (3 mL) at 0deg.C ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (300 mg, 522. Mu. Mol) was added methylmagnesium bromide (3M in THF, 522. Mu.L). The mixture was then stirred at 0 ℃ for 2 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) at 0 ℃, diluted with water (50 mL), and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with brine (25 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=80:1 to 50:1) to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol (750)mg，1.27mmol，49％)。m/zES+[M+H] ⁺ 591.2。

Step 4.3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (7.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A mixture of 1-methyl-cyclobutanol (750 mg,1.27 mmol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was then subjected to preparative HPLC (formic acid conditions; column: phenomenex Luna C, 150X 25mm X10 um; mobile phase: [ water (formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,10 min) purification to give 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-1-methyl-cyclobutanol (470 mg,1.02mmol, 80%). M/zES + [ M+H ]] ⁺ 461.1。

(1R, 3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol and (1S, 3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol

3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -1-methyl-cyclobutanol (470 mg,1.02 mmol) was isolated by SFC (basic conditions, column: daicel Chiralpak IG (250 mm. Times.30 mm, 10 um); mobile phase: [ heptane-ethanol (0.1% ammonium hydroxide) ]; (B%: 40% -40%,15 min) to give (1R, 3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-methylcyclobutanol (330 mg, 715. Mu. Mol, 70%) as a white solid and (1S, 3 s) -3- [4- [ 8-chloro-7- [ (2-methyl-3H-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -1-methyl-cyclobutanol (28.0 mg,5 mg) as a white solid.

¹ H NMR(400MHz,DMSO-d6):δppm 12.57-12.07(m,1H),9.31(s,1H),8.76(s,1H),8.38(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝2.4Hz,1H),6.94(dd,J＝2.0,8.4Hz,1H),5.32(s,1H),4.65(t,J＝8.4Hz,1H),2.64-2.54(m,4H),2.49(s,3H),1.35(s,3H)；m/z ES+[M+H] ⁺ 461.0。

¹ H NMR(400MHz,DMSO-d6):δppmδ＝12.71-12.10(m,1H),9.31(s,1H),8.80(s,1H),8.37(s,1H),7.95(d,J＝9.6Hz,1H),7.51(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝2.4,8.8Hz,1H),5.12(s,1H),5.11-5.03(m,1H),2.58-2.52(m,4H),2.49-2.48(m,3H),1.36(s,3H).m/zES+[M+H] ⁺ 461.0。

Example 94.Synthesis of 2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -8- (2, 5-dihydrofuran-3-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.5-bromo-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol

To 3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in chloroform (15 mL)]Pyrazol-4-yl]To a solution of quinoxalin-6-ol (900 mg,2.85 mmol) were added N-bromosuccinimide (1.01 g,5.69 mmol), triethylamine (288 mg,2.85 mmol) and nickel (II) chloride (369 mg,2.85 mmol). The mixture was stirred at 60℃for 2 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to give 5-bromo-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-ol (1.6 g, crude) as a yellow solid. M/zES + [ M+H ]] ⁺ 397.1。

Step 2N- [5- [ 5-bromo-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-nitro-phenyl ] -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

To 5-bromo-3- [1- [ (3, 3-difluorocyclobutyl) methyl in N, N-dimethylformamide (20 mL)]Pyrazol-4-yl]To a solution of quinoxalin-6-ol (1.25 g,3.16 mmol) were added potassium carbonate (874 mg,6.33 mmol) and tert-butyl N-tert-butoxycarbonyl-N- (5-fluoro-2-nitro-phenyl) carbamate (1.69 g,4.74 mmol). The mixture is mixed Stirred at 80℃for 12 hours. After completion, the reaction mixture was diluted with water (100 mL), and then extracted with ethyl acetate (100 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 5/1) to give N- [5- [ 5-bromo-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a brown oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-nitro-phenyl]-tert-butyl N-tert-butoxycarbonyl-carbamate (2.4 g,2.62mmol, 83%). M/zES + [ M+H ]] ⁺ 732.9。

Step 3.5- ((5-bromo-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) oxy) -2-nitroaniline

To N- [5- [ 5-bromo-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in dichloromethane (15 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-nitro-phenyl]To a solution of tert-butyl N-tert-butoxycarbonyl-carbamate (2.2 g,3.01 mmol) was added trifluoroacetic acid (5 mL). The mixture was stirred at 20℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to give 5- ((5-bromo-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy) -2-nitroaniline (1.1 g,1.86mmol, 62%) as a yellow solid. M/zES + [ M+H ] ] ⁺ 533.0。

Step 4.4- ((5-bromo-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) oxy) benzene-1, 2-diamine

To 5- [ 5-bromo-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in ethanol (20 mL) and water (2 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]To a solution of oxy-2-nitro-aniline (1 g,1.88 mmol) was added iron powder (526 mg,9.41 mmol) and ammonium chloride (1.01 g,18.8 mmol). The mixture was stirred at 60℃for 2 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4- ((5-bromo-3- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) quinoxalin-6-yl) oxy as a yellow solid) Benzene-1, 2-diamine (1 g, crude). M/zES + [ M+18 ]] ⁺ 502.8。

Step 5.8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-5-yl) oxy) quinoxaline

To 4- [ 5-bromo-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in methanol (20 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]To a solution of oxybenzene-1, 2-diamine (1 g,1.99 mmol) was added sulfamic acid (387 mg,3.99 mmol) and 1, 1-trimethoxyethane (1.20 g,9.97 mmol). The mixture was stirred at 20℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/methanol=1/0 to 4/1) to give 8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a red solid ]Imidazol-5-yl) oxy) quinoxaline (800 mg,1.43mmol, 72%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.31(s,1H),8.76(s,1H),8.37(s,1H),8.06(d,J＝9.2Hz,1H),7.73(d,J＝8.8Hz,1H),7.45-7.36(m,2H),7.25(s,1H),7.12(s,1H),7(s,1H),4.39(d,J＝6.0Hz,2H),2.70(s,2H),2.69(s,3H),2.66(s,1H),2.55(s,1H)；m/z ES+[M+18] ⁺ 524.9。

Step 6.8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-5-yl) oxy) quinoxaline

To 8-bromo-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] in anhydrous tetrahydrofuran (10 mL)]Pyrazol-4-yl]-7- [ (2-methyl-1H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (560 mg,1.07 mmol) was added sodium hydride (85.3 mg,2.13mmol,60% in mineral oil). The mixture was stirred at 0℃for 0.5 h. (2- (chloromethoxy) ethyl) trimethylsilane (355 mg,2.13 mmol) was then added dropwise and the resulting mixture was stirred at 20℃for 2 hours. After completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/methanol=1/0 to 5/1) to give 8-bromo-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2) as a yellow solid-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] ]Imidazol-5-yl) oxy) quinoxaline (170 mg,246 μmol, 23%). ¹ H NMR(400MHz,CD ₃ OD)δ9.14(d,J＝3.2Hz,1H),8.60(s,1H),8.37(s,1H),7.95(dd,J＝4.4,9.2Hz,1H),7.63(dd,J＝6.8,8.8Hz,1H),7.40-7.23(m,2H),7.13-7.04(m,1H),5.69-5.44(m,2H),4.40(d,J＝7.2Hz,2H),3.70-3.51(m,2H),2.73(dd,J＝8.0,12.4Hz,3H),2.65(d,J＝6.0Hz,3H),2.55-2.44(m,2H),0.97-0.74(m,2H),-0.04--0.14(m,9H)；m/z ES+[M+H] ⁺ 657.0。

Step 7.2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -5- (2, 5-dihydrofuran-3-yl) quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [5- [ 5-bromo-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in dioxane (1 mL) and water (0.2 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (50.0 mg,76.3 umol) was added 2- (2, 5-dihydrofuran-3-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (44.9 mg,229 umol), methanesulfonyl (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (6.5 mg,7.63 umol) and potassium carbonate (31.6 mg,229 umol). The mixture was stirred under nitrogen at 100 ℃ for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate: methanol=20:1) to give 2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]-5- (2, 5-dihydrofuran-3-yl) quinoxalin-6-yl]Oxy-2-methylbenzimidazol-1-yl ]Methoxy group]Ethyl-trimethyl-silane (50.0 mg,69.8 mol, 92%). M/zES + [ M+H ]] ⁺ 645.1。

Step 8.2- (1- ((3, 3-Difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -8- (2, 5-dihydrofuran-3-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in trifluoroacetic acid (0.5 mL)]Pyrazol-4-yl]-5- (2, 5-dihydrofuran-3-yl) quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Dissolution of ethyl-trimethyl-silane (30 mg, 46.5. Mu. Mol)The solution was stirred at 20℃for 0.5 h. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25.mu.m.150.mu.m; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 16% -46%,10 min) purification to give 2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -8- (2, 5-dihydrofuran-3-yl) -7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (8.8 mg,17.1 μmol, 36.7%). ¹ H NMR(400MHz,CDCl ₃ )δ9.07-8.97(m,1H),8.23-8.10(m,2H),7.95-7.85(m,1H),7.59(d,J＝8.8Hz,1H),7.29(d,J＝9.2Hz,1H),7.19(d,J＝2.0Hz,1H),7.07-6.98(m,1H),6.65(t,J＝2.0Hz,1H),5.43-5.24(m,2H),4.97-4.82(m,2H),4.35(d,J＝6.8Hz,2H),2.86-2.76(m,3H),2.73(s,3H),2.54-2.39(m,2H)；m/z ES+[M+H] ⁺ 515.0。

Example 95.3 Synthesis of 3- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) propan-2-yl) cyclobutanol and 3- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) propan-2-yl) cyclobutan-1-one and 8-chloro-2- (1- (2- (3, 3-difluorocyclobutyl) propan-2-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin

Step 1.3- (benzyloxy) -N-methoxy-N-methylcyclobutane carboxamide

To a solution of 3-benzyloxycyclobutane carboxylic acid (5 g,24.2 mmol) and N-methoxymethylamine (3.55 g,36.3mmol, HCl salt) in N, N-dimethylformamide (50 mL) was added N, N-diisopropylacetylene amine (12.5 g,96.9 mmol) and HATU (13.8 g,36.3 mmol). The mixture was stirred at 25℃for 12 hours. After completion, the reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (250 mL). The organic phase was separated, then washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=100/1 to 1/1) to give a solid3-benzyloxy-N-methoxy-N-methyl-cyclobutanecarboxamide (5 g,19.0mmol, 78%) as a coloured oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.27(s,5H),4.48-4.40(m,2H),4.06-3.95(m,1H),3.70-3.60(m,3H),3.23-3.14(m,3H),3.05-2.85(m,1H),2.49-2.38(m,2H),2.35-2.24(m,2H)；m/z ES+[M+H] ⁺ 250.1。

Step 2.1- (3- (benzyloxy) cyclobutyl) ethanone

To a solution of 3-benzyloxy-N-methoxy-N-methyl-cyclobutanecarboxamide (5 g,20.0 mmol) in tetrahydrofuran (25 mL) was added methyl magnesium bromide (1M, 26mL,26 mmol). The mixture was stirred at 0 ℃ for 2 hours under nitrogen atmosphere. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) at 0 ℃ and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1- (3-benzyloxycyclobutyl) ethanone (4 g,17.6mmol, 88%) as a brown oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.38-7.27(m,5H),4.49-4.39(m,2H),4.04-3.94(m,1H),2.73(dd,J＝8.0,9.6Hz,1H),2.53-2.40(m,2H),2.30-2.14(m,2H),2.11(s,3H)。

(E) -3- (3- (benzyloxy) cyclobutyl) but-2-enoic acid ethyl ester

To a solution of ethyl 2-diethoxyphosphorylacetate (4.74 g,21.1 mmol) in tetrahydrofuran (36 mL) was added sodium hydride (845 mg,21.1mmol,60% in mineral oil) and the mixture was stirred at 0deg.C for 0.5 hr. 1- (3-Benzyloxycyclobutyl) ethanone (3.60 g,17.6 mmol) was then added. The mixture was stirred at 25 ℃ for 11.5 hours under nitrogen atmosphere. After completion, the reaction mixture was quenched with water (50 mL) at 0 ℃ and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=100/1 to 3/1) to give ethyl (E) -3- (3-benzyloxycyclobutyl) but-2-enoate (4.30 g,15.3mmol, 87%) as a brown oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.42-7.28(m,5H),5.74-5.56(m,1H),4.43(s,2H),4.23-4.08(m,2H),4.02-3.87(m,1H),2.58-2.40(m,2H),2.36-2.19(m,1H),2.15-2.07(m,3H),1.99-1.83(m,2H),1.35-1.23(m,3H)；m/z ES+[M+H] ⁺ 275.1。

Step 4.3- (3- (benzyloxy) cyclobutyl) -3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) butanoic acid ethyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in acetonitrile (20 mL) ]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (2 g,3.94 mmol) was added 1, 8-diazabicyclo [5.4.0]Undec-7-ene (720 mg,4.73 mmol) and ethyl (E) -3- (3-benzyloxycyclobutyl) but-2-enoate (1.30 g,4.73 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=100/1 to 0/1) to give 3- (3-benzyloxycyclobutyl) -3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl butyrate (1.70 g,2.15mmol, 54%). M/zES + [ M+H ]] ⁺ 781.5。

Step 5.3- (3- (benzyloxy) cyclobutyl) -3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) butanal

To 3- (3-benzyloxycyclobutyl) -3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (75 mL) at-70deg.C ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of ethyl butyrate (1.50 g,1.92 mmol) was added dropwise diisobutylaluminum hydride (1M, 9.6mL,9.6 mmol). The mixture was stirred at-70 ℃ for 1 hour under nitrogen atmosphere. After completion, the reaction mixture was slowly quenched with methanol (5 mL) at-70 ℃ and then warmed to 25 ℃. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 3- (3-benzyloxycyclobutane as a yellow solidPhenyl) -3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Butyraldehyde (1.40 g,1.54mmol, 80%). M/zES + [ M+H ]] ⁺ 739.3。

Step 6.2- (1- (2- (3- (benzyloxy) cyclobutyl) propan-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 3- (3-benzyloxycyclobutyl) -3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in toluene (14 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Rh (PPh) was added to a solution of butyraldehyde (1.40 g,1.90 mmol) ₃ ) ₃ Cl (1.76 g,1.90 mmol). The mixture was stirred at 120 ℃ for 12 hours under nitrogen atmosphere. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=100/1 to 0/1) and reverse phase HPLC (0.1% formic acid conditions) to give 2- [ [6- [3- [1- [1- (3-benzyloxycyclobutyl) -1-methyl-ethyl ] as a white solid ]Pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (320 mg, 365. Mu. Mol, 19%). M/zES + [ M+H ]] ⁺ 709.3。

Step 7.3- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) propan-2-yl) cyclobutanol

At 0deg.C, to 2- [ [6- [3- [1- [1- (3-benzyloxycyclobutyl) -1-methyl-ethyl ] in dichloromethane (3 mL)]Pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (300 mg, 422. Mu. Mol) was added tribromoborane (317 mg,1.27 mmol). The mixture was stirred at 0 ℃ for 0.5 hours under nitrogen atmosphere. After completion, the reaction mixture was quenched with water (5 mL) at 0 ℃ and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: phenomenex Synergi C18:150×25mm×10um; mobile phase: [ water (formic acid) -acetonitrile)]；(B％：9％-39％10 min) to give 3- [1- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl ]-1-methyl-ethyl]Cyclobutanol (130 mg, 263. Mu. Mol, 62%). ¹ H NMR(400MHz,DMSO-d6)δ12.91-11.57(m,1H),9.38(s,1H),8.88-8.71(m,1H),8.34(s,1H),7.96(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.96(dd,J＝2.4,8.8Hz,1H),5.32-4.58(m,1H),3.84(q,J＝7.2Hz,1H),2.50(s,3H),2.29-2.05(m,3H),1.68-1.47(m,8H)；m/z ES+[M+H] ⁺ 489.0。

Step 8.3- (2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) propan-2-yl) cyclobutanone

To 3- [1- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in dichloromethane (1 mL) and N, N-dimethylformamide (0.1 mL) at 0deg.C]Quinoxalin-2-yl]Pyrazol-1-yl]-1-methyl-ethyl]To a solution of cyclobutanol (95.0 mg, 194. Mu. Mol) was added dess-Martin higher iodide (123 mg, 291. Mu. Mol). The mixture was stirred at 25 ℃ for 12 hours under nitrogen atmosphere. After completion, the reaction mixture was quenched with saturated aqueous sodium thiosulfate (10 mL) and saturated aqueous sodium bicarbonate (10 mL) at 0 ℃, then diluted with water (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: phenomenex Synergi C18:150×25mm×10um; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 11% -41%,10 min) purification to give 3- [1- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid ]Quinoxalin-2-yl]Pyrazol-1-yl]-1-methyl-ethyl]Cyclobutanone (70.0 mg, 143. Mu. Mol, 73%). ¹ H NMR(400MHz,DMSO-d6)δ12.97-11.54(m,1H),9.35(s,1H),8.86(s,1H),8.36(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝2.4,8.8Hz,1H),3.03(s,5H),2.48(s,3H),1.69(s,6H)；m/z ES+[M+H] ⁺ 487.0。

Step 9.8-chloro-2- (1- (2- (3, 3-difluorocyclobutyl) propan-2-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 3- [1- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in dichloromethane (1 mL) at 0deg.C]Quinoxalin-2-yl]Pyrazol-1-yl]-1-methyl-ethyl]To a solution of cyclobutanone (40.0 mg, 82.1. Mu. Mol) was added bis (2-methoxyethyl) aminothiotrifluoride (181 mg, 821. Mu. Mol). The mixture was stirred at 0 ℃ for 0.1 hour under nitrogen atmosphere. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) at 0 ℃, then diluted with water (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: phenomenex Synergi C18:150×25mm×10um; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 25% -45%,10 min) purification to give 8-chloro-2- [1- [1- (3, 3-difluorocyclobutyl) -1-methyl-ethyl ] as a white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ]Quinoxaline (26.5 mg, 51.6. Mu. Mol, 62%). ¹ H NMR(400MHz,DMSO-d6)δ12.72-11.88(m,1H),9.38(s,1H),8.85(s,1H),8.38(s,1H),7.97(d,J＝9.2Hz,1H),7.52(d,J＝7.6Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.95(dd,J＝2.0,8.4Hz,1H),2.83-2.66(m,1H),2.61-2.54(m,4H),2.50(s,3H),1.65(s,6H)；m/z ES+[M+H] ⁺ 508.9。

EXAMPLE 96.Synthesis of 3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanone

Step 1.3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanone

3- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A mixture of cyclobutanone (30.0 mg, 51.0. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC(formic acid conditions; column: phenomenex Luna C, 150X 25mm X10 um; mobile phase: [ Water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 19% -49%,10 min) purification to give 3- [4- [ 8-chloro-7- [ (4-fluoro-2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutanone (15.3 mg,32.7 μmol, 65%). ¹ HNMR(400MHz,DMSO-d ₆ )δ＝9.33(s,1H),8.96(s,1H),8.46(s,1H),7.95(d,J＝9.2Hz,1H),7.34(d,J＝8.8Hz,1H),7.24(d,J＝9.2Hz,1H),7.09(t,J＝8.0Hz,1H),5.44-5.29(m,1H),3.70-3.64(m,4H),2.53(s,3H)；m/z ES+[M+H] ⁺ 462.9。

EXAMPLE 97 Synthesis of (1S, 3 s) -3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol

Step 1.3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol

To 3- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in ethanol (3 mL) at 0deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (300 mg, 506. Mu. Mol) was added sodium borohydride (19 mg, 506. Mu. Mmol). The mixture was stirred at 0℃for 0.5 h. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) at 0 ℃ and extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with brine (25 ml×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=20:1) to give 3- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a white solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutylalcohol (200 mg, 333. Mu. Mol, 66%). ¹ HNMR(400MHz,DMSO-d6)δ＝9.34-9.32(m,1H),8.78(s,1H),8.38(s,1H),7.97-7.92(m,1H),7.54(d,J＝8.8Hz,1H),7.25-7.19(m,2H),5.65(s,2H),5.35(d,J＝6.8Hz,1H),4.56-4.45(m,1H),3.70-3.64(m,1H),3.56(t,J＝8.0Hz,2H),2.84-2.76(m,2H),2.62(s,3H),2.47-2.39(m,2H),0.86(t,J＝7.6Hz,2H),-0.07(s,9H)；m/z ES+[M+H] ⁺ 595.2。

(1S, 3 s) -3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol

3- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (2 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutanol (200 mg,340 mu mol) was stirred at 25 ℃ for 0.5 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C, 150X 25mm X10 um; mobile phase: [ water (formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 16% -46%,10 min) purification to give (1S, 3 s) -3- [4- [ 8-chloro-7- [ (4-fluoro-2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutanol (84.5 mg,0.18mmol, 54%). ¹ H NMR(400MHz,DMSO-d6)δ12.98-12.05(m,1H),9.32(s,1H),8.77(s,1H),8.38(s,1H),7.94(d,J＝9.2Hz,1H),7.31(s,1H),7.21(d,J＝9.2Hz,1H),7.10(s,1H),5.36(d,J＝6.8Hz,1H),4.57-4.45(m,1H),4.08-3.95(m,1H),2.86-2.74(m,2H),2.53(s,3H),2.46-2.39(m,2H)；m/z ES+[M+H] ⁺ 464.9。

EXAMPLE 98 Synthesis of 8-chloro-2- (1- (1- (3, 3-difluorocyclobutyl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.1- (3, 3-Difluorocyclobutyl) ethylmethanesulfonate

N, N-diisopropylacetylene amine (111 mg,1.10 mmol) and methanesulfonyl chloride (100 mg, 881. Mu. Mol) were added to a solution of 1- (3, 3-difluorocyclobutyl) ethanol (100 mg, 734. Mu. Mol) in dichloromethane (1 mL) at 0deg.C. The mixture was stirred at 25℃for 0.5 h. After completion, the reaction mixture was quenched with water (10 mL) at 0 ℃ and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1- (3, 3-difluorocyclobutyl) ethylmethanesulfonate (157 mg, crude) as a brown oil, which was used directly in the next step.

Step 2.8-chloro-2- (1- (1- (3, 3-difluorocyclobutyl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 394. Mu. Mol) and 1- (3, 3-difluorocyclobutyl) ethyl methanesulfonate (118 mg, 552. Mu. Mol) were added potassium carbonate (109 mg, 788. Mu. Mol) and potassium iodide (6.55 mg, 39.4. Mu. Mol). The mixture was stirred at 100℃for 12 hours. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=100/1 to 0/1) to give 8-chloro-2- (1- (1- (3, 3-difluorocyclobutyl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a brown solid]Imidazol-6-yl) oxy) quinoxaline (130 mg,204 μmol, 51%). M/zES + [ M+H ]] ⁺ 625.3。

Step 3.8-chloro-2- (1- (1- (3, 3-difluorocyclobutyl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-chloro-3- [1- [1- (3, 3-difluorocyclobutyl) ethyl ] in trifluoroacetic acid (1 mL) ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (130 mg, 207. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column Phenomenex Synergi C18:150.25 mm.10 um; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 16% -46%,10 min) purification to give 8-chloro-2- [1- [1- (3, 3- ] in the form of a white solidDifluoro-cyclobutyl) ethyl]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (41.9 mg, 84.7. Mu. Mol, 40%). ¹ H NMR(400MHz,DMSO-d6)δ12.92-11.84(m,1H),9.31(s,1H),8.79(s,1H),8.37(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝1.6Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.65-4.46(m,1H),2.83-2.59(m,2H),2.55-2.51(m,1H),2.49(s,3H),2.47-2.39(m,2H),1.48(d,J＝6.8Hz,3H)；m/z ES+[M+H] ⁺ 495.0。

EXAMPLE 99 Synthesis of (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) (3-hydroxyazetidin-1-yl) methanone

To 2- [ [6- [3- [1- (azetidin-3-yl) pyrazol-4-yl ] in dichloromethane (10 mL) under nitrogen]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl ]Methoxy group]Triethylamine (180 mg,1.78 mmol) was added in one portion to a mixture of ethyl-trimethyl-silane (500 mg, 889. Mu. Mol) and (4-nitrophenyl) chloroformate (178 mg, 889. Mu. Mol). The mixture was stirred at 20℃for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl azetidine-1-carboxylic acid 4-nitrophenyl ester (0.6 g,578umol, 65%). M/zES + [ M+H ]] ⁺ 727.4

Step 2. (3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) (3-hydroxyazetidin-1-yl) methanone

At the temperature of 25 deg.c,to 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a mixture of azetidine-1-carboxylic acid (4-nitrophenyl) ester (300 mg, 413. Mu. Mol) and azetidine-3-ol hydrochloride (135.58 mg,1.24 mmol) was added N, N-diisopropylacetylene amine (41.7 mg, 413. Mu. Mol, 57.4. Mu.L) in one portion. The mixture was stirred at 25℃for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give (3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) (3-hydroxyazetidin-1-yl) methanone (80 mg,96.8 μmol, 24%). M/zES + [ M+H ]] ⁺ 661.4。

Step 3. (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) (3-hydroxyazetidin-1-yl) methanone

(3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (3 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) (3-hydroxyazetidin-1-yl) methanone (80 mg,121 μmol) was stirred at 25 ℃ for 1H. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25.mu.m.150.mu.m; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 7% -37%,10 min) to give 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ]) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) azetidin-1-yl) (3-hydroxyazetidin-1-yl) methanone (26.4 mg,49.8 μmol, 41%). ¹ H NMR(400MHz,CD ₃ OD)δ9.20(s,1H),8.66(s,1H),8.42(s,1H),7.99(d,J＝9.2Hz,1H),7.76(d,J＝9.6Hz,1H),7.49(d,J＝9.2Hz,1H),7.36-7.28(m,2H),5.41-5.29(m,1H),4.61-4.53(m,1H),4.52-4.45(m,2H),4.44-4.37(m,2H),4.26-4.19(m,2H),3.83(dd,J＝4.4,9.2Hz,2H),2.83(s,3H)；m/z ES+[M+H] ⁺ 531.0。

Example 100.Synthesis of 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethyl azetidine-1-carboxamide

Step 1.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethylazetidine-1-carboxamide

To 2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in dichloromethane (4 mL) at 0 ℃]To a mixture of imidazol-6-yl) oxy quinoxaline (150 mg, 267. Mu. Mol) and N, N-dimethylcarbamoyl chloride (28.7 mg, 267. Mu. Mol, 24.5. Mu.L) was added N, N-diisopropylacetylene amine (81.0 mg, 801. Mu. Mol, 111. Mu.L). The mixture was stirred at 0℃for 30min. After completion, the reaction mixture was quenched with water (5 mL) at 20 ℃ and then extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with brine (5 ml×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethyl azetidine-1-carboxamide (80 mg,125 μmol, 47%). M/zES + [ M+H ] ] ⁺ 633.4。

Step 2.3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N, N-dimethylazetidine-1-carboxamide

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of-N, N-dimethyl-azetidine-1-carboxamide (70 mg, 111. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLCColumn: phenomenex Luna C18, 150×25mm×10um; mobile phase: [ Water (formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 11% -41%,10 min) purification to give 3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as an off-white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-N, N-dimethyl-azetidine-1-carboxamide (25.3 mg,50.1 μmol, 45%). ¹ H NMR(400MHz,CD ₃ OD)δ9.21-9.07(m,1H),8.68(s,1H),8.42(s,1H),8.02-7.96(m,1H),7.75(d,J＝9.6Hz,1H),7.51-7.46(m,1H),7.35-7.28(m,2H),5.38-5.28(m,1H),4.55-4.49(m,2H),4.48-4.39(m,2H),2.93(s,6H),2.83(s,3H)；m/z ES+[M+H] ⁺ 503.0。

Example 101.1 Synthesis of- ((4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclopropane

Step 1.7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) methyl) -1H-pyrazol-4-yl) quinoxaline

7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in toluene (2 mL)]Imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (80.0 mg, 157. Mu. Mol), (1-tetrahydropyran-2-yloxycyclopropyl) methanol (32.5 mg, 189. Mu. Mol), diisopropyl azodicarboxylate (47.7 mg, 236. Mu. Mol), triphenylphosphine (61.9 mg, 236. Mu. Mol) were degassed and purged 3 times with a nitrogen atmosphere, and then the mixture was stirred under a nitrogen atmosphere at 60℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) -2- (1- ((1- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) methyl) -1H-pyrazol-4-yl) quinoxaline (50 mg,37.7 μmol, 24%). M/zES + [ M+H ]] ⁺ 663.1。

Step 2.1- ((4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclopropanol

7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (1 mL) ]The solution of imidazol-6-yl) oxy) -2- (1- ((1- ((tetrahydro-2H-pyran-2-yl) oxy) cyclopropyl) methyl) -1H-pyrazol-4-yl) quinoxaline (50 mg, 75.4. Mu. Mol) was stirred at 20 ℃ for 1H. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Synergi C18.25.mu.m.150.mu.m; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 17% -44%,9 min) purification to give 1- ((4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ]) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl cyclopropane (10.4 mg,23.3 μmol, 31%). ¹ H NMR(400MHz,CD ₃ OD)δ9.11(s,1H),8.53(s,1H),8.24(s,1H),8.05(d,J＝9.2Hz,1H),7.61(dd,J＝2.8,9.2Hz,1H),7.31(d,J＝9.2Hz,1H),7.16(d,J＝2.4Hz,1H),4.30(s,2H),2.61(s,3H),0.83(d,J＝5.6Hz,4H)；m/z ES+[M+H] ⁺ 449.0。

Example 102.Synthesis of 2- (4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanol

Step 1.2- (4- (7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanol

To 2- [ [5, 7-difluoro-2-methyl-6- [3- (1H-pyrazol-4-yl) quinoxalin-6-yloxy-benzoimidazol-1-yl ] in N, N-dimethylformamide (1.5 mL)]Methoxy group]To a solution of ethyl-trimethyl-silane (70 mg, 138. Mu. Mol) was added 1, 3-dioxolan-2-one (36.4 mg, 413. Mu. Mol). The mixture was stirred at 140℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to give 2- (4- (7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl)) ethoxy) as a brown oil Methyl) -1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanol (70 mg, crude). M/zES + [ M+H ]] ⁺ 553.3。

Step 2.2- (4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanol

2- (4- (7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanol (70 mg,127 μmol) was stirred at 20 ℃ for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 17% -47%,10 min) to afford 2- (4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ]) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanol (30.1 mg, 70.6. Mu. Mol, 56%). ¹ H NMR(400MHz,CD ₃ OD)δ9.10(s,1H),8.47(s,1H),8.26(s,1H),8.06(d,J＝9.2Hz,1H),7.62(dd,J＝2.8,9.2Hz,1H),7.37(dd,J＝1.2,9.2Hz,1H),7.18(d,J＝2.4Hz,1H),4.31(t,J＝5.2Hz,2H),3.94(t,J＝5.2Hz,2H),2.65(s,3H)；m/z ES+[M+H] ⁺ 423.0。

Example 103.Synthesis of 1- (4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol

Step 1.1- (4- (7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol

To 7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (60 mg, 118. Mu. Mol) was added cesium carbonate (76.9 mg, 236. Mu. Mol) and 2, 2-dimethyloxirane (25.5 mg, 354. Mu. Mol). Will be mixedThe mixture was stirred at 100℃for 1 hour. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- (4- (7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a brown solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (60 mg, crude). M/zES + [ M+H ]] ⁺ 581.1。

Step 2.1- (4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol

1- (4- (7- ((5, 7-difluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (0.5 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (60 mg,103 μmol) was stirred at 20 ℃ for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: phenomenex C18 x 30mm x 3um; mobile phase: [ water (formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -52%,7 min) purification to give 1- (4- (7- ((5, 7-difluoro-2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (22.1 mg,48.0 μmol, 47%). ¹ H NMR(400MHz,CD ₃ OD)δ9.09(s,1H),8.44(s,1H),8.23(s,1H),8.05(d,J＝9.2Hz,1H),7.61(dd,J＝2.8,9.2Hz,1H),7.33(d,J＝9.6Hz,1H),7.17(d,J＝2.6Hz,1H),4.17(s,2H),2.63(s,3H),1.21(s,6H)；m/z ES+[M+H] ⁺ 451.0。

Example 104.1 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanol

Step 1.1- (hydroxymethyl) cyclobutanol

A solution of lithium aluminum hydride (653 mg,17.2 mmol) in tetrahydrofuran (5 mL) was degassed and purged 3 times with nitrogen. Then at 25 DEG C1-Hydroxycyclobutanecarboxylic acid (500 mg,4.31 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was then stirred at 70℃for 1 hour. After completion, the mixture was quenched with sodium sulfate tetrahydrate (20 g). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1 to 0/1) to give 1- (hydroxymethyl) cyclobutanol (350 mg,3.43mmol, 79%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ3.73-3.58(m,2H),2.86(s,1H),2.35-1.97(m,5H),1.87-1.70(m,1H),1.62-1.39(m,1H)。

Step 2.1- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanol

8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in toluene (1 mL)]A mixture of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (100 mg, 197. Mu. Mol), 1- (hydroxymethyl) cyclobutanol (40 mg, 391. Mu. Mol), triphenylphosphine (77.6 mg, 295. Mu. Mol) and diisopropyl azodicarboxylate (59.8 mg, 295. Mu. Mol) was degassed and purged 3 times with nitrogen. The mixture was then stirred at 60 ℃ under nitrogen for 16 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC purification (silica gel, petroleum ether/ethyl acetate=1/2) to give 1- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanol (100 mg,169 μmol, 85%). M/zES + [ M+H ]] ⁺ 591.2。

Step 3.1- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanol

1- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanol (100 mg,169 μmol) was stirred at 25 ℃ for 10min. After completion, the mixture was concentrated under reduced pressure. The residue was taken up by means of preparative HP LC (column Phenomenex Luna C, 150.25 mm.10 um; mobile phase: [ Water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 25% -35%,7 min) purification to give 1- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl cyclobutanol (36.2 mg,77.2 μmol, 45%). ¹ HNMR(400MHz,DMSO-d6)δ9.22(s,1H),8.61(s,1H),8.36(s,1H),7.98(d,J＝9.2Hz,1H),7.68(d,J＝8.8Hz,1H),7.45(d,J＝9.2Hz,1H),7.27(d,J＝2.4Hz,1H),7.21(dd,J＝2.4,8.8Hz,1H),4.40(s,2H),2.74(s,3H),2.36-2.19(m,2H),2.17-2.01(m,2H),1.90-1.78(m,1H),1.76-1.58(m,1H)；m/z ES+[M+H] ⁺ 461.0。

Example 105.Synthesis of 2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-morpholinoethane

Step 1.2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-morpholinoethane one

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (100 mg, 190. Mu. Mol) was added potassium carbonate (53 mg, 381. Mu. Mol) and 2-chloro-1-morpholinoethanone (34 mg, 210. Mu. Mol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 ml×3). The combined organic layers were washed with brine (20 ml×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1-morpholinoethanone (150 mg, crude). M/zES + [ M+H ]] ⁺ 652.3。

Step 2.2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-morpholinoethane

2- [4- [ 8-chloro-7- [ 4-fluoro-2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1.8 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1-morpholinoethanone (150 mg, 230. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: shim-pack C18 150X 25X 10um; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,10 min) purification to give 2- (4- (8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1-morpholinoethane (30.9 mg,0.059mmol, 26%). ¹ HNMR(400MHz,DMSO-d6)δ9.38(s,1H),8.65(s,1H),8.38(s,1H),8.02(d,J＝9.2Hz,1H),7.64(d,J＝8.8Hz,1H),7.44-7.36(m,2H),5.32(s,2H),3.69-3.44(m,8H),2.81(s,3H)；m/z ES+[M+H] ⁺ 521.9。

Example 106.8 Synthesis of chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-chloro-7- ((7-fluoro-2-methyl-1H-benzo [ d) in dimethyl sulfoxide (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (150 mg, 285. Mu. Mol) and 4, 4-difluorocyclohexyl methanesulfonate (122 mg, 571. Mu. Mol) was added cesium carbonate (186 mg, 571. Mu. Mmol) and potassium iodide (47.4 mg, 285. Mu. Mol). The mixture was then stirred at 80℃for 16 hours. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1- ((2- (trimethyl)) as a yellow oilSilyl) ethoxy) methyl) -1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxaline (180 mg,279 mu mol, 97%). M/zES + [ M+H ]] ⁺ 643.2。

Step 2.8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-chloro-3- [1- (4, 4-difluorocyclohexyl) pyrazol-4-yl ] in trifluoroacetic acid (1 mL)]Quinoxalin-6-yl]Oxy-7-fluoro-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (180 mg, 279. Mu. Mol) was stirred at 25℃for 10min. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25.mu.m.150.mu.m; mobile phase: [ water (formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 33% -63%,10 min) purification to give 8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((7-fluoro-2-methyl-1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxaline (100 mg,190 μmol, 68%). ¹ H NMR(400MHz,CD ₃ OD)δ9.22(s,1H),8.67(s,1H),8.39(s,1H),7.96(d,J＝9.2Hz,1H),7.52(dd,J＝1.2,8.8Hz,1H),7.38(d,J＝8.8Hz,1H),7.30(dd,J＝7.2,8.8Hz,1H),4.60-4.43(m,1H),2.82(s,3H),2.31-2.22(m,6H),2.09-2.01(m,2H)；m/z ES+[M+H] ⁺ 512.9。

Example 107.8 Synthesis of chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

Step 1.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

To 8-chloro-7- ((2-methyl-1H-benzo [ d) in methanol (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (50 mg,108 umol) and oxetan-3-one (23.5 mg,326 umol) were added sodium acetate (11.6 mg,141 umol) and sodium cyanoborohydride (20.5 mg,326 umol). The mixture was stirred at 25℃for 6 hours. At the position ofAfter completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mm X5 um; mobile phase: [ water (0.05% ammonium hydroxide v/v) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 18% -48%,9 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as an off-white solid ]Imidazol-6-yl) oxy) -2- (1- (1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (47.6 mg,92.4umol, 77%). ¹ H NMR(400MHz,CD ₃ OD)δ9.12(s,1H),8.60(s,1H),8.33(s,1H),7.86(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.18(d,J＝2.0Hz,1H),7(dd,J＝2.4,8.8Hz,1H),4.77-4.68(m,2H),4.67-4.60(m,2H),4.38-4.26(m,1H),3.57(q,J＝6.4Hz,1H),2.95(d,J＝10.8Hz,2H),2.57(s,3H),2.20(dd,J＝3.6,9.2Hz,3H),2.18-2.04(m,3H)；m/z ES+[M+H] ⁺ 516.1。

EXAMPLE 108 Synthesis of 2- (1- (2-azabicyclo [2.2.1] heptan-5-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- (2-isopropyl-2-azabicyclo [2.2.1] heptan-5-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.5-methylsulfonyloxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To a solution of tert-butyl 5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylate (500 mg,2.34 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (403 mg,3.52 mmol) and triethylamine (719mg, 7.03 mmol). The mixture was stirred at 0 ℃ for 1 hour. After completion, the reaction mixture was quenched with water (40 mL) and extracted with dichloromethane (40 ml×3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 5-methylsulfonyloxy-2-azabicyclo [2.2.1] heptane-2-carboxylate (550 mg, crude) as an orange oil.

Step 2.5- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (5 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (400 mg,789 umol) was added potassium carbonate (327 mg,2.37 mmol) and 5- ((methylsulfonyl) oxy) -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (460 mg,1.58 mmol). The mixture was stirred at 80℃for 14 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 90% -95%,5 min) to give 5- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as an orange oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (200 mg,0.29mmol, 36%). M/zES + [ M+H ]] ⁺ 702.6。

Step 3.2- (1- (2-azabicyclo [2.2.1] heptan-5-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

5- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-azabicyclo [2.2.1 ]A solution of tert-butyl heptane-2-carboxylate (200 mg, 283. Mu. Mol) was stirred at 30℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 3% -33%,10 min) purification to give 2- (1- (2-azabicyclo [ 2.2.1) as an off-white solid]Heptane-5-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (39.3 mg,83.4umol, 29%). ¹ H NMR(400MHz,DMSO-d ₆ )δ13.20-11.54(m,1H),9.35(s,1H),8.83(s,1H),8.42(s,1H),7.97(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.22(d,J＝2.0Hz,1H),6.95(dd,J＝2.4,8.8Hz,1H),4.93(dd,J＝4.8,7.6Hz,1H),4.30(s,1H),3.14-3.07(m,1H),3.05-2.99(m,1H),2.85(s,1H),2.50(s,3H),2.42-2.33(m,1H),2.28-2.16(m,2H),1.71(d,J＝11.6Hz,1H)；m/z ES+[M+H] ⁺ 472.1。

Step 4.8-chloro-2- (1- (2-isopropyl-2-azabicyclo [2.2.1] heptan-5-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- (1- (2-azabicyclo [ 2.2.1) in methanol (1 mL)]Heptane-5-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d]To a solution of imidazol-6-yl) oxy quinoxaline (60.0 mg,127 umol), acetone (22.2 mg, 321 umol) was added a solution of zinc chloride (22.5 mg,165 umol) and sodium triacetoxyborohydride (35.0 mg,165 umol) in methanol (0.5 mL). The mixture was stirred at 20℃for 12 hours. Sodium cyanoborohydride (10.4 mg,165 umol) and sodium acetate (13.4 mg,165 umol) were then added, and the mixture was stirred at 20℃for 2 hours. After completion, the reaction mixture was quenched with water (0.2 mL) and then concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,10 min) purification to give 8-chloro-2- (1- (2-isopropyl-2-azabicyclo [2.2.1 ]) as a white solid]Heptane-5-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (9.0 mg,17.5umol, 14%). ¹ H NMR(400MHz,DMSO-d ₆ )δ＝12.95-11.51(m,1H),9.33(s,1H),8.83(s,1H),8.35(s,1H),8.16(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝2.4,8.4Hz,1H),4.79(dd,J＝3.6,7.6Hz,1H),3.62(s,2H),3.01-2.96(m,1H),2.84(td,J＝6.0,12.0Hz,1H),2.49(s,3H),2.28-2.21(m,2H),2.04-1.97(m,1H),1.90(d,J＝10.0Hz,1H),1.57(d,J＝10.0Hz,1H),1.13(d,J＝6.4Hz,3H),1.07(d,J＝6.0Hz,3H)；m/z ES+[M+H] ⁺ 514.1。

EXAMPLE 109 Synthesis of 2- (1- (2-oxabicyclo [2.1.1] hexan-4-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

(3, 3-Dimethoxycyclobutane-1, 1-diyl) dimethanol

Lithium aluminum hydride (3.95 g,104 mmol) was added in portions to a solution of diisopropyl 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate (10 g,34.68 mmol) in tetrahydrofuran (100 mL) at 0deg.C. The mixture was stirred at 25℃for 12 hours. The mixture was diluted with tetrahydrofuran (100 mL) and then carefully quenched by dropwise addition of water (4 mL), 15% sodium hydroxide (4 mL) and water (12 mL). The suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 0/1) to give (3, 3-dimethoxycyclobutane-1, 1-diyl) dimethanol (3.89 g,22.08mmol, 64%) as a white solid. ¹ H NMR(400MHz,DMSO-d6)δ＝4.47(t,J＝5.4Hz,2H),3.35(d,J＝5.5Hz,4H),3(s,6H),1.77(s,4H)。

(3, 3-Dimethoxycyclobutane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate)

To [1- (hydroxymethyl) -3, 3-dimethoxy-cyclobutyl in pyridine (40 mL) at 0deg.C]To a solution of methanol (3.89 g,22.08 mmol) was added 4-methylbenzenesulfonyl chloride (12.6 g,66.23 mmol). The mixture was stirred at 0 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to give (3, 3-dimethoxycyclobutane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (4.5 g,12.13mmol, 55%) as a white solid. ¹ H NMR(400MHz,DMSO-d6)δ＝7.74(d,J＝8.2Hz,4H),7.49(d,J＝8.1Hz,4H),3.93(s,4H),2.89(s,6H),2.43(s,6H),1.85(s,4H)。

(3-Oxocyclobutane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate)

To a solution of (3, 3-dimethoxycyclobutane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (1.06 g,2.19 mmol) in acetonitrile (7 mL) was added hydrogen chloride/dioxane (4M, 2.73 mL). The mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (3-oxocyclobutane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (860 mg, crude) as a white solid. ¹ H NMR(400MHz,DMSO-d6)δ＝7.82(d,J＝8.2Hz,4H),7.55(d,J＝8.1Hz,4H),4.23(s,4H),2.92(s,4H),2.49(s,6H)。

(3-hydroxycyclobutane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate)

To a solution of (3-oxocyclobutane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (860 mg,1.96 mmol) in tetrahydrofuran (10 mL) was added sodium borohydride (148 mg,3.92 mmol) at 0 ℃. The mixture was stirred at 25℃for 2 hours. The reaction mixture was poured into saturated ammonium chloride (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/1) to give (3-hydroxycyclobutane-1, 1-diyl) bis (methylene) bis (4-methylbenzenesulfonate) (79mg, 1.79mmol, 91%) as a white solid. ¹ H NMR(400MHz,DMSO-d6)δ＝7.74(t,J＝7.6Hz,4H),7.48(d,J＝8.0Hz,4H),5.09(d,J＝6.4Hz,1H),4.01-3.95(m,1H),3.90(d,J＝17.6Hz,4H),2.43(s,6H),1.99-1.93(m,2H),1.64-1.57(m,2H)。

Step 5.2-oxabicyclo [2.1.1] hexane-4-ylmethyl 4-methylbenzenesulfonate

To a solution of (3-hydroxycyclobutane-1, 1-diyl) bis (4-methylbenzenesulfonate) (79mg, 1.79 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (215 mg,5.38mmol,60% in mineral oil) at 0 ℃. The mixture was stirred at 25℃for 12 hours. The reaction mixture was poured into saturated ammonium chloride (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 1/1) to give 2-oxabicyclo [2.1.1] as a white solid ]Hexane-4-ylmethyl 4-methylbenzenesulfonate (140 mg,490umol, 27%). . ¹ H NMR(400MHz,CDCl ₃ )δ＝7.80(d,J＝8.4Hz,2H),7.37(d,J＝8.1Hz,2H),4.54(s,1H),4.30(s,2H),3.57(s,2H),2.47(s,3H),1.75(d,J＝5.0Hz,2H),1.56-1.52(m,2H)。

Step 6.2- (1- (2-oxabicyclo [2.1.1] hexan-4-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (100 mg,98.6 umol) and 2-oxabicyclo [2.1.1]To a solution of hexane-4-ylmethyl 4-methylbenzenesulfonate (63.5 mg,118 umol) was added potassium carbonate (81.8 mg, 298 umol). The mixture was stirred at 80℃for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (1- (2-oxabicyclo [ 2.1.1) as a yellow oil]Hexane-4-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (150 mg, crude). M/zES + [ M+H ]] ⁺ 603.3。

Step 7.2- (1- (2-oxabicyclo [2.1.1] hexan-4-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-chloro-3- [1- (2-oxabicyclo [2.1.1 ] in trifluoroacetic acid (3 mL)]Hexane-4-ylmethyl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (140 mg,232 umol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 13% -43%,10 min) purification to give 2- (1- (2-oxabicyclo [ 2.1.1) as a yellow solid]Hexane-4-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (22.7 mg,47.9umol, 21%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.31(s,1H),8.69(s,1H),8.38(s,1H),8.17(s,1H),7.95(d,J＝9.3Hz,1H),7.51(d,J＝8.6Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝1.3Hz,1H),6.94(dd,J＝2.2,8.6Hz,1H),4.65(s,2H),4.46(s,1H),3.51(s,2H),2.49(s,3H),1.72(d,J＝4.5Hz,2H),1.49-1.42(m,2H)；m/z ES+[M+H] ⁺ 473.1。

EXAMPLE 110 Synthesis of 2- (1- (aziridin-2-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

(1-tritylaziridin-2-yl) methanol

To a solution of methyl 1-tritylaziridine-2-carboxylate (700 mg,2.04 mmol) in tetrahydrofuran (15 mL) was added lithium borohydride (164 mg,7.54 mmol) at 0deg.C. The mixture was stirred at 20℃for 2 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride (10 mL) at 0 ℃, then diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1-tritylaziridin-2-yl) methanol (900 mg, crude) as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ＝7.45(d,J＝7.6Hz,6H),7.26(d,J＝8.0Hz,9H),3.87(dd,J＝3.2,11.2Hz,1H),3.69(dd,J＝2.8,11.2Hz,1H),2.18(d,J＝4.8Hz,1H),1.86(d,J＝3.2Hz,1H),1.56(qd,J＝3.2,6.4Hz,1H),1.12(d,J＝6.4Hz,1H)。

Step 2.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1-tritylaziridin-2-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

To (1-tritylaziridin-2-yl) methanol (280 mg,887 umol) and 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in dichloromethane (6 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Triphenylphosphine (233 mg,887 umol) was added to a solution of ethyl-trimethyl-silane (300 mg,592 umol). Diisopropyl azodicarboxylate (178 mg,887 umol) was then added at 0deg.C, and the mixture was stirred at 2Stirred at 5℃for 1 hour. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (0.1% formic acid conditions) to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) -2- (1- ((1-tritylaziridin-2-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (350 mg,0.44mmol, 66%). ¹ H NMR(400MHz,DMSO-d6)δ9.28(d,J＝4.4Hz,1H),8.77(s,1H),8.29(s,1H),7.96(dd,J＝1.6,9.2Hz,1H),7.69-7.55(m,1H),7.41(d,J＝7.6Hz,6H),7.33-7.25(m,8H),7.23-7.16(m,3H),7.09-6.99(m,1H),5.64-5.51(m,2H),4.61(dd,J＝5.6,14.0Hz,1H),4.36(dd,J＝5.6,14.0Hz,1H),3.58-3.44(m,2H),2.57(d,J＝7.2Hz,3H),1.93(d,J＝2.8Hz,1H),1.73(dd,J＝2.8,5.6Hz,1H),1.08(d,J＝6.0Hz,1H),0.88-0.75(m,2H),-0.07(s,4H),-0.14--0.17(m,5H)；m/z ES+[M+H] ⁺ 804.1。

Step 3.2- (1- (aziridin-2-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in dichloromethane (1 mL)]Imidazol-6-yl) oxy) -2- (1- ((1-tritylaziridin-2-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (100 mg,124 umol) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 20℃for 1 hour. After completion, the reaction mixture was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (1- (aziridin-2-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (100 mg, crude). M/zES + [ M+H ]] ⁺ 562.2。

Step 4.2- (1- (aziridin-2-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- (1- (aziridin-2-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (tri) in trifluoroacetic acid (1 mL)Methylsilyl) ethoxy) methyl) -1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxaline (60 mg,107 umol) was stirred at 20 ℃ for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Synergi C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -25%,10 min) purification and purification by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 17% -47%,9 min) re-purification to give 2- (1- (aziridin-2-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) quinoxaline (14.6 mg,33.9umol, 32%). ¹ H NMR(400MHz,DMSO-d6)δ12.23(s,1H),9.33(s,1H),8.71(s,1H),8.38(s,1H),7.96(d,J＝9.2Hz,1H),7.59-7.41(m,1H),7.37-7.22(m,2H),7.17(s,1H),7-6.86(m,1H),4.34-4.18(m,1H),4.12-4(m,1H),2.48-2.45(m,3H),2.37(d,J＝7.6Hz,1H),1.74(d,J＝2.8Hz,1H),1.45-1.29(m,1H)；m/zES+[M+H] ⁺ 432.1。

EXAMPLE 111.Synthesis of 2- (1- (5, 8-dioxaspiro [3.4] oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (5 mL)]Imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (500 mg, 480 umol) and 2-bromo-5, 8-dioxaspiro [3.4]]To a solution of octane (210 mg,1.1 mmol) was added potassium carbonate (408 mg,3.0 mmol) and potassium iodide (16 mg,99 umol). The mixture was stirred at 100℃for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with 50mL x 2 of ethyl acetate. The combined organic layers were washed with brine (15 ml x 2), dried over anhydrous sodium sulfate Filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=100:1 to 10:1) to give 2- (1- (5, 8-dioxaspiro [ 3.4) as a yellow solid]Oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (360 mg,0.58mmol, 52%). M/zES + [ M+H ]] ⁺ 619.3。

Step 2.2- (1- (5, 8-dioxaspiro [3.4] oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- (1- (5, 8-dioxaspiro [3.4 ]) in trifluoroacetic acid (0.5 mL)]Oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (50 mg,81 umol) was stirred at 25 ℃ for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 35% -65%,9 min) purification to give 2- (1- (5, 8-dioxaspiro [3.4 ]) as a white solid]Oct-2-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ]Imidazol-6-yl) oxy) quinoxaline (8.7 mg,17.7umol, 22%). ¹ H NMR(400MHz,DMSO-d6)δ＝12.39-12.18(m,1H),9.31(d,J＝3.2Hz,1H),8.81(s,1H),8.41(s,1H),7.95(dd,J＝5.2,9.2Hz,1H),7.57-7.44(m,1H),7.37-7.27(m,1H),7.27-7.15(m,1H),6.98-6.89(m,1H),4.89(t,J＝8.0Hz,1H),3.96-3.90(m,2H),3.89-3.83(m,2H),2.96-2.87(m,2H),2.86-2.77(m,2H),2.49-2.46(m,3H)；m/z ES+[M+H] ⁺ 489.1。

EXAMPLE 112 Synthesis of 2- (1-allylpyrazol-4-yl) -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [3- (1-allylpyrazol-4-yl) -5-chloro-quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethylsilane

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL) at 0deg.C]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a mixture of ethyl-trimethylsilane (100 mg, 197umol) was added sodium hydride (15.8 mg, 390 umol,60% in mineral oil). The mixture was stirred at 0℃for 0.5 h. 3-Bromoprop-1-ene (40.0 mg, 330.65. Mu. Mol) was then added, and the mixture was stirred at 20℃for 1.5 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 ml×3). The combined organic phases are dried over anhydrous sodium sulfate, filtered and concentrated to give 2- [ [6- [3- (1-allylpyrazol-4-yl) -5-chloro-quinoxalin-6-yl ] as a yellow solid]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethylsilane (120 mg, crude). M/zES + [ M+H ]] ⁺ 547.1。

Step 2.2- (1-allylpyrazol-4-yl) -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [3- (1-allylpyrazol-4-yl) -5-chloro-quinoxalin-6-yl ] in trifluoroacetic acid (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (100 mg, 183umol) was stirred at 25℃for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,7 min) purification to give 2- (1-allylpyrazol-4-yl) -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy) as a yellow solid]Quinoxaline (50.4 mg,0.12mmol, 66%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.35(s,1H),8.70(s,1H),8.39(s,1H),7.99(d,J＝9.2Hz,1H),7.65(d,J＝8.8Hz,1H),7.44-7.29(m,2H),7.17-7.06(m,1H),6.17-6.02(m,1H),5.33-5.17(m,2H),4.91(br.d,J＝5.6Hz,2H),2.62(s,3H)；m/z ES+[M+H] ⁺ 417.1。

EXAMPLE 113 Synthesis of 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -N- (2-hydroxyethyl) acetamide

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in tetrahydrofuran (8 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 390 umol) was added sodium hydride (50.0 mg,1.25mmol,60% in mineral oil). The mixture was stirred at 25℃for 0.5 h. 2-Bromoacetic acid (80.0 mg, 576. Mu. Mol) was then added and the mixture was stirred at 60℃for 1.5 hours. After completion, the reaction mixture was quenched with water (2 mL) at 25 ℃ and then adjusted to ph=6 with saturated citric acid. The mixture was filtered and the filter cake was collected to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Acetic acid (200 mg,0.35mmol, 86%). M/zES + [ M+H ]] ⁺ 565.2。

Step 2.2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -N- (2-hydroxyethyl) acetamide

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in acetonitrile (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of acetic acid (100 mg,177 umol) was added tris (2, 2-trifluoroethyl) borate (120 mg,390 umol) and 2-aminoethanol (17 mg,278 umol). The mixture was stirred at 100℃for 16 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (mobile phase: [ water (0.1% ammonium hydroxide) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 45% -80%,6 min) purification to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]N- (2-hydroxyethyl) acetamide (60 mg,98.8umol, 55%). M/zES + [ M+H ]] ⁺ 608.2。

Step 3.2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -N- (2-hydroxyethyl) acetamide

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of N- (2-hydroxyethyl) acetamide (35 mg, 58. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 8% -38%,7 min) purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-N- (2-hydroxyethyl) acetamide (23.6 mg,49.5umol, 86%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.35(s,1H),8.69(s,1H),8.37(s,1H),8.29(br.t,J＝5.6Hz,1H),7.99(d,J＝9.2Hz,1H),7.61(d,J＝8.8Hz,1H),7.37(d,J＝9.2Hz,1H),7.31(d,J＝2.4Hz,1H),7.10-7.02(m,1H),5.01-4.88(m,2H),4.85-4.65(m,1H),3.45(br.t,J＝6.0Hz,2H),3.22-3.17(m,2H),2.58(s,3H)；m/z ES+[M+H] ⁺ 478.1。

Example 114.Synthesis of 2- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] ethylamino ] ethanol

Step 1.2- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] ethylamino ] ethanol

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A mixture of ethyl methanesulfonate (500 mg, 795. Mu. Mol) and 2-aminoethanol (971 mg,15.9 mmol) was stirred at 80℃for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 2- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethylamino group]Ethanol (0.22 g, 298 umol)，37％)。m/zES+[M+H] ⁺ 594.5。

Step 2.2- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] ethylamino ] ethanol

2- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethylamino group]A mixture of ethanol (0.22 g, 370. Mu. Mol) was stirred at 20℃for 2 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column Phenomenex Luna C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 2- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Ethylamino group]Ethanol (63.6 mg,137umol, 37%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(s,1H),8.92-8.69(m,2H),8.48(s,1H),8.05(d,J＝9.2Hz,1H),7.78(d,J＝8.8Hz,1H),7.50-7.41(m,2H),7.24(dd,J＝2.3,8.8Hz,1H),4.61(t,J＝6.4Hz,2H),3.72-3.61(m,2H),3.58-3.45(m,2H),3.08(br.s,2H),2.74(s,3H)；m/z ES+[M+H] ⁺ 464.1。

Example 115.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (2-methyl-2-azabicyclo [2.2.1] heptan-5-yl) -1H-pyrazol-4-yl) quinoxaline Synthesis

Step 1.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (2-methyl-2-azabicyclo [2.2.1] heptan-5-yl) -1H-pyrazol-4-yl) quinoxaline

To 2- (1- (2-azabicyclo [ 2.2.1) in N, N-dimethylformamide (1 mL)]Heptane-5-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d]To a solution of imidazol-6-yl) oxy quinoxaline (60.0 mg,127 mmole) was added formic acid (122 mg,2.54 mmol) and paraformaldehyde (76.4 mg,2.54 mmol). The mixture was stirred at 60℃for 13 hours. After completion, the reaction mixture was filtered,and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.2% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 3% -33%,10 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (2-methyl-2-azabicyclo [ 2.2.1)]Heptan-5-yl) -1H-pyrazol-4-yl) quinoxaline (55.5 mg,114umol, 89%). ¹ H NMR(400MHz,DMSO-d ₆ )δ13.05-10.51(m,1H),9.34(s,1H),8.83(s,1H),8.42(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.22(d,J＝2.0Hz,1H),6.94(dd,J＝2.0,8.8Hz,1H),5.03-4.96(m,1H),4.05(s,1H),3.11-3.04(m,1H),3.04-2.98(m,1H),2.81(s,4H),2.49(s,3H),2.37(d,J＝12.4Hz,1H),2.22-2.11(m,2H),1.97(d,J＝11.2Hz,1H)；m/z ES+[M+H] ⁺ 486.1。

EXAMPLE 116.Synthesis of 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -N- (2-hydroxyethyl) acetamide

(3-Methyloxetan-3-yl) methyl methanesulfonate

To a solution of (3-methyloxetan-3-yl) methanol (300 mg,2.94 mmol) in dichloromethane (5 mL) was added triethylamine (891 mg,1.23 mL) and methanesulfonyl chloride (504 mg,4.41 mmol). The mixture was stirred at 0 ℃ for 1 hour. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 25 ℃ and then extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-methyloxetan-3-yl) methyl methanesulfonate (500 mg, crude) as a yellow oil. ¹ HNMR(400MHz,CDCl ₃ )δ4.51(d,J＝6.4Hz,2H),4.43(d,J＝6.4Hz,2H),4.32(s,2H),3.07(s,3H),1.39(s,3H)。

Step 2.2- [ [6- [ 5-chloro-3- [1- [ (3-methyloxetan-3-yl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (3 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (150 mg, 255 umol) was added potassium carbonate (122 mg,887 umol), potassium iodide (49.1 mg, 255 umol) and (3-methyloxetan-3-yl) methyl methanesulfonate (90.0 mg,499 umol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- [ [6- [ 5-chloro-3- [1- [ (3-methyloxetan-3-yl) methyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (220 mg, crude). M/zES + [ M+H ]] ⁺ 591.3。

Step 3.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [ (3-methyloxetan-3-yl) methyl ] pyrazol-4-yl ] quinoxaline

To 2- [ [6- [ 5-chloro-3- [1- [ (3-methyloxetan-3-yl) methyl ] in trifluoroacetic acid (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (150 mg, 255 umol) was added trifluoroacetic acid (770 mg,6.75 mmol). The mixture was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,7 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow solid]-2- [1- [ (3-Methyloxetan-3-yl) methyl]Pyrazol-4-yl]Quinoxaline (65.6 mg,142umol, 56%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.44(s,1H),9.37(s,2H),8.05(d,J＝9.2Hz,1H),7.53(d,J＝8.4Hz,1H),7.45(d,J＝9.2Hz,1H),7.25(d,J＝2.4Hz,1H),6.99-6.93(m,1H),4.66(d,J＝12.0Hz,2H),4.45(d,J＝12.0Hz,2H),3.54(s,2H),2.49(s,3H),1.33(s,3H)；m/z ES+[M+H] ⁺ 461.1。

EXAMPLE 117 Synthesis of 4- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] piperidine-1-carboxamide

Step 1.4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxamide

To 2- [ [6- [ 5-chloro-3- [1- (4-piperidinylmethyl) pyrazol-4-yl ] in dichloromethane (2 mL) at 0deg.C ]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 330. Mu.l) and diisopropylethylamine (130 mg, 990. Mu.l) was added isocyanato (trimethyl) silane (46 mg, 400. Mu.l). The mixture was stirred at 25℃for 2 hours. The reaction mixture was treated with H ₂ O (10 mL) was diluted and extracted with dichloromethane (25 mL. Times.2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a white solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Piperidine-1-carboxamide (100 mg,155 mol, 46%). M/zES + [ M+H ]] ⁺ 647.2。

Step 2.4- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] piperidine-1-carboxamide

4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.7 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of piperidine-1-carboxamide (70 mg,108 umol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (basic: column: waters Xridge 150X 25mm X5 um; mobile phase: [ water (0.05% ammonium hydroxide v/v) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,9 min) purification to give 4- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazole) as a white solid-5-yl) oxy]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Piperidine-1-carboxamide (27.6 mg,53.5umol, 48%). ¹ HNMR(400MHz,DMSO-d6)δ＝12.16-11.91(m,1H),9.26(s,1H),8.63(s,1H),8.33(s,1H),7.95(d,J＝8.8Hz,1H),7.57-7.42(m,1H),7.39-7.32(m,1H),7.27-7.07(m,1H),6.98-6.88(m,1H),5.61(s,2H),4.17(d,J＝7.2Hz,2H),3.93(d,J＝13.2Hz,2H),2.74-2.64(m,2H),2.49-2.49(m,3H),2.19-2.03(m,1H),1.55(d,J＝11.2Hz,2H),1.17(m,2H)；m/z ES+[M+H] ⁺ 517.1。

EXAMPLE 118 Synthesis of 2- (1- ((1 s,4 s) -4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 2- (1- ((1 r,4 r) -4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.1, 4-dioxaspiro [4.5] decan-8-ylmethane sulfonate

To 1, 4-dioxaspiro [4.5] in dichloromethane (6 mL)]To a solution of decan-8-ol (500 mg,3.16 mmol) were added methanesulfonyl chloride (543 mg,4.74mmol, 367. Mu.L) and triethylamine (640 mg,6.32mmol, 880. Mu.L). The mixture was stirred at 0 ℃ for 1 hour. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1, 4-dioxaspiro [4.5] as a yellow solid]Decane-8-ylmethane sulfonate (800 mg, crude). ¹ H NMR(400MHz,DMSO-d6)δ4.76(td,J＝3.6,7.6Hz,1H),3.89-3.84(m,4H),3.17(s,3H),1.93-1.75(m,4H),1.73-1.50(m,4H)。

Step 2.2- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 1, 4-dioxaspiro [4.5 ] in N, N-dimethylformamide (6 mL)]To a solution of decane-8-ylmethane sulfonate (373 mg,1.58 mmol) was added 2- [ [6- [ 5-chloro-3 ]- (1H-pyrazol-4-yl) quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (400 mg,789 umol), potassium iodide (131 mg,789 umol) and cesium carbonate (771 mg,2.37 mmol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=20/1 to 10/1) to give 2- (1, 4-dioxaspiro [ 4.5) as a yellow oil]Decane-8-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (600 mg, crude). M/zES + [ M+H ]] ⁺ 647.2。

Step 3.4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclohexanone

To 2- (1, 4-dioxaspiro [4.5 ]) in dichloromethane (6 mL) ]Decane-8-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]To a solution of imidazol-6-yl) oxy quinoxaline (600 mg,927 umol) was added formic acid (3 mL). The mixture was stirred at 40℃for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure to give 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl cyclohexanone (600 mg, crude). M/zES + [ M+H ]] ⁺ 603.1。

Step 4.2- (1- (4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in methanol (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclohexanone (250 mg,414 umol) and azetidine (116 mg,1.24mmol, HCl salt) were added triethylamine (126 mg,1.24 mmol) and acetic acid (373 mg,6.22 mmol). Then at 0 DEG CSodium triacetoxyborohydride (176 mg,829 umol) was added in two portions (slightly exothermic). The reaction mixture was stirred at 40 ℃ for 16 hours. After completion, the reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (0.1% formic acid conditions) to give 2- (1- (4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil ]Imidazol-6-yl) oxy) quinoxaline (100 mg,156umol, 36%). M/zES + [ M+H ]] ⁺ 644.2。

Step 5.2- (1- ((1 s,4 s) -4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 2- (1- ((1 r,4 r) -4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- (1- (4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxaline (65 mg,101 umol) was stirred at 20 ℃ for 30min. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18.25 mm. Times.10 um; mobile phase: [ water (0.2% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -20%,12 min) purification and further SFC (column: daicel ChiralPak IG (250X 30mm, 10 um); mobile phase: [0.1% NH) ₃ H ₂ O MEOH]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 55% -55%,6.1min;60 min) to give 2- (1- ((1 s,4 s) -4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d) as a yellow gum ]Imidazol-6-yl) oxy) quinoxaline (9.1 mg,17.7umol, 18%) as a yellow solid and 2- (1- ((1 r,4 r) -4- (azetidin-1-yl) cyclohexyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d)]Imidazol-6-yl) oxy) quinoxaline (16.8 mg,32.7umol, 31%).

¹ H NMR(400MHz,DMSO-d6)δ12.44-12.16(m,1H),9.34(s,1H),8.73(s,1H),8.32(s,1H),7.95(d,J＝9.2Hz,1H),7.73-7.42(m,2H),7.35-7.11(m,2H),6.94(d,J＝7.6Hz,1H),4.33-4.19(m,1H),3.09(t,J＝6.8Hz,4H),2.50(s,3H),2.27(s,1H),2.20-2.08(m,2H),1.93(td,J＝6.4,13.2Hz,2H),1.83-1.74(m,2H),1.67(d,J＝12.0Hz,2H),1.50(d,J＝13.2Hz,2H)；m/z ES+[M+H] ⁺ 514.1。

¹ H NMR(400MHz,DMSO-d6)δ10.65-10.51(m,1H),9.34(s,1H),8.73(s,1H),8.38(s,1H),8(d,J＝9.2Hz,1H),7.67(d,J＝8.8Hz,1H),7.40(d,J＝9.2Hz,1H),7.35(s,1H),7.22-7.03(m,2H),4.41-4.33(m,1H),4.16-4.04(m,4H),3.27(s,1H),2.64(s,3H),2.48-2.36(m,2H),2.21(d,J＝10.8Hz,2H),2.13-2.04(m,2H),1.92-1.81(m,2H),1.45-1.36(m,2H)；m/z ES+[M+H] ⁺ 514.1。

EXAMPLE 119.Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [ (3-methyltetrahydrof-n-3-yl) methyl ] pyrazol-4-yl ] quinoxaline

(3-methyltetrahydrofuran-3-yl) methyl methanesulfonate

To a solution of (3-methyltetrahydrofuran-3-yl) methanol (500 mg,4.30 mmol) in dichloromethane (5 mL) was added triethylamine (1.31 g,12.9 mmol) and methanesulfonyl chloride (739 mg,6.46 mmol) at 0deg.C. The mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with water (15 mL) at 0 ℃ and then extracted with dichloromethane (10 ml×3). The combined organic layers were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (3-methyltetrahydrofuran-3-yl) methyl methanesulfonate (600 mg,3.09mmol, 72%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ -d)δ4.06(s,2H),3.88(dt,J＝6.4,8.0Hz,2H),3.74-3.68(m,1H),3.40(d,J＝8.8Hz,1H),3.02(s,3H),1.90-1.82(m,1H),1.70(ddd,J＝6.0,8.0,12.8Hz,1H),1.20(s,3H)。

Step 2.2- [ [6- [ 5-chloro-3- [1- [ (3-methyltetrahydrofuran-3-yl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxaline in N, N-dimethylformamide (1.5 mL)Lin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (150 mg, 298. Mu. Mol) and (3-methyltetrahydrofuran-3-yl) methyl methanesulfonate (74.7 mg, 385. Mu. Mol) was added cesium carbonate (289 mg, 887. Mu. Mol) and potassium iodide (49.1 mg, 294. Mu. Mol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 ml×3). The combined organic layers were washed with brine (3 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- [ [6- [ 5-chloro-3- [1- [ (3-methyltetrahydrofuran-3-yl) methyl ] as a yellow oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (150 mg, crude). M/zES + [ M+H ]] ⁺ 605.3。

Step 3.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [ (3-methyltetrahydrof-n-3-yl) methyl ] pyrazol-4-yl ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [ (3-methyltetrahydrofuran-3-yl) methyl ] in trifluoroacetic acid (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group ]A solution of ethyl-trimethyl-silane (130 mg,215 umol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -32%,7 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as an off-white solid]-2- [1- [ (3-methyltetrahydrofuran-3-yl) methyl]Pyrazol-4-yl]Quinoxaline (43.5 mg,91.2umol, 43%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.34(s,1H),8.73(s,1H),8.38(s,1H),8.13(s,1H),7.99(d,J＝9.2Hz,1H),7.62(d,J＝8.8Hz,1H),7.37(d,J＝9.2Hz,1H),7.31(d,J＝2.4Hz,1H),7.07(dd,J＝2.4,8.8Hz,1H),4.26(d,J＝1.6Hz,2H),3.81-3.77(m,2H),3.34(d,J＝8.4Hz,2H),2.59(s,3H),1.98(br d,J＝12.0Hz,1H),1.71-1.57(m,1H),1.02(s,3H)；m/z ES+[M+H] ⁺ 475.1。

Example 120.synthesis of 8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in dimethyl sulfoxide (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (100 mg, 197umol), 4-difluorocyclohexyl methanesulfonate (84.5 mg, 390 umol) was added cesium carbonate (192 mg,591 umol) and potassium iodide (32.7 mg, 197umol). The mixture was stirred at 80℃for 12 hours. After completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (30 ml x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=20:1) to give 8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid ]Imidazol-6-yl) oxy) quinoxaline (90 mg,144umol, 73%). M/zES + [ M+H ]] ⁺ 625.3。

Step 2.8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxaline (85 mg,135 umol) was stirred at 25 ℃ for 10min. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 20% -50%,7 min) purification to give 8-chloro-2- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (33.5 mg,67.9umol, 49%). ¹ H NMR(400MHz,CD ₃ OD)δ9.27-9.02(m,1H),8.72-8.54(m,1H),8.46-8.25(m,1H),8.15(s,1H),8.01-7.77(m,1H),7.66-7.54(m,1H),7.46-7.29(m,1H),7.23(d,J＝2.0Hz,1H),7.18-7.01(m,1H),4.50(s,1H),2.67(s,3H),2.30-1.98(m,8H)；m/z ES+[M+H] ⁺ 495.1。

Example 121.Synthesis of 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-1-ol

Step 1.2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropanoic acid methyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (6 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (400 mg,789 umol) and methyl 2-bromo-2-methyl-propionate (171 mg,947 umol) was added cesium carbonate (514 mg,1.58 mmol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=100/1 to 80/1) to give 2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropanoic acid methyl ester (410 mg, 268 umol, 79%). M/zES + [ M+H ]] ⁺ 607.3。

Step 2.2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-1-ol

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in ethanol (6 mL) at 0deg.C ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of methyl-2-methyl-propionate (410 mg,675 umol)Sodium borohydride (76.6 mg,2.03 mmol). The mixture was stirred at 25℃for 4 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=1/0 to 80/1) to give 2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-1-ol (280 mg,377umol, 56%). M/zES + [ M+H ]] ⁺ 579.3。

Step 3.2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-1-ol

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 2-methyl-propan-1-ol (80 mg, 108. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,10 min) purification to give 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -2-methylpropan-1-ol (33.5 mg,74.7umol, 69%). ¹ HNMR(400MHz,DMSO-d6)δ＝9.37(s,1H),8.73(s,1H),8.35(s,1H),8.13(s,1H),7.96(d,J＝9.3Hz,1H),7.55(d,J＝8.6Hz,1H),7.32(d,J＝9.3Hz,1H),7.25(d,J＝2.3Hz,1H),6.99(dd,J＝2.3,8.7Hz,1H),5.20-5.01(m,1H),3.66(s,2H),2.53(s,3H),1.57(s,6H)；m/z ES+[M+H] ⁺ 449.1。

EXAMPLE 122 Synthesis of 8-chloro-2- (1- ((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- ((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- [1- [ (3S, 4S) -3-fluoro-4-piperidinyl ] in tetrahydrofuran (5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg,329 umol) was added oxetan-3-one (47.4 mg, 258 umol). The mixture was stirred at 25℃for 0.5 h. Sodium triacetoxyborohydride (209 mg,987 umol) was then added at 0deg.C. The mixture was stirred at 25℃for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (20 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-chloro-2- (1- ((3 s,4 s) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid ]Imidazol-6-yl) oxy) quinoxaline (230 mg, crude). M/zES + [ M+H ]] ⁺ 664.3。

Step 2.8-chloro-2- (1- ((3S, 4S) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- [1- [ (3S, 4S) -3-fluoro-1- (oxetan-3-yl) -4-piperidinyl ] in tetrahydrofuran (5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (210 mg, 316. Mu.L) was added tetrabutylammonium fluoride (1M in THF, 632. Mu.L). The mixture was stirred at 80℃for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 11% -41%,10 min) and purified by preparative HPLC (neutral conditions; column: waters Xridge 150X 25mM 5um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 27% -57%,10 min) which was re-purified by preparative HPLC (formic acid conditions; column: shim-pack C18. Times.25.times.10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]；(B%:5% -35%,10 min) to give 8-chloro-2- (1- ((3 s,4 s) -3-fluoro-1- (oxetan-3-yl) piperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as a yellow solid ]Imidazol-6-yl) oxy) quinoxaline (6.12 mg,11.5umol, 3.7%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.32(s,1H),8.84(s,1H),8.44(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.94(dd,J＝2.3,8.6Hz,1H),5.11-4.90(m,1H),4.59-4.56(m,2H),4.48(td,J＝6.2,12.6Hz,2H),3.65-3.59(m,1H),3.25-3.20(m,1H),2.82(d,J＝10.4Hz,1H),2.53-2.51(m,1H),2.49(s,3H),2.20-2.02(m,4H)；m/z ES+[M+H] ⁺ 534.1。

Example 123 Synthesis of 2- (1- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 2- (1- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 5-hydroxy-2-azabicyclo [2.2.1] in dichloromethane (5 mL)]To a solution of tert-butyl heptane-2-carboxylate (500 mg,2.20 mmol) and triethylamine (569 mg,4.40 mmol) was added methanesulfonyl chloride (302 mg,2.64 mmol). The mixture was stirred at 25℃for 1 hour. After completion, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (10 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate 6/1 to 3/1) to give 5-methylsulfonyloxy-2-azabicyclo [2.2.1] as a colorless oil]Heptane-2-carboxylic acid tert-butyl ester (500 mg,1.64mmol, 74%). ¹ H NMR(400MHz,CDCl ₃ )δ5.06-4.93(m,1H),4.30-4.09(m,2H),2.94(s,3H),2.11-1.57(m,8H),1.44-1.37(m,9H)。

Step 2.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N-methylpyrrolidone (10 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (300 mg, 592. Mu. Mol) was added cesium carbonate (245 mg,0.79 mmol) and 3-methylsulfonyloxy-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (217 mg,0.71 mmol). The mixture was stirred at 80℃for 1 hour. After completion, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane/methanol 80/1 to 20/1) to give-3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (450 mg, crude). M/zES + [ M+H ]] ⁺ 716.3。

Step 3.2- (1- (8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL) ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -8-azabicyclo [3.2.1]A solution of tert-butyl octane-8-carboxylate (400 mg, 5538. Mu. Mol) was stirred at 30℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give 2- (1- (8-azabicyclo [ 3.2.1) as a yellow oil]Oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxaline (270 mg, crude). M/zES + [ M+H ]] ⁺ 486.2。

Step 4.2- (1- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 2- (1- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- (1- (8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline (80 mg, crude) was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C18.150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 4% -34%,10 min) to give 2- (1- ((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline (24.9 mg, 51.3. Mu.m, 31%) and 2- (1- ((1R, 3s, 5S) -8-azabicyclo [3.2.1] oct-3-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline as off-white solids as yellow solids.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.31(s,1H),8.73(s,1H),8.40(s,1H),8.36(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝2.4Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.85(td,J＝6.0,11.5Hz,1H),3.96(s,2H),2.49(s,3H),2.37-2.23(m,2H),2.11(dd,J＝4.8,10.8Hz,2H),1.97(s,4H)；m/z ES+[M+H] ⁺ 486.1。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(s,1H),9.09(s,1H),8.91(s,2H),8.41(s,1H),8.04(d,J＝9.2Hz,1H),7.77(d,J＝8.8Hz,1H),7.49-7.44(m,2H),7.23(dd,J＝2.4,8.8Hz,1H),4.67(t,J＝6.4Hz,1H),4.09(s,2H),2.98(d,J＝16.0Hz,2H),2.73(s,3H),2.53(dd,J＝2.4,7.6Hz,2H),1.90-1.79(m,2H),1.69(d,J＝8.0Hz,2H)；m/z ES+[M+H] ⁺ 486.1。

Example 124.8 Synthesis of 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1R, 3r, 5S) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) quinoxaline and 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1R, 3s, 5S) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) quinoxaline

Step 1.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1R, 3r, 5S) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) quinoxaline and 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1R, 3s, 5S) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) quinoxaline

To a solution of 2- (1- (8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline (100 mg,206 umol) in N, N-dimethylformamide (1 mL) was added formic acid (198 mg,4.12 mmol) and paraformaldehyde (124 mg,4.12 mmol). The mixture was stirred at 60℃for 13 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 4% -34%,10 min) to give 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1 r,3r,5 s) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) quinoxaline (9.3 mg,18.6umol, 9%) and 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1 r,3s,5 s) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1H-pyrazol-4-yl) quinoxaline (9.3 mg,18.6umol, 9%) as an off-white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.30(s,1H),8.75(s,1H),8.36(s,1H),8.30(s,2H),7.94(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝2.4Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.73(td,J＝5.6,11.6Hz,1H),3.43(s,2H),2.48(s,3H),2.39(s,3H),2.26(t,J＝11.6Hz,2H),2.13-2.04(m,2H),1.95(dd,J＝5.2,10.0Hz,2H),1.82(d,J＝8.0Hz,2H)；m/zES+[M+H] ⁺ 500.1。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.34(s,1H),9(s,1H),8.36(s,1H),8.32(s,2H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.94(dd,J＝2.0,8.8Hz,1H),4.54(s,1H),3.50-3.41(m,2H),2.77-2.64(m,2H),2.61-2.51(m,2H),2.49(s,3H),2.43-2.36(m,3H),2.03-1.89(m,2H),1.55(d,J＝8.4Hz,2H)；m/z ES+[M+H] ⁺ 500.1。

Example 125.8 Synthesis of chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- (3-oxabicyclo [3.1.0] hexan-6-ylmethyl) pyrazol-4-yl ] quinoxaline

Step 1.3-oxabicyclo [3.1.0] hexane-6-yl methanol

To 3-oxabicyclo [3.1.0] in tetrahydrofuran (10 mL) at 0deg.C]A solution of hexane-6-carboxylic acid (750 mg,5.85 mmol) was added lithium aluminum hydride (333 mg,8.78 mmol) in portions. The mixture was stirred at 25℃for 1 hour. After completion, the mixture was carefully quenched with sodium dodecahydrate sulfate (10 g) and then dried over magnesium sulfate. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 1/1) to give 3-oxabicyclo [3.1.0] as a colorless oil]Hexane-6-yl-methanol (250 mg,2.19mmol, 37%). ¹ H NMR(400MHz,CDCl ₃ )δ3.88(d,J＝8.2Hz,2H),3.70(d,J＝8.2Hz,2H),3.53(d,J＝7.2Hz,2H),1.62-1.62(m,1H),1.56-1.54(m,2H),1.10(d,J＝3.6,7.2Hz,1H)。

Step 2.2- [ [6- [ 5-chloro-3- [1- (3-oxabicyclo [3.1.0] hexane-6-ylmethyl) pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in dichloromethane (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (100 mg, 197umol) was added 3-oxabicyclo [3.1.0 ]Hexane-6-yl-methanol (27.0 mg, 236. Mu. Mol) and triphenylphosphine (77.6 mg, 295. Mu. Mol). Diisopropyl azodicarboxylate (59.8 mg, 255 umol) was then added at 0℃and the mixture was stirred at 25℃for 12 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=20:1) to give 2- [ [6- [ 5-chloro-3- [1- (3-oxabicyclo [3.1.0] as a white solid]Hexane-6-ylmethyl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-siliconAlkane (25 mg,41.5umol, 21%). M/zES + [ M+H ]] ⁺ 603.1。

Step 3.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- (3-oxabicyclo [3.1.0] hexan-6-ylmethyl) pyrazol-4-yl ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- (3-oxabicyclo [3.1.0] in trifluoroacetic acid (0.6 mL)]Hexane-6-ylmethyl) pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (25 mg,41.5 umol) was stirred at 25℃for 0.5 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,8 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as an off-white solid]-2- [1- (3-oxabicyclo [ 3.1.0)]Hexane-6-ylmethyl) pyrazol-4-yl]Quinoxaline (6.4 mg,13.6umol, 32%). ¹ H NMR(400MHz,CD ₃ OD)δ9.19(d,J＝4.4Hz,1H),8.63(d,J＝3.2Hz,1H),8.38(d,J＝2.8Hz,1H),7.93(dd,J＝4.4,9.2Hz,1H),7.56(d,J＝8.8Hz,1H),7.37(dd,J＝2.6,9.2Hz,1H),7.20(d,J＝2.2Hz,1H),7.04(dd,J＝2.4,8.8Hz,1H),4.23(d,J＝7.2Hz,2H),3.88(d,J＝8.4Hz,2H),3.72(d,J＝8.0Hz,2H),2.60(s,3H),1.87(s,2H),1.34(td,J＝3.8,7.2Hz,1H)；m/z ES+[M+H] ⁺ 473.1。

EXAMPLE 126 Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [ (4-methylsulfonylcyclohexyl) methyl ] pyrazol-4-yl ] quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [ (4-methylsulfonylcyclohexyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- [1- [ (4-methylsulfanyl cyclohexyl) methyl ] in acetonitrile (1 mL) and water (1 mL) at 0deg.C]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (20.0)To a solution of 30.8umol, oxatones (56.8 mg,92.4 umol) were added. The mixture was stirred at 0 ℃ for 1 hour. After completion, the mixture was poured into saturated sodium sulfate (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- [ [6- [ 5-chloro-3- [1- [ (4-methylsulfonyl cyclohexyl) methyl ] as a yellow oil ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (20 mg, crude). M/zES + [ M+H ]] ⁺ 681.1。

Step 2.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [ (4-methylsulfonyl-cyclohexyl) methyl ] pyrazol-4-yl ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [ (4-methylsulfonyl cyclohexyl) methyl ] in trifluoroacetic acid (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (20.0 mg,29.4 umol) was stirred at 25℃for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,7 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as an off-white solid]-2- [1- [ (4-methylsulfonyl cyclohexyl) methyl]Pyrazol-4-yl]Quinoxaline (6.0 mg,10.9umol, 37%). ¹ H NMR(400MHz,CD ₃ OD)δ＝9.18(s,1H),8.68-8.50(m,1H),8.35(s,1H),8.11(s,1H),7.94(d,J＝9.2Hz,1H),7.64(d,J＝8.8Hz,1H),7.41(d,J＝9.2Hz,1H),7.25(d,J＝1.8Hz,1H),4.30(d,J＝8.0Hz,2H),4.16(d,J＝7.2Hz,1H),2.98-2.86(m,3H),2.70(s,3H),2.49-2.48(m,1H),2.45-2.28(m,1H),2.24(d,J＝10.2Hz,1H),2.10-1.94(m,3H),1.88(d,J＝14.2Hz,1H),1.78-1.60(m,3H),1.58-1.46(m,1H),1.34-1.12(m,1H)；m/z ES+[M+H] ⁺ 551.1。

EXAMPLE 127 Synthesis of 8-chloro-2- (1- (((3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline, 8-chloro-2- (1- (((3S, 4S) -3-fluoro-1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- ((3-fluoropiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.3-fluoro-4- (methylsulfonyloxymethyl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 3-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate (500 mg,2.14 mmol) in dichloromethane (5 mL) was added triethylamine (651 mg,6.43 mmol) and methanesulfonyl chloride (365 mg,3.22 mmol). The mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with water (4 mL) at 0 ℃ and extracted with dichloromethane (3 ml×3). The combined organic layers were washed with brine (5 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-fluoro-4- (methylsulfonyloxymethyl) piperidine-1-carboxylic acid tert-butyl ester (600 mg, crude) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ4.62-3.94(m,5H),3.03(d,J＝0.4Hz,3H),2.84(br.d,J＝12.4Hz,2H),2.10-1.94(m,1H),1.64-1.52(m,1H),1.45(s,9H)。

Step 2.4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 390 umol) was added potassium carbonate (164 mg,1.18 mmol) and 3-fluoro-4- (methylsulfonyloxymethyl) piperidine-1-carboxylic acid tert-butyl ester (184 mg,591 umol). The mixture was stirred at 100℃for 12 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 ml×3). The combined organic layers were washed with brine (3 ml×3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=50:1 to 20:1) to give 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzo ] as a yellow oil Imidazol-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (190 mg,263umol, 67%). M/zES + [ M+H ]] ⁺ 722.1。

Step 3.2- [ [6- [ 5-chloro-3- [1- [ (3-fluoro-4-piperidinyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in dichloromethane (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of tert-butyl 3-fluoro-piperidine-1-carboxylate (50 mg,69.2 umol) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25℃for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (2 mL) at 25 ℃, then diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- [ [6- [ 5-chloro-3- [1- [ (3-fluoro-4-piperidinyl) methyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (40 mg, crude). M/zES + [ M+H ]] ⁺ 622.1。

Step 4.8-chloro-2- [1- [ (3-fluoro-4-piperidinyl) methyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 2- [ [6- [ 5-chloro-3- [1- [ (3-fluoro-4-piperidinyl) methyl ] in tetrahydrofuran (0.5 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (40 mg, 64.3. Mu.L) was added tetrabutylammonium fluoride (1M in THF, 129. Mu.L). The mixture was stirred at 80℃for 16 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,7 min) purification to give 8-chloro-2- [1- [ (3-fluoro-4-piperidinyl) methyl ] as a yellow solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (2.6 mg,5.27umol, 8.2%). ¹ H NMR(400MHz,CD ₃ OD)δ9.14(s,1H),8.62-8.59(m,1H),8.40-8.37(m,1H),8.32(s,2H),7.89(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.35(d,J＝9.2Hz,1H),7.19(d,J＝2.4Hz,1H),7.01(dd,J＝2.4,8.8Hz,1H),4.85-4.55(m,2H),4.54-4.28(m,2H),3.71-3.58(m,1H),3.49-3.34(m,1H),3.25-3.14(m,1H),3.11-2.99(m,1H),2.58(s,3H),2.08-1.87(m,1H),1.83-1.83(m,1H),1.83-1.60(m,1H)；m/z ES+[M+H] ⁺ 492.2。

Step 5.8-chloro-2- (1- (((3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- (((3R, 4S) -3-fluoro-1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To a solution of 8-chloro-2- [1- [ (3-fluoro-4-piperidinyl) methyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline (60 mg,122 umol) in N, N-dimethylformamide (1 mL) was added formic acid (117 mg,2.44 mmol) and paraformaldehyde (73.2 mg,2.44 mmol). The mixture was stirred at 60℃for 12 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile ]; (B%: 20% -50%,10 min) and further purified by preparative HPLC (column: phenomenex Luna C150X 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 2% -32%,10 min)) to give 8-chloro-2- (1- (((3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline (4.1 mg,7.84umol, 6.4%) and 8-chloro-2- (1- (((3R, 4S) -3-fluoro-1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline as an off-white solid (3R, 4S) -3-fluoro-1-methylpiperidin-4-yl) methyl-4-yl ] 3H-1-3-yl-quinoxaline (39.19 mg,1 mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ9.31(s,1H),8.73(s,1H),8.40(s,1H),8.25(s,2H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.73-4.44(m,2H),4.34(br dd,J＝7.6,13.6Hz,1H),4.22-4.17(m,1H),3.03(br.d,J＝11.2Hz,1H),2.79(br.d,J＝11.2Hz,1H),2.49-2.48(m,3H),2.15(s,3H),2.08-1.95(m,1H),1.90(br.t,J＝10.8Hz,1H),1.70-1.51(m,1H),1.46-1.28(m,1H)；m/z ES+[M+H] ⁺ 506.1。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.73(s,1H),8.40(s,1H),8.20(s,2H),7.97(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.22(d,J＝2.0Hz,1H),6.95(dd,J＝2.4,8.8Hz,1H),4.59-4.25(m,4H),3.13-3.06(m,1H),2.66(br.d,J＝11.6Hz,1H),2.50(br.s,3H),2.22-2.19(m,3H),2-1.93(m,1H),1.89-1.79(m,1H),1.59-1.49(m,1H),1.39-1.24(m,1H)；m/z ES+[M+H] ⁺ 506.1。

EXAMPLE 128.4 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclohex-1-ol

Step 1.4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] cyclohexanol

To 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in methanol (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of cyclohexanone (150 mg, 243. Mu. Mol) was added sodium cyanoborohydride (37.0 mg, 589. Mu. Mol) and acetic acid (42.0 mg, 699. Mu. Mol). The mixture was stirred at 25℃for 1 hour. After completion, the mixture was quenched with saturated sodium bicarbonate (1 mL) and extracted with ethyl acetate (3 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Cyclohexanol (150 mg, crude). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.31(d,J＝4.0Hz,1H),8.69-8.62(m,1H),8.36(s,1H),7.99-7.92(m,1H),7.59(d,J＝8.8Hz,1H),7.45-7.39(m,1H),7.31-7.27(m,1H),7.03-6.96(m,1H),5.54(s,2H),3.55(br.t,J＝8.0Hz,1H),3.51-3.44(m,2H),3.40-3.37(m,2H),2.57-2.55(m,3H),1.74-1.64(m,3H),1.64-1.51(m,4H),1.46-1.38(m,2H),0.82

-0.74(m,2H)；m/z ES+[M+H] ⁺ 619.2。

Step 2.4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclohex-1-ol

4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of cyclohexanol (90.0 mg,145 umol) was stirred at 25℃for 1.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18X 30mM 3um; mobile phase [ water (10 mM ammonium bicarbonate) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 16% -46%,8 min) purification to give 4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl cyclohex-1-ol (18.5 mg,37.9umol, 26%). ¹ HNMR(400MHz,DMSO-d ₆ )δ9.31(s,1H),8.67(s,1H),8.36(s,1H),7.97(d,J＝9.2Hz,1H),7.55(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.25(d,J＝2.0Hz,1H),7.01-6.97(m,1H),4.51(br.s,1H),4.08(d,J＝7.2Hz,2H),3.54-3.45(m,1H),2.53(s,3H),1.83(br.d,J＝10.0Hz,3H),1.63-1.48(m,2H),1.16-0.99(m,4H)；m/z ES+[M+H] ⁺ 489.1。

Example 129.synthesis of 4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclohexanone

Step 1.4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclohexanone

4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of cyclohexanone (60 mg,97.2 umol) was stirred at 25℃for 2 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C18 75 x 30mm x 3um; mobile phase: [ Water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,7 min) purification to give 4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl cyclohexanone (22.6 mg,46.4umol, 48%). ¹ HNMR(400MHz,DMSO-d6):δ＝9.31(s,1H),8.71(s,1H),8.39(s,1H),7.96(d,J＝9.2Hz,1H),7.55(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.25(d,J＝2.4Hz,1H),7.04-6.95(m,1H),4.28-4.20(m,2H),2.55-2.52(m,3H),2.45-2.34(m,3H),2.23(br d,J＝14.8Hz,2H),1.93-1.82(m,2H),1.55-1.41(m,2H)；m/z ES+[M+H] ⁺ 487.1。

Example 130.3 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanol

(3- (benzyloxy) cyclobutyl) methanol

A solution of lithium aluminum hydride (356 mg,19.4 mmol) in anhydrous tetrahydrofuran (10 mL) was degassed and purged 3 times with nitrogen, then 3-benzyloxycyclobutane carboxylic acid (1 g,4.85 mmol) in anhydrous tetrahydrofuran (5 mL) was added at 0deg.C. The mixture was stirred at 25 ℃ for 16 hours under nitrogen atmosphere. After completion, the reaction mixture was quenched at 0 ℃ by the addition of water (1 mL), 15% sodium hydroxide (1 mL) and water (3 mL). The mixture was filtered. The filtrate was dried over anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give (3- (benzyloxy) cyclobutyl) methanol (900 mg,4.68mmol, 96%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ ):δ＝7.31-7.18(m,5H),4.38-4.32(m,2H),3.90-3.80(m,1H),3.54-3.52(m,2H),2.30-2.27(m,2H),2.12-2.08(m,1H),1.71-1.62(m,2H)。

(3- (benzyloxy) cyclobutyl) methyl methanesulfonate

To a solution of (3-benzyloxycyclobutyl) methanol (500 mg,2.60 mmol) in dichloromethane (5 mL) was added triethylamine (780 mg,7.80 mmol) and methanesulfonyl chloride (447 mg,3.90 mmol) at 0deg.C. Will be mixedThe mixture was stirred at 0℃for 1 hour. After completion, the reaction mixture was quenched by addition of water (3 mL) and extracted with dichloromethane (3 mL x 3). The combined organic layers were washed with brine (3 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (3-benzyloxycyclobutyl) methyl methanesulfonate (600 mg,2.22mmol, 85%) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ ):δ＝7.26-7.19(m,5H),4.34(s,2H),4.13-4.09(m,2H),3.89(t,J＝7.2Hz,1H),2.92(s,3H),2.41-2.29(m,2H),2.20-2.13(m,1H),1.78-1.68(m,2H)。

Step 3.2- (1- ((3- (benzyloxy) cyclobutyl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To a solution of (3-benzyloxycyclobutyl) methyl methanesulfonate (320 mg,1.18 mmol) in N, N-dimethylformamide (5 mL) was added cesium carbonate (643 mg,1.97 mmol), potassium iodide (164 mg, 986. Mu. Mol) and 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (500 mg, 986. Mu. Mol). The mixture was stirred at 80℃for 16 hours. After completion, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 ml×3). The combined organic layers were washed with brine (3 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- (1- ((3- (benzyloxy) cyclobutyl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil ]Imidazol-6-yl) oxy) quinoxaline (780 mg, crude). M/zES + [ M+H ]] ⁺ 681.2。

Step 4.3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanol

To 2- (1- ((3- (benzyloxy) cyclobutyl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] at 0deg.C]To a mixture of imidazol-6-yl) oxy quinoxaline (50 mg, 73.4. Mu. Mol) was added boron trichloride (1M in toluene, 734. Mu.L). The mixture was stirred at 0 ℃ for 2 hours. After completion, the reaction is carried outPoured into water (3 mL) and adjusted to pH-7 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (3 ml×3). The combined organic layers were washed with brine (3 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,7 min) purification twice to give 3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl cyclobutanol (12.8 mg,27.5 μmol, 37%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.30(s,1H),8.66(s,1H),8.34(s,1H),8.25(s,1H),7.95(d,J＝9.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.20(br d,J＝1.6Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.35-4.13(m,3H),3.98-3.91(m,1H),2.49(s,3H),2.32-2.06(m,3H),2-1.60(m,2H)；m/zES+[M+H] ⁺ 461.1。

EXAMPLE 131.3 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanone

Step 1.3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanone

A mixture of 3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanone (45.0 mg, 76.4. Mu. Mol) in trifluoroacetic acid (0.5 mL) was stirred at 25℃for 2 hours. After completion, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column: phenomenex Gemini-NX 18X 30mm 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 12% -42%,7 min)) to give 3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanone as a yellow gum

(3.2mg，6.71μmol，8.8％)。 ¹ H NMR(400MHz,DMSO-d6):δ＝9.31(s,1H),8.78(s,1H),8.39(s,1H),8.32(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.99-6.88(m,1H),4.49(d,J＝6.4Hz,2H),3.17-3.12(m,2H),3.03-2.97(m,3H),2.50(m,3H)；m/z ES+[M+H] ⁺ 459.1。

Example 132.8 Synthesis of chloro-6-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.7-bromo-6-methyl-quinoxalin-2-ol and 6-bromo-7-methyl-quinoxalin-2-ol

To a solution of 4-bromo-5-methyl-benzene-1, 2-diamine (7 g,34.8 mmol) in ethanol (100 mL) was added ethyl 2-oxoacetate (8.53 g,41.7 mmol). The mixture was stirred at 60℃for 16 hours. The mixture was diluted with petroleum ether (200 mL) and stirred at 25 ℃ for 0.5 hours. The solid formed was isolated by filtration and dried in vacuo to give a mixture of 7-bromo-6-methyl-quinoxalin-2-ol and 6-bromo-7-methyl-quinoxalin-2-ol (7.0 g, crude) as a brown solid. M/zES + [ M+1 ]] ⁺ 239.0。

Step 2.7-bromo-2-chloro-6-methyl-quinoxaline

To a solution of 7-bromo-6-methyl-quinoxalin-2-ol (2 g,8.37mmol, mixture of regioisomers) in toluene (15 mL) was added phosphorus oxychloride (12.8 g,83.6 mmol) and the mixture was stirred at 100 ℃ for 3 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 0/1) to give 7-bromo-2-chloro-6-methyl-quinoxaline (1 g,3.84mmol, 45%) as a white solid. M/zES + [ M+1 ]] ⁺ 258.9

Step 3.4- [ [4- (7-bromo-6-methyl-quinoxalin-2-yl) pyrazol-1-yl ] methyl ] piperidine-1-carboxylic acid tert-butyl ester

7-bromo-2-chloro-6-methyl-quinoxaline (1 g,3.88 mmol), 4- [ [4- (4, 5-tetramethyl-1) in dioxane (10 mL) and water (2.5 mL) 3, 2-Dioxopentaborane-2-yl) pyrazol-1-yl]Methyl group]Tert-butyl piperidine-1-carboxylate (1.52 g,3.88 mmol), cyclopent-2, 4-dien-1-yl (diphenyl) phosphine; palladium dichloride; a solution of iron (284 mg, 3838 umol) and potassium acetate (762 mg,7.77 mmol) was stirred under nitrogen at 60℃for 12 hours. The reaction mixture was quenched with water (20 mL) at 25 ℃ and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 0/1) to give 4- [ [4- (7-bromo-6-methyl-quinoxalin-2-yl) pyrazol-1-yl ] as a brown solid]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (0.90 g,1.85mmol, 40%). M/zES + [ M+1 ]] ⁺ 488.1。

Step 4.4- ((4- (7-hydroxy-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

A solution of 4- ((4- (7-bromo-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester (1.5 g,3.08 mmol), tris (dibenzylideneacetone) dipalladium (282 mg, 308. Mu. Mol), t-Bu XPhos (130 mg, 308. Mu. Mol), potassium hydroxide (1.73 g,30.8 mmol) in dioxane (16 mL) and water (8 mL) was stirred under nitrogen at 100deg.C for 3 hours. After completion, the reaction mixture was quenched by addition of water (20 mL) at 25 ℃ and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1 to 0/1) to give tert-butyl 4- ((4- (7-hydroxy-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (1.3 g,3.08mmol, 99%) as a brown solid. ¹ H NMR(400MHz,DMSO-d6):δ＝10.48(d,J＝30Hz,2H),9.03(d,J＝29.6Hz,2H),8.52(d,J＝21.6Hz,2H),8.22(d,J＝15.2Hz,1H),7.72(d,J＝5.6Hz,1H),7.23(d,J＝16.8Hz,1H),4.09(d,J＝7.2Hz,2H),3.92(d,J＝10.4Hz,2H),3.17(d,J＝5.2Hz,1H),2.67(s,2H),2.35(d,J＝5.2Hz,3H),2.05(s,1H),1.49(d,J＝11.6Hz,2H),1.37(s,9H),1.16-1.04(m,2H)。

Step 5.4- ((4- (8-chloro-7-hydroxy-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- ((4- (7-hydroxy-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (1.1 g,2.60 mmol) in acetonitrile (10 mL) was added N-chlorosuccinimide (312 mg,2.34 mmol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was quenched by addition of water (20 mL) at 25 ℃ and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) and SFC (column: daicel Chiralcel OJ (250 mm. Times. 30mm,10 um); mobile phase: [0.1% ammonium hydroxide/methanol]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 70% -70%,5.5min; total run 50 min) to give tert-butyl 4- ((4- (8-chloro-7-hydroxy-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (0.3 g,0.66mmol, 25%) as a yellow solid. ¹ H NMR(400MHz,DMSO-d6):δ＝10.55-9.92(m,1H),9.11(s,1H),8.58(s,1H),8.29(s,1H),7.76(s,1H),4.13(d,J＝7.2Hz,2H),3.93(d,J＝11.6Hz,2H),2.75-2.61(m,2H),2.42(s,3H),2.12-1.99(m,1H),1.50(d,J＝12.0Hz,2H),1.38(s,9H),1.17-1.04(m,2H)；m/z ES+[M+H] ⁺ 458.2。

Step 6.4- ((4- (7- (3-amino-4-nitrophenoxy) -8-chloro-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4- ((4- (8-chloro-7-hydroxy-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (300 mg, 655. Mu. Mol), tert-butyl N-tert-butoxycarbonyl-N- (5-fluoro-2-nitro-phenyl) carbamate (350 mg, 982. Mu. Mol), potassium carbonate (181 mg,1.31 mmol) and potassium iodide (10.8 mg, 65.5. Mu. Mol) in N, N-dimethylformamide (5 mL) was stirred at 100℃for 16H. After completion, the reaction mixture was quenched by addition of water (20 mL) at 25 ℃ and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 4- ((4- (7- (3-amino-4-nitrophenoxy) -8-chloro-6-methyl) as a yellow solidQuinoxalin-2-yl) -1H-pyrazol-1-yl) methyl piperidine-1-carboxylic acid tert-butyl ester (0.2 g,0.34mmol, 51%). M/zES + [ M+H ]] ⁺ 594.3。

Step 7.4- ((4- (8-chloro-6-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- ((4- (7- (3-amino-4-nitrophenoxy) -8-chloro-6-methylquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (0.17 g, 286. Mu. Mol) in ethanol (10 mL) and water (3 mL) was added ammonium chloride (153 mg,2.86 mmol) and iron powder (79.9 mg,1.43 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the mixture was filtered and the filtrate concentrated in vacuo and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 4- ((4- (8-chloro-6-methyl-7- ((2-methyl-1H-benzo [ d)) as a green solid ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl piperidine-1-carboxylic acid tert-butyl ester (0.13 g,0.22mmol, 77%). M/zES + [ M+H ]] ⁺ 588.2。

Step 8.8-chloro-6-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline

To 4- [ [4- [ 8-chloro-6-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] in dichloromethane (10 mL)]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (0.1 g, 170. Mu. Mol) was added trifluoroacetic acid (3.08 g,27.0 mmol). The mixture was stirred at 25℃for 1 hour. After completion, the mixture was concentrated in vacuo to give 8-chloro-6-methyl-7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline (0.1 g, tfa salt, crude). M/zES + [ M+H ]] ⁺ 488.1。

Step 9.8-chloro-6-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

8-chloro-6-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in N, N-dimethylformamide (3 mL)]-2- [1- (4-piperidinylmethyl) pyrazol-4-yl]Quinoxaline (0.09 g, 149. Mu. Mol, TFA salt), polymethine A solution of aldehyde (89.7 mg,2.99 mmol) and formic acid (143 mg,2.99 mmol) was stirred at 60℃for 16 hours. After completion, the mixture was filtered and the filtrate concentrated in vacuo and the residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,7 min) purification to give 8-chloro-6-methyl-7- ((2-methyl-1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) -2- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (16 mg,31.8 μmol, 21%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.35(s,1H),8.67(s,1H),8.35(s,1H),8.23(s,1H),8.03(s,1H),7.51-7.36(m,1H),6.85-6.71(m,2H),4.14(d,J＝7.2Hz,2H),2.90(d,J＝10.8Hz,2H),2.43(s,3H),2.33(s,3H),2.27(s,3H),2.08(t,J＝10.8Hz,2H),1.93-1.86(m,1H),1.54(d,J＝11.6Hz,2H),1.36-1.26(m,2H)；m/z ES+[M+H] ⁺ 502.1。

EXAMPLE 133.4 Synthesis of- ((1 r,3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) morpholine and 4- ((1 s,3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) morpholine

Step 1.4- (3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) morpholine

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (1 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of cyclobutanone (65 mg, 110. Mu. Mol) and morpholine (30 mg, 340. Mu. Mol, 30. Mu.L) was added acetic acid (9.5 mg, 160. Mu. Mol, 9. Mu.L) andmolecular sieves (100 mg). The reaction was then cooled to 0 ℃ and sodium cyanoborohydride (14 mg,230 μmol) was added. The mixture was stirred at 25℃for 2Hours. After completion, the reaction mixture was filtered. The filtrate was diluted with water (10 mL) and extracted with dichloromethane (50 ml×2). The combined organic layers were washed with saturated sodium bicarbonate (10 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, DCM: meoh=20:1) to give 2- [ [6- [ 5-chloro-3- [1- (3-morpholinocyclobutyl) pyrazol-4-yl as a white solid]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (30 mg,46.4 μmol, 41%). M/zES + [ M+H ]] ⁺ 646.3。

Step 2.4- ((1 r,3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) morpholine and 4- ((1 s,3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) morpholine

A solution of 2- [ [6- [ 5-chloro-3- [1- (3-morpholinocyclobutyl) pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane (30 mg, 46. Mu. Mol) in trifluoroacetic acid (0.3 mL) was stirred at 25℃for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C18150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 30% -33%,10 min) to give 4- ((1 r,3 r) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -1H-pyrazol-1-yl) cyclobutyl) morpholine (7.6 mg, 14.7. Mu. Mol, 32%) and 4- ((1 s,3 s) -3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) morpholine (1.9 mg, 3.7. Mu. Mol, 8.0%) as a white solid.

1HNMR(400MHz,DMSO-d6):δ＝12.78-11.72(m,1H),9.33(s,1H),8.80(s,1H),8.38(s,1H),7.94(s,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.94(dd,J＝2.0,8.4Hz,1H),4.83-4.70(m,1H),3.63(s,4H),2.80-2.55(m,4H),2.49-2.49(m,3H),2.41(s,5H)；m/z ES+[M+H] ⁺ 516.1。

1HNMR(400MHz,DMSO-d6)δ＝12.76-11.80(m,1H),9.33(s,1H),8.80(s,1H),8.39(s,1H),7.96(d,J＝9.6Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.94(dd,J＝2.4,8.4Hz,1H),4.84-4.71(m,1H),3.64(s,4H),2.72-2.60(m,4H),2.49-2.48(m,3H),2.46-2.36(m,4H),2.33(s,1H)；m/z ES+[M+H] ⁺ 516.1。

EXAMPLE 134 Synthesis of 8-chloro-2- (1- (((1 s,4 s) -4-methoxycyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- (((1 r,4 r) -4-methoxycyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- ((4-methoxycyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 1- (bromomethyl) -4-methoxy-cyclohexane (45 mg,217 umol) and 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl in N, N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Potassium carbonate (54.5 mg, 390 umol) was added to a mixture of ethyl-trimethyl-silane (100 mg, 197umol), and the mixture was stirred at 80℃for 12 hours. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2- [ [6- [ 5-chloro-3- [1- [ (4-methoxycyclohexyl) methyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (150 mg, crude). M/zES + [ M+H ]] ⁺ 633.2。

Step 2.8-chloro-2- (1- (((1 s,4 s) -4-methoxycyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- (((1 r,4 r) -4-methoxycyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

A solution of 2- [ [6- [ 5-chloro-3- [1- [ (4-methoxycyclohexyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane (140 mg,221 umol) in trifluoroacetic acid (2 mL) was stirred at 20℃for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: unisil 3-100C18 Ultra 150*50mm*3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 20% -50%,10 min) to give 8-chloro-2- (1- (((1 s,4 s) -4-methoxycyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline (29.5 mg, 58.6. Mu. Mol, 27%) and 8-chloro-2- (1- (((1 r,4 r) -4-methoxycyclohexyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline (57 mg, 113. Mu. Mol, 51%) as an off-white solid.

¹ H NMR(400MHz,DMSO-d6):δ＝9.35(s,1H),8.69(s,1H),8.36(s,1H),8.02(d,J＝9.2Hz,1H),7.72(d,J＝8.8Hz,1H),7.45-7.38(m,2H),7.19(br d,J＝9.2Hz,1H),4.10(d,J＝7.2Hz,2H),3.45(d,J＝2.8Hz,1H),3.22(s,3H),2.68(s,3H),2.04-1.96(m,2H),1.88-1.81(m,1H),1.65-1.58(m,2H),1.11-1.02(m,4H)；m/z ES+[M+H] ⁺ 503.1。

¹ H NMR(400MHz,DMSO-d6):δ＝9.34(s,1H),8.70(s,1H),8.36(s,1H),8.01(d,J＝9.2Hz,1H),7.70(d,J＝8.8Hz,1H),7.45-7.36(m,2H),7.21-7.14(m,1H),4.11(d,J＝7.2Hz,2H),3.50-3.44(m,1H),3.20(s,3H),2.67(s,3H),2.04-1.90(m,1H),1.86-1.74(m,2H),1.47-1.20(m,6H)；m/z ES+[M+H] ⁺ 503.1。

EXAMPLE 135.4 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -N, N-dimethylcyclohexylamine

Step 1.4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -N, N-dimethylcyclohexylamine

To methanol (2)mL), 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ]]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of cyclohexanone (100 mg, 162. Mu. Mol) was added N-methyl methylamine hydrochloride (75.0 mg, 920. Mu. Mol). The mixture was stirred at 25℃for 0.2 h. Sodium cyanoborohydride (25.0 mg, 390 umol) was then added, and the mixture solution was stirred at 40℃for 11.8 hours. After completion, the mixture was quenched with 1N hydrochloric acid solution to adjust pH to 7, and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-N, N-dimethyl-cyclohexylamine (60 mg,92.9 μmol, 57%). M/zES + [ M+H ]] ⁺ 646.2。

Step 2.4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -N, N-dimethylcyclohexylamine

4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.8 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of N, N-dimethyl-cyclohexylamine (30 mg, 46.4. Mu. Mol) was stirred at 25℃for 1.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: unisil 3-100C18 Ultra150*50mm*3um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,10 min) purification to give 4- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-N, N-dimethyl-cyclohexylamine (9.1 mg, 17.6. Mu. Mol, 38%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.31(s,1H),8.70(d,J＝17.2Hz,1H),8.38(d,J＝4.8Hz,1H),8.18(s,1H),7.95(d,J＝9.2Hz,1H),7.51(br d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.20(s,1H),6.97-6.91(m,1H),4.30-4.10(m,2H),2.94-2.82(m,1H),2.61(s,6H),2.49(s,3H),2.04-1.82(m,2H),1.81-1.61(m,3H),1.57-1.42(m,2H),1.40-1.21(m,1H),1.18-1.02(m,1H)；m/z ES+[M+H] ⁺ 516.1。

Example 136.Synthesis of 2- (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-4-yl) ethanol

Step 1.2- (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-4-yl) ethanol

To 4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in acetonitrile (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (90.0 mg, 123. Mu. Mol) was added hydrochloric acid (6M, 1 mL). The mixture was stirred at 60℃for 3 hours. After completion, the reaction mixture was concentrated in vacuo and purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-4-yl ethanol (31.7 mg,55.3 μmol,45%, formate). ¹ HNMR(400MHz,DMSO-d6):δ＝9.38(s,1H),8.99(s,1H),8.43(s,1H),8.20(s,1H),7.97(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝1.6Hz,1H),6.94(dd,J＝2.0,8.4Hz,1H),3.31-3.15(m,4H),2.88-2.72(m,4H),2.49(s,3H),2.27(t,J＝11.6Hz,2H),2(t,J＝6.4Hz,2H)；m/zES+[M+H] ⁺ 504.1。

EXAMPLE 137.Synthesis of 2- (1- ((1 s,4 s) -2-oxabicyclo [2.1.1] hexan-1-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

(1 s,4 s) -1- (iodomethyl) -2-oxabicyclo [2.1.1] hexane

To atTo a solution of methyl tert-butyl ether (2 mL) and (3-methylenecyclobutyl) methanol (200 mg,2.04 mmol) in water (1 mL) was added sodium bicarbonate (348 mg,4.08 mmol) and iodine (1.03 g,4.08 mmol). The mixture was stirred at 25℃for 16 hours. After completion, the mixture was quenched with sodium thiosulfate (100 mg) and extracted with ethyl acetate (30 ml x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 10/1) to give (1 s,4 s) -1- (iodomethyl) -2-oxabicyclo [2.1.1] as a yellow oil]Hexane (70 mg,0.31mmol, 15%). ¹ H NMR(400MHz,CDCl ₃ ):δ＝3.85(s,2H),3.49(s,2H),2.87(t,J＝3.2Hz,1H),1.8-1.78(m,2H),1.57-1.55(m,2H)。

Step 2.2- (1- ((1 s,4 s) -2-oxabicyclo [2.1.1] hexan-1-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To (1S, 4 s) -1- (iodomethyl) -2-oxabicyclo [2.1.1 in N, -N1-dimethylformamide]Hexane (53.0 mg, 236. Mu. Mol) and 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ]]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (100 mg, 197. Mu. Mol) was added cesium carbonate (192 mg, 591. Mu. Mol). The mixture was stirred at 80℃for 16 hours. After completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (30 ml x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 2- (1- ((1 s,4 s) -2-oxabicyclo [ 2.1.1) as a yellow solid]Hexane-1-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (110 mg,182 μmol, 92%). M/zES + [ M+H ]] ⁺ 603.2。

Step 3.2- (1- ((1 s,4 s) -2-oxabicyclo [2.1.1] hexan-1-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Will be described in trifluoroacetic acid (1 mL)2- (1- ((1 s,4 s) -2-oxabicyclo [ 2.1.1) ]Hexane-1-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]Imidazol-6-yl) oxy) quinoxaline (110 mg, 182. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,10 min) purification to give 2- (1- ((1 s,4 s) -2-oxabicyclo [ 2.1.1) as a white solid]Hexane-1-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxaline (50.1 mg,106 μmol, 58%). ¹ H NMR(400MHz,CD ₃ OD):δ＝9.26-9.08(m,1H),8.55(s,1H),8.31(s,1H),7.97(d,J＝9.2Hz,1H),7.73(d,J＝9.2Hz,1H),7.46(d,J＝9.2Hz,1H),7.33-7.26(m,2H),4.60(s,2H),3.78(s,2H),2.94(t,J＝3.2Hz,1H),2.81(s,3H),1.94-1.83(m,2H),1.47(dd,J＝1.6,4.4Hz,2H)；m/z ES+[M+H] ⁺ 473.1。

EXAMPLE 138 Synthesis of (R) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydrothiophene 1, 1-dioxide and (S) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydrothiophene 1, 1-dioxide

(1, 1-tetrahydrothiophen-3-yl) methyl 4-methylbenzenesulfonate

To a solution of (1, 1-dioxothialan-3-yl) methanol (100 mg,666 umol) in dichloromethane (5 mL) was added 4-dimethylaminopyridine (80 mg,65 umol) and 4-methylbenzenesulfonyl chloride (126 mg, 661umol) at 0 ℃. Triethylamine (138 mg,1.37mmol, 190. Mu.L) was then added and the mixture was stirred at 25℃for 1 hour. After completion, the mixture was quenched with water (6 mL) and then extracted with dichloromethane (8 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was passed through a column Chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/2) gave (1, 1-dioxothian-3-yl) methyl 4-methylbenzenesulfonate (120 mg, 390 umol, 58%) as a white solid. ¹ H NMR(400MHz,CDCl ₃ ):δ＝7.79(d,J＝8.4Hz,2H),7.38(d,J＝8.0Hz,2H),4.15-4.02(m,2H),3.22-3.12(m,2H),3.09-2.98(m,1H),2.87-2.72(m,2H),2.47(s,3H),2.38-2.27(m,1H),2.02-1.89(m,1H)。

Step 2.3- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydrothiophene 1, 1-dioxide

To a solution of (1, 1-dioxothialan-3-yl) methyl 4-methylbenzenesulfonate (80 mg,263 umol) in N, N-dimethylformamide (3 mL) was added cesium carbonate (170 mg,522 umol) and 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ]]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (135 mg,266 umol). The mixture was stirred at 80℃for 4 hours. After completion, the mixture was quenched with water (3 mL) and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2- [ [6- [ 5-chloro-3- [1- [ (1, 1-dioxo-thialan-3-yl) methyl ] as a yellow oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (220 mg, crude). M/zES + [ M+H ] ] ⁺ 639.2。

Step 3.3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydrothiophene 1, 1-dioxide

2- [ [6- [ 5-chloro-3- [1- [ (1, 1-dioxo-thialan-3-yl) methyl ] in trifluoroacetic acid (3 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (220 mg,344 umol) was stirred at 25℃for 2 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: [ water (0.1% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 30% -62%,8 min) purification to give 3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazole-1-Base group]Methyl group]Thiane 1, 1-dioxide (120 mg,236umol, 67%). M/zES + [ M+H ]] ⁺ 509.3。

(R) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydrothiophene 1, 1-dioxide and (S) -3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydrothiophene 1, 1-dioxide

3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] thiane 1, 1-dioxide (120 mg,236 umol) was isolated by SFC (column: daicel Chiralcel OJ (250 mm. Times.30 mm. Times.10 um), mobile phase [ [0.1% ammonium hydroxide/ethanol ]; (B%: 60% -60%,3.5min, total run 40 min) and further purified by preparative HPLC (column: phenomenex Gemini-NX C18. Times.30 mm. 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 12% -42%,7 min) to give (3R) -3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] methyl ] thiane 1, 1-dioxide (58.5 min), and off-1- [ 9mg ] quinoxalin-2-yl ] methyl ] thiane 1, 1-3-ol (58.5 mg, 9%) as yellow solids and (3 mg, 28 mg) of 3- [ [ 3R) -3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl ] oxy ] quinoxalin-2-yl ] methyl ] thiane.

¹ H NMR(400MHz,DMSO-d6):δ＝9.33(s,1H),8.76(s,1H),8.41(s,1H),7.98(d,J＝8.8Hz,1H),7.57(d,J＝8.8Hz,1H),7.36(d,J＝9.2Hz,1H),7.27(s,1H),7.02(d,J＝8.8Hz,1H),4.40(d,J＝4.4Hz,2H),3.21(d,J＝5.6Hz,2H),3.13(d,J＝9.2Hz,1H),3(d,J＝6.8Hz,2H),2.55(s,3H),2.27-2.13(m,1H),1.99-1.82(m,1H)；m/z ES+[M+H] ⁺ 509.0。

¹ H NMR(400MHz,DMSO-d6):δ＝9.31(s,1H),8.75(s,1H),8.41(s,1H),8.19(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.98-6.90(m,1H),4.40(d,J＝4.8Hz,2H),3.29-3.20(m,2H),3.18-3.07(m,1H),3.04-2.96(m,2H),2.49(s,3H),2.25-2.13(m,1H),1.97-1.81(m,1H)；m/z ES+[M+H] ⁺ 509.0。

EXAMPLE 139.Synthesis of 2- (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamide

Step 1.2- (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamide

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in acetonitrile (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (70.0 mg, 118. Mu. Mol) and 2-bromoacetamide (18.0 mg, 130. Mu. Mol) were added sodium iodide (1.8 mg, 11.8. Mu. Mol) and potassium carbonate (32.8 mg, 237. Mu. Mol). The mixture was stirred at 60℃for 3 hours. After completion, the mixture was filtered and concentrated under reduced pressure to give 2- (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl acetamide (75 mg,116 μmol, 97%). M/zES + [ M+H ]] ⁺ 647.3。

Step 2.2- (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) acetamide

2- [4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1-piperidinyl group]A solution of acetamide (75 mg, 115. Mu. Mol) was stirred at 25℃for 0.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,5 min) purification to give 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl acetamide (25.5 mg,49.3 μmol, 42%). ¹ H NMR(400MHz,CD ₃ OD):δ＝9.18(s,1H),8.64(s,1H),8.44-8.31(m,1H),8.11(s,1H),7.93(d,J＝9.2Hz,1H),7.61(d,J＝8.8Hz,1H),7.39(d,J＝9.2Hz,1H),7.23(d,J＝2.4Hz,1H),7.12(dd,J＝2.4,8.8Hz,1H),4.64-4.50(m,1H),3.70(s,2H),3.53(d,J＝12.4Hz,2H),3.10-2.96(m,2H),2.67(s,3H),2.50-2.26(m,4H)；m/z ES+[M+H] ⁺ 517.1。

EXAMPLE 140 Synthesis of 2- (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-methylacetamide

Step 1.2- (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-methylacetamide

8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in acetonitrile (1 mL) ]A solution of imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (70 mg, 118. Mu. Mol), 2-chloro-N-methylacetamide (14.0 mg, 130. Mu. Mol) and potassium phosphate (50.3 mg, 237. Mu. Mol) was stirred at 40℃for 16 hours. After completion, the mixture was filtered and concentrated under reduced pressure to give 2- (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-methylacetamide (75 mg, crude). M/zES + [ M+H ]] ⁺ 661.3。

Step 2.2- (4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-methylacetamide

2- (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-methylacetamide (75 mg, crude) was stirred at 25 ℃ for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ Water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,7 min) purification to give 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -N-methylacetamide (38.0 mg, 71.6. Mu. Mol, 62%). ¹ H NMR(400MHz,CD ₃ OD):δ＝9.21(s,1H),8.66(s,1H),8.40(s,1H),8.12(s,1H),7.97(d,J＝9.2Hz,1H),7.69(d,J＝9.2Hz,1H),7.45(d,J＝9.2Hz,1H),7.29(d,J＝2.4Hz,1H),7.22(dd,J＝2.4,8.8Hz,1H),4.73-4.55(m,1H),3.81(s,2H),3.61(d,J＝12.4Hz,2H),3.24-3.11(m,2H),2.84(s,3H),2.76(s,3H),2.60-2.36(m,4H)；m/z ES+[M+H] ⁺ 531.1。

EXAMPLE 141.Synthesis of 4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N-methylpiperidine-1-carboxamide

Step 1.4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N-methylpiperidine-1-carboxamide

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in dichloromethane (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (70 mg, 118. Mu. Mol) and triethylamine (36.0 mg,355. Mu. Mol) was added methylcarbamoyl chloride (13.3 mg, 142. Mu. Mol). The mixture was stirred at 25℃for 1 hour. After completion, the mixture was poured into water (5 mL) and extracted with dichloromethane (10 ml×3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N-methylpiperidine-1-carboxamide (75 mg, crude). M/zES + [ M+H ]] ⁺ 647.2。

Step 2.4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N-methylpiperidine-1-carboxamide

4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N-methylpiperidine-1-carboxamide (75 mg,115 μmol) was stirred at 25 ℃ for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,7 min) purification to give 4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -N-methylpiperidine-1-carboxamide (34.4 mg,66.5 μmol, 57%). ¹ H NMR(400MHz,CD ₃ OD):δ＝9.16(d,J＝2.4Hz,1H),8.61(s,1H),8.33(s,1H),8.10(s,1H),7.92(d,J＝9.2Hz,1H),7.64(d,J＝8.8Hz,1H),7.40(d,J＝9.2Hz,1H),7.25(d,J＝2.0Hz,1H),7.17(dd,J＝2.4,8.0Hz,1H),4.59-4.43(m,1H),4.18(d,J＝13.6Hz,2H),3.09-2.95(m,2H),2.75(s,3H),2.71(s,3H),2.17(d,J＝10.8Hz,2H),2.07-1.96(m,2H)；m/z ES+[M+H] ⁺ 517.1。

EXAMPLE 142.8 Synthesis of chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (2- (oxetan-3-yl) -2-azabicyclo [2.2.1] heptan-5-yl) -1H-pyrazol-4-yl) quinoxaline

Step 1.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (2- (oxetan-3-yl) -2-azabicyclo [2.2.1] heptan-5-yl) -1H-pyrazol-4-yl) quinoxaline

To 2- (1- (2-azabicyclo [ 2.2.1) in methanol (1 mL)]Heptane-5-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d]To a solution of imidazol-6-yl) oxy quinoxaline (40.0 mg, 84.8. Mu. Mol) was added sodium cyanoborohydride (6.92 mg, 110. Mu. Mol), oxetan-3-one (18.3 mg, 254. Mu. Mol) and sodium acetate (9.04 mg, 110. Mu. Mol). The mixture was stirred at 25℃for 12 hours. After completion, the reaction mixture was quenched with water (0.2 mL) and depressurizedConcentrating under the condition. The residue was purified by preparative HPLC (neutral; column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 28% -58%,10 min) and purified by preparative HPLC (basic condition; column: waters Xridge 150X 25mm X5 um; mobile phase: [ water (0.05% ammonium hydroxide v/v) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 20% -50%,8 min) re-purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as a white solid]Imidazol-6-yl) oxy) -2- (1- (2- (oxetan-3-yl) -2-azabicyclo [2.2.1 ]Heptan-5-yl) -1H-pyrazol-4-yl) quinoxaline (33.7 mg, 63.9. Mu. Mol, 75%). ¹ H NMR(400MHz,DMSO-d6):δ＝12.40-12.19(m,1H),9.32(s,1H),8.82(s,1H),8.34(s,1H),7.96(d,J＝8.8Hz,1H),7.60-7.44(m,1H),7.38-7.14(m,2H),6.95(t,J＝8.0Hz,1H),4.67-4.54(m,3H),4.47(td,J＝5.6,20.0Hz,2H),3.99(t,J＝6.0Hz,1H),3.36(s,1H),2.62(td,J＝2.8,5.6Hz,1H),2.58(s,1H),2.50-2.48(m,3H),2.46(s,1H),2.26(dd,J＝2.8,13.2Hz,1H),2.05-1.96(m,1H),1.83(d,J＝10.0Hz,1H),1.54(d,J＝10.0Hz,1H)；m/z ES+[M+H] ⁺ 528.1。

EXAMPLE 143.Synthesis of 2- (5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-azabicyclo [2.2.1] heptan-2-yl) acetamide

Step 1.2- (5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-azabicyclo [2.2.1] heptan-2-yl) acetamide

To 2- (1- (2-azabicyclo [ 2.2.1) in N, N-dimethylformamide (1 mL)]Heptane-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]To a solution of imidazol-6-yl) oxy quinoxaline (100 mg, 162. Mu. Mol) was added cesium carbonate (159 mg, 487. Mu. Mol) and 2-bromoacetamide (22.4 mg, 162. Mu. Mol). The mixture was stirred at 25℃for 13 hours. After completion, the reaction mixture was quenched with water (0.2 mL)) and purifiedConcentrated under reduced pressure and the residue was purified by reverse phase HPLC (column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 2- (5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -2-azabicyclo [2.2.1]Heptane-2-yl) acetamide (40 mg,59.4 μmol, 32%). M/zES + [ M+H ]] ⁺ 673.5。

Step 2.2- (5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-azabicyclo [2.2.1] heptan-2-yl) acetamide

2- (5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -2-azabicyclo [2.2.1]A solution of heptane-2-yl) acetamide (40.0 mg, 59.4. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 2- (5- ((4- (8-chloro-7- ((2-methyl-1H-benzo) d) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -2-azabicyclo [2.2.1]Heptane-2-yl) acetamide (20.2 mg,37.3 μmol, 63%). ¹ H NMR(400MHz,DMSO-d6)δ12.72-11.72(m,1H),9.31(s,1H),8.74(s,1H),8.37(s,1H),8.16(s,1H),7.95(d,J＝9.2Hz,1H),7.54-7.41(m,2H),7.31(d,J＝9.2Hz,2H),7.20(s,1H),6.94(dd,J＝2.4,8.8Hz,1H),4.37(dd,J＝4.8,7.6Hz,2H),4.22-4.06(m,1H),3.43(s,1H),3.19(d,J＝14.4Hz,3H),2.89-2.65(m,1H),2.49(s,3H),2.25(s,1H),1.96-1.21(m,5H)；m/zES+[M+H] ⁺ 543.1。

Example 144.5 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-azabicyclo [2.2.1] heptane-2-carboxamide

Step 1.5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-azabicyclo [2.2.1] heptane-2-carboxamide

To 2- (1- (2-azabicyclo [ 2.2.1) in dichloromethane (1 mL)]Heptane-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]To a solution of imidazol-6-yl) oxy quinoxaline (130 mg, 211. Mu. Mol) was added diisopropylethylamine (81.8 mg, 633. Mu. Mol) followed by isocyanato (trimethyl) silane (29.2 mg, 253. Mu. Mol) at 0 ℃. The mixture was stirred at 25℃for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, ethyl acetate: ethanol=5:1) to give 5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -2-azabicyclo [2.2.1]Heptane-2-carboxamide (100 mg,152 μmol, 54%). M/zES + [ M+H ]] ⁺ 659.3。

Step 2.5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -2-azabicyclo [2.2.1] heptane-2-carboxamide

5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -2-azabicyclo [2.2.1]A solution of heptane-2-carboxamide (100 mg, 152. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was then adjusted to pH 8 with saturated ammonium hydroxide and then concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 21% -51%,10 min) purification to give 5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazole-1-yl) methyl) -2-azabicyclo [2.2.1]Heptane-2-carboxamide (11.1 mg,21.0 μmol, 14%). ¹ H NMR(400MHz,DMSO-d6):δ＝12.47-12.14(m,1H),9.31(s,1H),8.76(s,1H),8.36(s,1H),7.95(d,J＝9.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝2.0,8.8Hz,1H),5.73(s,2H),4.32-4.17(m,2H),4.12(s,1H),3.48(d,J＝10.0Hz,1H),3.08(d,J＝8.0Hz,1H),2.69-2.60(m,1H),2.49(s,3H),2.36-2.32(m,1H),1.84-1.74(m,1H),1.64(d,J＝8.0Hz,1H),1.58-1.47(m,1H),1.30-1.20(m,1H)；m/z ES+[M+H] ⁺ 529.1。

EXAMPLE 145.5 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -N-methyl-2-azabicyclo [2.2.1] heptane-2-carboxamide

Step 1.5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -N-methyl-2-azabicyclo [2.2.1] heptane-2-carboxamide

To 2- (1- (2-azabicyclo [ 2.2.1) in dichloromethane (1 mL)]Heptane-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]To a solution of imidazol-6-yl) oxy quinoxaline (80.0 mg, 130. Mu. Mol) was added triethylamine (39.4 mg, 389. Mu. Mol) and methylcarbamoyl chloride (14.6 mg, 156. Mu. Mol). The mixture was stirred at 25℃for 13 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, ethyl acetate: ethanol=10:1) to give 5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -N-methyl-2-azabicyclo [2.2.1]Heptane-2-carboxamide (80.0 mg,119 μmol, 76%). M/zES + [ M+H ]] ⁺ 673.2。

Step 2.5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -N-methyl-2-azabicyclo [2.2.1] heptane-2-carboxamide

5- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -N-methyl-2-azabicyclo [2.2.1 ]A solution of heptane-2-carboxamide (80.0 mg, 119. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,10 min) purification to give 5- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-methyl) -N-methyl-2-azabicyclo [2.2.1]Heptane-2-carboxamide (23.0 mg,42.3 μmol, 36%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.32(s,1H),8.76(s,1H),8.36(s,1H),7.98(d,J＝9.2Hz,1H),7.59(d,J＝8.8Hz,1H),7.36(d,J＝9.2Hz,1H),7.29(d,J＝2.0Hz,1H),7.04(dd,J＝2.4,8.8Hz,1H),6.13-5.96(m,1H),4.35-4.18(m,2H),4.13(s,1H),3.46(d,J＝9.6Hz,1H),3.09(dd,J＝2.4,9.6Hz,1H),2.67(d,J＝4.4Hz,1H),2.62-2.58(m,3H),2.57(s,3H),2.35(s,1H),1.89-1.71(m,1H),1.68-1.48(m,2H),1.36-1.13(m,1H)；m/z ES+[M+H] ⁺ 543.2。

Example 146.Synthesis of 2- (3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidin-1-yl) -N-methylacetamide

Step 1.2- (3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidin-1-yl) -N-methylacetamide

To 2- [1- (azetidin-3-ylmethyl) pyrazol-4-yl in tetrahydrofuran (3 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (50 mg,102umol, formic acid) was added triethylamine (31.7 mg,314 umol), potassium iodide (33.8 mg,203 umol) and 2-chloro-N-methyl-acetamide (10 mg,93 umol). The mixture was stirred at 25℃for 20 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mm X5 um; mobile phase: [ water (0.05% ammonium hydroxide v/v) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -42%,8 min) purification to give 2- [3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Azetidin-1-yl]-N-methyl-acetamide (17.9 mg,34.6umol, 34%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.31(s,1H),8.71(s,1H),8.36(s,1H),7.95(d,J＝9.2Hz,1H),7.61(br d,J＝3.6Hz,1H),7.50(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.20(d,J＝2.0Hz,1H),6.95-6.89(m,1H),4.48(d,J＝7.2Hz,2H),3.36(t,J＝7.2Hz,2H),3.11(t,J＝6.4Hz,2H),2.99(s,2H),2.93-2.85(m,1H),2.58(d,J＝4.4Hz,3H),2.48(s,3H)；m/z ES+[M+H] ⁺ 517.1。

Example 147.Synthesis of 1- (azetidin-1-yl) -2- (3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidin-1-yl) ethanone

Step 1.1- (azetidin-1-yl) -2- (3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidin-1-yl) ethanone

To 2- [1- (azetidin-3-ylmethyl) pyrazol-4-yl in N, N-dimethylformamide (1.5 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (55 mg,123 umol) were added potassium carbonate (55.0 mg, 390 umol), 1- (azetidin-1-yl) -2-chloro-ethanone (16 mg,120 umol) and potassium iodide (55.0 mg,331 umol). The mixture was stirred at 25℃for 2 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mm X5 um; mobile phase: [ water (0.05% ammonium hydroxide v/v) -acetonitrile ]；(B％：15％-45％，8 min) and purified by preparative HPLC (column: phenomenex Gemini-NX C18 75 x 30mm x 3um; mobile phase: [ Water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,8 min) repurification to give 1- (azetidin-1-yl) -2- [3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as an off-white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Azetidin-1-yl]Ethanone (10.0 mg,18.4umol,14% formate). ¹ H NMR(400MHz,DMSO-d6):δ＝9.30(s,1H),8.71(s,1H),8.35(s,1H),8.22(s,1H),7.94(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.30(d,J＝9.2Hz,1H),7.21(s,1H),6.94(d,J＝8.8Hz,1H),4.44(d,J＝7.2Hz,2H),4.10(t,J＝7.6Hz,2H),3.81(t,J＝7.6Hz,2H),3.40(t,J＝7.6Hz,2H),3.18(t,J＝6.4Hz,2H),3.10(s,2H),2.99-2.87(m,1H),2.49(br s,3H),2.23-2.10(m,2H)；m/z ES+[M+H] ⁺ 543.1。

EXAMPLE 148 Synthesis of 2- (3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidin-1-yl) -1- (3-hydroxyazetidin-1-yl) ethanone

Step 1.2- (3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidin-1-yl) -1- (3-hydroxyazetidin-1-yl) ethanone

To 2- [1- (azetidin-3-ylmethyl) pyrazol-4-yl in 1-methyl-2-pyrrolidone (1 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (60 mg,122umol, formic acid) were added sodium phosphate (58 mg,354 umol) and 2-chloro-1- (3-hydroxyazetidin-1-yl) ethanone (18.0 mg,120 umol). The mixture was stirred at 40℃for 2.5 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mm X5 um; mobile phase: [ water (0.05% ammonium hydroxide v/v) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -42%,8 min) purification to give 2- [3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxaline-2-yl]Pyrazol-1-yl]Methyl group]Azetidin-1-yl]-1- (3-hydroxyazetidin-1-yl) ethanone (29.8 mg,53.3umol, 44%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.30(s,1H),8.71(s,1H),8.35(s,1H),7.95(d,J＝9.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.20(d,J＝2.0Hz,1H),6.96-6.90(m,1H),4.46-4.38(m,3H),4.28(t,J＝8.0Hz,1H),4.03-3.95(m,1H),3.88-3.80(m,1H),3.55(d,J＝4.4Hz,1H),3.32(t,J＝7.2Hz,2H),3.07(t,J＝6.4Hz,2H),3.02(s,2H),2.94-2.85(m,1H),2.48(s,3H)；m/z ES+[M+H] ⁺ 559.1。

Example 149.Synthesis of 2- (3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidin-1-yl) acetonitrile

Step 1.2- (3- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) azetidin-1-yl) acetonitrile

To 2- [1- (azetidin-3-ylmethyl) pyrazol-4-yl in acetonitrile (2 mL)]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (55 mg, 112. Mu.l, formate) were added potassium carbonate (33 mg, 239. Mu.l) and 2-bromoacetonitrile (11 mg, 91.7. Mu.l). The mixture was stirred at 25℃for 4 hours. After completion, the mixture was quenched with water (2 mL) and extracted with ethyl acetate (4 ml×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative TLC (silica gel, dichloromethane: methanol=12:1) to give 2- [3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as an off-white solid ]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Azetidin-1-yl]Acetonitrile (34.9 mg,72umol, 63%). ¹ H NMR(400MHz,DMSO-d6):δ＝12.51-12.16(m,1H),9.28(s,1H),8.72(s,1H),8.34(s,1H),7.93(d,J＝9.2Hz,1H),7.51(d,J＝2.0Hz,1H),7.36-7.13(m,2H),6.94(d,J＝6.4Hz,1H),4.43(d,J＝7.2Hz,2H),3.61(s,2H),3.39-3.35(m,2H),3.16(t,J＝6.0Hz,2H),3-2.87(m,1H),2.49(s,3H)；m/z ES+[M+H] ⁺ 485.1。

Example 150.Synthesis of 1- (azetidin-1-yl) -2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanone

Step 1.1- (azetidin-1-yl) -2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanone

Sodium hydride (25 mg,630 μmol,60% in mineral oil) was added to a solution of 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane (100 mg,200 μmol) in tetrahydrofuran (2 mL) at 25 ℃. The mixture was stirred at 25℃for 0.5 h. 1- (azetidin-1-yl) -2-chloro-ethanone (38 mg, 290. Mu. Mol) was then added. The reaction mixture was stirred at 60℃for 1.5 hours. After completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with brine (25 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- (azetidin-1-yl) -2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow oil

Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethanone (220 mg, crude). M/zES + [ M+H ]] ⁺ 604.3。

Step 2.1- (azetidin-1-yl) -2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethanone

1- (azetidin-1-yl) -2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of ethanone (200 mg, 330. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: A)Alcohol=10:1) to give 1- (azetidin-1-yl) -2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Ethanone (17.8 mg, 37.6. Mu. Mol, 11.3%). ¹ HNMR(400MHz,DMSO-d6):δ＝12.40-12.18(m,1H),9.33(s,1H),8.66(s,1H),8.38(s,1H),7.96(d,J＝8.8Hz,1H),7.58-7.43(m,1H),7.32(d,J＝10.4Hz,1H),7.27-7.14(m,1H),6.95(t,J＝8.8Hz,1H),4.99(s,2H),4.21(t,J＝8.0Hz,2H),3.93(t,J＝7.6Hz,2H),2.49-2.47(m,3H),2.35-2.20(m,2H)；m/zES+[M+H] ⁺ 474.1。

EXAMPLE 151 Synthesis of 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-hydroxyazetidin-1-yl) ethanone

Step 1.2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-hydroxyazetidin-1-yl) ethanone

To a solution of 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane (150 mg, 295. Mu. Mol) in tetrahydrofuran (3 mL) was added sodium hydride (17.7 mg, 447 umol,60% in mineral oil) at 25 ℃. The mixture was stirred at 25℃for 0.5 h. 2-chloro-1- (3-hydroxyazetidin-1-yl) ethanone (66.4 mg, 443. Mu. Mol) was then added. The resulting mixture was stirred at 60℃for 1.5 hours. After completion, the reaction mixture was quenched with water (20 mL) at 25 ℃. The mixture was then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% ammonium hydroxide condition) to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] as a yellow solid

Pyrazol-1-yl]-1- (3-hydroxyazetidin-1-yl) ethanone (80.0 mg, 129. Mu. Mol, 40%). ¹ H NMR(400MHz,CDCl ₃ ):δ＝9(d,J＝4.0Hz,1H),8.41(d,J＝2.8Hz,1H),8.29(d,J＝2.0Hz,1H),7.90-7.83(m,1H),7.68(d,J＝8.8Hz,1H),7.45-7.38(m,1H),7.15(d,J＝2.4Hz,1H),7.10-7.01(m,1H),5.50(s,1H),5.41(s,1H),4.88(s,2H),4.75-4.65(m,1H),4.42-4.29(m,2H),4.10-3.93(m,2H),3.58-3.49(m,2H),2.67(d,J＝2.4Hz,3H),0.94-0.85(m,2H),-0.04(d,J＝16.0Hz,9H)。

Step 2.2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-hydroxyazetidin-1-yl) ethanone

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.5 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1- (3-hydroxyazetidin-1-yl) ethanone (75.0 mg, 120. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mm X5 um; mobile phase: [ water (0.05% ammonium hydroxide v/v) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 14% -44%,8 min) purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as an off-white solid]Quinoxalin-2-yl]Pyrazol-1-yl]1- (3-hydroxyazetidin-1-yl) ethanone (22.1 mg, 45. Mu. Mol, 36%). ¹ H NMR(400MHz,DMSO-d6):δ＝12.44-12.15(m,1H),9.33(s,1H),8.66(s,1H),8.38(s,1H),8.06-7.89(m,1H),7.58-7.43(m,1H),7.38-7.14(m,2H),7-6.89(m,1H),5.80(d,J＝6.0Hz,1H),5.02(s,2H),4.58-4.46(m,1H),4.41-4.33(m,1H),4.18-4.07(m,1H),3.98-3.89(m,1H),3.70-3.62(m,1H),2.49(s,3H)；m/z ES+[M+H] ⁺ 490.1。

EXAMPLE 152.Synthesis of 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) acetamide

Step 1.2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) acetamide

To 2- [ [6- [ 5-chloro- ] in acetonitrile (3 mL)3- (1H-pyrazol-4-yl) quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (100 mg, 197umol) was added cesium carbonate (200 mg,614 umol), potassium iodide (70 mg, 428 umol) and 2-bromoacetamide (30.0 mg,218 umol). The mixture was stirred at 80℃for 2 hours. After completion, the mixture was quenched with water (3 mL) and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Acetamide (110 mg, crude). M/zES + [ M+H ]] ⁺ 564.2。

Step 2.2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) acetamide

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of acetamide (110 mg, 195. Mu. Mol) was stirred at 25℃for 2 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 8% -38%,7 min) purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]Acetamide (45.5 mg, 105. Mu. Mol, 54%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.34(s,1H),8.67(s,1H),8.37(s,1H),7.98(d,J＝9.2Hz,1H),7.64(s,1H),7.57(d,J＝8.8Hz,1H),7.35(d,J＝9.2Hz,2H),7.27(d,J＝2.4Hz,1H),7.05-6.98(m,1H),4.92(s,2H),2.54(s,3H)；m/z ES+[M+H] ⁺ 434.0。

Example 153.Synthesis of 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-hydroxypyrrolidin-1-yl) ethanone

Step 1.2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) acetic acid ethyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in tetrahydrofuran (20 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Sodium hydride (118 mg,2.96mmol,60% in mineral oil) was added to a solution of ethyl-trimethylsilane (500 mg, 986. Mu. Mol) and the mixture was stirred at 25℃for 0.5 h. Ethyl 2-bromoacetate (247 mg,1.48mmol, 164. Mu.L) was then added, and the mixture was stirred at 60℃for 1.5 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) at 20 ℃ and then diluted with water (70 mL). The mixture was extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with brine (150 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by column chromatography (silica gel, dichloromethane: ethanol=90:1 to 80:1) to give 2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl ethyl acetate (280 mg,0.47mmol, 48%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.36-9.34(m,1H),8.73(s,1H),8.42(s,1H),7.97(d,J＝9.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.44(d,J＝2.4Hz,1H),7.34(d,J＝9.2Hz,1H),7.01(dd,J＝2.4,8.8Hz,1H),5.54(s,2H),5.24(s,2H),4.20(q,J＝7.2Hz,2H),3.48(t,J＝8.0Hz,2H),2.56(s,3H),1.24(t,J＝7.2Hz,3H),0.79(t,J＝8.0Hz,2H),-0.14(s,9H)；m/z ES+[M+H] ⁺ 593.1。

Step 2.2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-hydroxypyrrolidin-1-yl) ethanone

To a solution of pyrrolidin-3-ol (29.4 mg, 337. Mu. Mol) in ethanol (2 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido [1,2-a ]]Pyrimidine (46.9 mg, 337. Mu. Mol) and 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl acetate (100 mg, 169. Mu. Mol). The mixture was stirred at 25℃for 2 hours. After completion, willThe reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC (silica gel, dichloromethane: ethanol=10:1) to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1- (3-hydroxypyrrolidin-1-yl) ethanone (38 mg, 60. Mu. Mol, 36%). M/zES + [ M+H ]] ⁺ 634.2。

Step 3.2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-hydroxypyrrolidin-1-yl) ethanone

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.8 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1- (3-hydroxypyrrolidin-1-yl) ethanone (35.0 mg, 55.2. Mu. Mol) was stirred at 25℃for 2 hours. After completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC (column: phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 3% -33%,10 min) purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow gum]Quinoxalin-2-yl]Pyrazol-1-yl]-1- (3-hydroxypyrrolidin-1-yl) ethanone (7.7 mg, 15.3. Mu. Mol, 28%). ¹ H NMR(400MHz,DMSO-d6):δ＝9.33(s,1H),8.64(s,1H),8.36(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.22(d,J＝2.0Hz,1H),6.95(dd,J＝2.4,8.8Hz,1H),5.22(d,J＝2.0Hz,1H),5.17(d,J＝6.8Hz,1H),4.41-4.28(m,1H),3.67-3.60(m,2H),3.42-3.32(m,3H),2.49(s,3H),2.05-1.74(m,2H)；m/z ES+[M+H] ⁺ 504.1。

Example 154.Synthesis of 1- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol

Step 1.1- (3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in methanol (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of cyclobutanone (130 mg, 230. Mu. Mol), azetidine-3-ol hydrochloride (74 mg, 680. Mu. Mol), titanium tetraisopropoxide (130 mg, 450. Mu. Mol, 130. Mu. L) and diisopropylethylamine (88 mg, 680. Mu. Mol, 120. Mu. L) was stirred at 60℃for 2 hours. Sodium cyanoborohydride (14 mg, 230. Mu. Mol) was then added and the reaction mixture was stirred at 25℃for 2 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 1- (3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a white solid ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol (25 mg,40 μmol, 17%). M/zES + [ M+H ]] ⁺ 632.5。

Step 2.1- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) cyclobutyl) azetidin-3-ol

1- [3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (0.3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutyl group]A solution of azetidin-3-ol (20 mg, 31. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,10 min) purification to give 1- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Cyclobutyl group]Azetidin-3-ol (8.4 mg, 16. Mu. Mol,44% formate). ¹ HNMR(400MHz,DMSO-d6):δ＝9.35-9.29(m,1H),8.80(d,J＝8.0Hz,1H),8.40(d,J＝1.6Hz,1H),8.15(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝2.0,8.8Hz,1H),5.16-4.70(m,1H),4.34-4.26(m,1H),3.75-3.69(m,2H),3.45(s,1H),3.35-3.30(m,1H),3.22(s,1H),3.02(s,1H),2.69-2.57(m,2H),2.49(s,3H),2.43-2.31(m,2H)；m/z ES+[M+H] ⁺ 502.1。

Example 155.synthesis of 8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -3-methyl-1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -5-methyl-1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.2- [ [6- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] -5-methyl-pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [6- [ 5-chloro-3- (5-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 383. Mu. Mol) was added potassium carbonate (1599 mg,1.15 mmol) and (3, 3-difluorocyclobutyl) methyl methanesulfonate (99.8 mg, 498. Mu. Mol). The mixture was stirred at 80℃for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (0.1% ammonium hydroxide) to give 2- [ [6- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]-5-methyl-pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (mixture of regioisomers, 70.0mg,111 μmol, 28%). M/zES + [ M+H ]] ⁺ 625.2。

Step 2.8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] -5-methyl-pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

To 2- [ [6- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in trifluoroacetic acid (0.5 mL) ]-5-methyl-pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (60.0 mg, 95.9. Mu. Mol) was added trifluoroacetic acid (923 mg,8.10 mmol). The mixture was stirred at 2Stirred at 5℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 20% -50%,7 min) purification to give 8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a white solid]-5-methyl-pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (mixture of regioisomers, 45.0mg, 90.9. Mu. Mol, 94%). M/zES + [ M+H ]] ⁺ 495.0。

Step 3.8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] -3-methyl-pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline and 8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] -5-methyl-pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] -5-methyl-pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline (45.0 mg, 43.0. Mu. Mol) was isolated by SFC (column: daicel Chiralpak AD (250 mm. Times.30 mm, 10. Mu.); mobile phase: [ methanol-acetonitrile ]; (B%: 60% -60%,6min, total run 60 min) to give 8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] -3-methyl-pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline (21.3 mg, 43.0. Mu. Mol, 47%) as a white solid and 8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] -5-methyl-pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline (15.34 mg,32. Mu. Mol) as a white solid.

¹ H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.80(s,1H),7.96(d,J＝9.2Hz,1H),7.55(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.25(d,J＝2.4Hz,1H),6.01-6.96(m,1H),4.28(d,J＝6.0Hz,2H),2.77-2.70(m,2H),2.70(s,3H),2.68-2.66(m,1H),2.57-2.53(m,2H),2.52(s,3H)；m/z ES+[M+H] ⁺ 495.0。

¹ H NMR(400MHz,DMSO-d6)δ12.54-12.11(m,1H),9.32(s,1H),8.44(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.30(d,J＝9.2Hz,1H),7.22(d,J＝2.0Hz,1H),6.97-6.92(m,1H),4.33(d,J＝5.6Hz,2H),2.90(s,3H),2.73-2.63(m,3H),2.58-2.52(m,2H),2.49(s,3H)；m/z ES+[M+H] ⁺ 495.0。

Example 156.Synthesis of 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-methoxypyrrolidin-1-yl) ethan-1-one

Step 1.2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-methoxypyrrolidin-1-yl) ethan-1-one

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in dichloromethane (1.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Acetic acid (100 mg, 176. Mu. Mol), 3-methoxypyrrolidine (36.0 mg, 265. Mu. Mol) and 3- (ethyliminomethyleneamino) propyl-dimethylaminoonium; to a mixture of chlorides (50.8 mg, 265. Mu. Mol) were added hydroxybenzotriazole (35.8 mg, 265. Mu. Mol) and diisopropylethylamine (68.6 mg, 530. Mu. Mol). The reaction mixture was stirred at 25 ℃ for 2 hours. After completion, the reaction mixture was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (2×20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1- (3-methoxypyrrolidin-1-yl) ethanone (110 mg, 169. Mu. Mol, 96%). M/zES + [ M+H ]] ⁺ 648.1。

Step 2.2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (3-methoxypyrrolidin-1-yl) ethan-1-one

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A mixture of 1- (3-methoxypyrrolidin-1-yl) ethanone (90.0 mg, 138. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated in vacuo and the residue was taken up in the preparative formHPLC (column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 25% -55%,8 min) purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-1- (3-methoxypyrrolidin-1-yl) ethanone (23.5 mg, 45.5. Mu. Mol, 33%). ¹ H NMR(400MHz,DMSO-d6)δ12.78-11.97(m,1H),9.34(s,1H),8.64(s,1H),8.37(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.0Hz,1H),7.22(d,J＝2.0Hz,1H),6.95(m,1H),5.29-5.13(m,2H),4.11-3.94(m,1H),3.72-3.46(m,4H),3.27(d,J＝16.0Hz,3H),2.49(s,3H),2.13-1.90(m,2H)；m/z ES+[M+H] ⁺ 518.1。

EXAMPLE 157.4 Synthesis of- ((4- (8-bromo-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydro-2H-thiopyran 1, 1-dioxide and 3- (2- (4- (8-bromo-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) tetrahydrothiophene 1, 1-dioxide

Step 1.8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((tetrahydro-2H-thiopyran-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

To 2- [ [6- [ 5-bromo-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (1 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (30.0 mg, 54.4. Mu. Mol) and tetrahydrothiopyran-4-ylmethyl mesylate (14.9 mg, 70.7. Mu. Mol) was added potassium carbonate (22.6 mg, 163. Mu. Mol). The mixture was stirred at 80℃for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) -2- (1- ((tetrahydro-2H-thiopyran-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (35.0 mg, crude).m/zES+[M+H] ⁺ 667.2。

Step 2.4- ((4- (8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydro-2H-thiopyran 1, 1-dioxide

To 2- [ [6- [ 5-bromo-3- [1- (tetrahydrothiopyran-4-ylmethyl) pyrazol-4-yl ] in dichloromethane (1 mL) at 0deg.C]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (35.0 mg, 52.6. Mu. Mol) was added meta-chloroperbenzoic acid (23.5 mg, 116. Mu. Mol,85% purity). The mixture was stirred at 25℃for 2 hours. The mixture was poured into aqueous sodium sulfite solution (20 mL), and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 4- ((4- (8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl-tetrahydro-2H-thiopyran 1, 1-dioxide (36.0 mg, crude). M/zES + [ M+H ]] ⁺ 697.2。

Step 3.4- ((4- (8-bromo-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydro-2H-thiopyran 1, 1-dioxide and 3- (2- (4- (8-bromo-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) tetrahydrothiophene 1, 1-dioxide

A solution of 2- [ [6- [ 5-bromo-3- [1- [ (1, 1-dioxothian-4-yl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane (36.0 mg, 51.6. Mu. Mol) in trifluoroacetic acid (1 mL) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: phenomenex Luna C, 150, 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 11% -41%,10 min) to give 4- ((4- (8-bromo-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydro-2H-thiopyran 1, 1-dioxide (3.8 mg,6.6 μmol, 13%) and 3- (2- (4- (8-bromo-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) ethyl) tetrahydrothiophene 1, 1-dioxide (8.2 mg,14.3 μmol, 28%) as a white solid.

¹ H NMR(400MHz,DMSO-d6)δ＝9.28(s,1H),8.70(s,1H),8.40(s,1H),8.18(s,1H),7.99(d,J＝9.2Hz,1H),7.59-7.43(m,1H),7.36-7.11(m,2H),6.93(d,J＝6.4Hz,1H),4.25(d,J＝7.2Hz,2H),3.14(d,J＝12.0Hz,2H),3.09-3.02(m,2H),2.49-2.48(m,3H),2.31-2.22(m,1H),1.93(d,J＝13.2Hz,2H),1.72(d,J＝12.4Hz,2H)；m/z ES+[M+H] ⁺ 569.0。

¹ H NMR(400MHz,DMSO-d6)δ＝9.28(s,1H),8.74(s,1H),8.38(s,1H),8.16(s,1H),7.99(d,J＝9.2Hz,1H),7.57-7.46(m,1H),7.33-7.14(m,2H),6.97-6.90(m,1H),4.31(t,J＝6.8Hz,2H),3.27-3.15(m,2H),3.08-2.98(m,1H),2.85-2.77(m,1H),2.49-2.48(m,3H),2.34-2.24(m,2H),2.11-2.02(m,2H),1.80(t,J＝10.4Hz,1H)；m/z ES+[M+H] ⁺ 569.0。

EXAMPLE 158 Synthesis of 1- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -2-methyl-propan-2-ol

Step 1.1- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -2-methyl-propan-2-ol

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (1.5 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (100 mg, 197. Mu. Mol) was added cesium carbonate (193 mg, 592. Mu. Mol) and 2, 2-dimethylethylene oxide (15.6 mg, 217. Mu. Mol). The mixture was stirred at 100℃for 2 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 ml×3). The combined organic layers were washed with brine (3 ml×3), dried over sodium sulfate, filtered and concentrated in vacuo to give 1- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazole-1-yl]-2-methyl-propan-2-ol (200 mg, crude). ¹ H NMR(400MHz,DMSO-d6)δ9.34(d,J＝4.0Hz,1H),8.61(s,1H),8.36(s,1H),7.95(s,1H),7.70-7.55(m,1H),7.47-7.23(m,2H),7.01(br dd,J＝2.0,8.8Hz,1H),5.67-5.45(m,2H),4.84(s,1H),4.15(s,2H),3.61-3.43(m,2H),2.57(br d,J＝7.2Hz,3H),1.13(s,6H),0.79(s,2H),-0.01--0.11(m,4H),-0.12--0.19(m,5H)。

Step 2.1- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -2-methyl-propan-2-ol

1- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazolo in trifluoroacetic acid (0.2 mL)

-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 2-methyl-propan-2-ol (200 mg, 345. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Luna C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,10 min) and then purified by preparative HPLC (column: shim-pack C18. Times.25.times.10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) re-purification to give 1- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-2-methyl-propan-2-ol (42.4 mg, 94.4. Mu. Mol, 27%). ¹ H NMR(400MHz,DMSO-d6)δ12.66-11.98(m,1H),9.33(s,1H),8.61(s,1H),8.36(s,1H),8.19(s,1H),7.96(d,J＝9.2Hz,1H),7.51(br d,J＝7.6Hz,1H),7.32(br d,J＝9.2Hz,1H),7.21(br s,1H),6.94(br d,J＝8.8Hz,1H),4.83(br s,1H),4.16(s,2H),2.49-2.49(m,3H),1.14(s,6H)；m/z ES+[M+H] ⁺ 449.1。

EXAMPLE 159.Synthesis of 8-chloro-2- [1- [ (3-methoxycyclobutyl) methyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] cyclobutanol

To 3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in ethanol (1.5 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of cyclobutanone (140 mg, 238. Mu. Mol) was added sodium borohydride (18.0 mg, 475. Mu. Mol). The mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with water (3 mL) at 0 ℃ and then extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 ml x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give 3- [ [4- [ 8-chloro-7- [ 2-methyl-3-2 trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Cyclobutylalcohol (110 mg, 186. Mu. Mol, 78%). M/zES + [ M+H ]] ⁺ 591.1。

Step 2.2- [ [6- [ 5-chloro-3- [1- [ (3-methoxycyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in tetrahydrofuran (1 mL) at 0deg.C]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of cyclobutanol (100 mg, 169. Mu. Mol) was added aqueous sodium hydroxide (10.2 mg, 254. Mu. Mol,60 wt%). The mixture was stirred at 0℃for 0.5 h. Methyl iodide (24.0 mg, 169. Mu. Mol) was then added. The mixture was stirred at 25℃for 1.5 hours. The reaction mixture was quenched with water (6 mL) at 0 ℃ and then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 ml x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give 2- [ [6- [ 5-chloro-3- [1- [ (3-methoxycyclobutyl) methyl ] as a brown solid ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (140 mg, crude). M/zES + [ M+H ]] ⁺ 605.2。

Step 3.8-chloro-2- [1- [ (3-methoxycyclobutyl) methyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro- ] in trifluoroacetic acid (1.5 mL)3- [1- [ (3-methoxycyclobutyl) methyl]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A mixture of ethyl-trimethyl-silane (140 mg, 231. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,10 min) purification to give 8-chloro-2- [1- [ (3-methoxycyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (26.3 mg, 55.4. Mu. Mol, 24%). ¹ H NMR(400MHz,DMSO-d6)δ9.33(d,J＝1.6Hz,1H),8.77-8.66(m,1H),8.35(s,1H),8.14(d,J＝2.0Hz,1H),7.99(br d,J＝9.2Hz,1H),7.65(br d,J＝8.8Hz,1H),7.38(br d,J＝9.2Hz,1H),7.33(s,1H),7.10(br d,J＝8.8Hz,1H),4.37-4.21(m,2H),4-3.70(m,1H),3.17-3.03(m,3H),2.79-2.68(m,1H),2.67(br s,1H),2.62(s,3H),2.33-2.10(m,2H),1.66(br d,J＝8.0Hz,2H)；m/zES+[M+H] ⁺ 475.1。

EXAMPLE 160.Synthesis of 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanamide

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (14 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (700 mg,1.38 mmol) and ethyl 3-methylbut-2-enoate (265 mg,2.07mmol, 288. Mu.L) was added cesium carbonate (900 mg,2.76 mmol). The mixture was stirred at 25 ℃ for 48 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum etherEthyl acetate = 1/0 to 1/9) to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanoic acid ethyl ester (340 mg, 455. Mu. Mol, 33%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.38-9.36(m,1H),8.79(s,1H),8.34(s,1H),7.96(d,J＝9.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.44(d,J＝2.3Hz,1H),7.34-7.30(m,1H),7.01(dd,J＝2.4,8.8Hz,1H),5.56-5.52(m,2H),3.96(q,J＝7.2Hz,2H),3.51-3.46(m,2H),3(s,2H),2.57-2.54(m,3H),1.73(s,6H),1.07(t,J＝7.2Hz,3H),0.81-0.75(m,2H),-0.12--0.16(m,9H)。

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in methanol (2.5 mL), tetrahydrofuran (2.5 mL) and water (2.5 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of ethyl 3-methyl-butyrate (270 mg, 361. Mu. Mol,85% purity) was added lithium hydroxide monohydrate (45.5 mg,1.08 mmol). The mixture was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo and then adjusted to pH-5 with aqueous citric acid. The mixture was filtered and the filter cake was collected to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanoic acid (150 mg, crude product). M/zES + [ M+H ]] ⁺ 607.3。

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in N, N-dimethylformamide (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of 3-methyl-butyric acid (150 mg, 247. Mu. Mol) and ammonium chloride (132 mg,2.47 mmol) were added diisopropylethylamine (95.8 mg, 741. Mu. Mol, 129. Mu.L) and 2- (7-aza-1H-benzotriazole-1-yl) -1, 3-tetramethyluronium hexafluorophosphate (141 mg, 371. Mu. Mol). The mixture was stirred at 25℃for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanamide (180 mg, crude). M/zES + [ M+H ]] ⁺ 606.3。

3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 3-methyl-butyramide (50.0 mg, 82.5. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,10 min) purification to give 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an off-white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -3-methylbutanamide (17.8 mg,37.4 μmol, 45%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.36(s,1H),8.75(s,1H),8.35(s,1H),7.96(d,J＝9.2Hz,1H),7.53(d,J＝8.6Hz,1H),7.33-7.27(m,2H),7.23(s,1H),6.97(d,J＝8.6Hz,1H),6.82(s,1H),2.74(s,2H),2.49-2.48(m,3H),1.73(s,6H)；m/z ES+[M+H] ⁺ 476.1。

EXAMPLE 161 Synthesis of 8-chloro-2- [1- [ (3, 3-difluorocyclopentyl) methyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

(3, 3-Difluorocyclopentyl) methyl methanesulfonate

To a solution of (3, 3-difluorocyclopentyl) methanol (100 mg, 730. Mu.L) in dichloromethane (3 mL) were added triethylamine (145 mg,1.44mmol, 200. Mu.L) and methyl methane disulfonyl chloride (104 mg, 284. Mu.L, 70. Mu.L). The mixture was stirred at 0 ℃ for 1 hour. After completion, the mixture was quenched with water (3 mL) and extracted with ethyl acetate (10 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give (3, 3-difluorocyclopentyl) methyl methanesulfonate (200 mg, crude) as a yellow oil.

Step 2.2- [ [6- [ 5-chloro-3- [1- [ (3, 3-difluorocyclopentyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To (3, 3-difluorocyclopentyl) methyl mesylate (66.4 mg,310 umol) and 2- [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Potassium carbonate (75.0 mg,543 umol) was added to a solution of ethyl-trimethyl-silane (100 mg, 197umol). The mixture was stirred at 80℃for 12 hours. After completion, the mixture was quenched with water (3 mL) and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1 to 0/1) to give 2- [ [6- [ 5-chloro-3- [1- [ (3, 3-difluorocyclopentyl) methyl ] as a yellow oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (100 mg,160 μmol, 80%). M/zES + [ M+H ]] ⁺ 625.2。

Step 3.8-chloro-2- [1- [ (3, 3-difluorocyclopentyl) methyl ] pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [ 5-chloro-3- [1- [ (3, 3-difluorocyclopentyl) methyl ] in trifluoroacetic acid (2 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (100 mg,160 umol) was stirred at 20℃for 2 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]；(B％：20％-50％，7min) and purified by preparative HPLC (column: waters Xbridge 150 x 25mm x 5um; mobile phase: [ Water (0.05% ammonium hydroxide v/v) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 33% -63%,9 min) re-purification to give 8-chloro-2- [1- [ (3, 3-difluorocyclopentyl) methyl ] as a white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (27 mg, 54. Mu. Mol, 34%). ¹ HNMR(400MHz,DMSO-d6)δ12.60-12(m,1H),9.31(s,1H),8.74(s,1H),8.38(s,1H),7.95(d,J＝9.2Hz,1H),7.51(br d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(br s,1H),7.01-6.86(m,1H),4.28(d,J＝7.2Hz,2H),2.79-2.64(m,1H),2.49(br s,3H),2.28-1.80(m,5H),1.65-1.53(m,1H)；m/z ES+[M+H] ⁺ 495.1。

EXAMPLE 162.Synthesis of 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -1- (3, 3-difluoropyrrolidin-1-yl) ethanone

Step 1.2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -1- (3, 3-difluoropyrrolidin-1-yl) ethanone

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of acetic acid (100 mg, 177. Mu. Mol), 3-difluoropyrrolidine hydrochloride (38.1 mg, 265. Mu. Mol) and diisopropylethylamine (68.6 mg, 531. Mu. Mol, 92.5. Mu.L) was added 3- (ethyliminomethyleneamino) propyl-dimethylaminoonium; chloride (50.9 mg, 265. Mu. Mol) and hydroxybenzotriazole (35.9 mg, 265. Mu. Mol). The mixture was stirred at 25℃for 2 hours. After completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 ml×2). The combined organic layers were washed with brine (60 ml x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1- (3, 3-difluoropyrrolidine)-1-yl) ethanone (121 mg, crude). M/zES + [ M+H ]] ⁺ 654.2。

Step 2.2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -1- (3, 3-difluoropyrrolidin-1-yl) ethanone

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1.8 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1- (3, 3-difluoropyrrolidin-1-yl) ethanone (112 mg, 171. Mu. Mol) was stirred at 25℃for 2 hours. After completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC (column: phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 9% -39%,10 min) purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-1- (3, 3-difluoropyrrolidin-1-yl) ethanone (41.6 mg,79 μmol, 46%). ¹ H NMR(400MHz,DMSO-d6)δ＝12.61-12.06(m,1H),9.34(s,1H),8.64(d,J＝4.4Hz,1H),8.38(d,J＝1.2Hz,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.0Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.95(dd,J＝2.4,8.8Hz,1H),5.31-5.20(m,2H),4.10(t,J＝13.2Hz,1H),3.88-3.73(m,2H),3.59(t,J＝7.6Hz,1H),2.63-2.53(m,1H),2.49(s,3H),2.46-2.37(m,1H)；m/z ES+[M+H] ⁺ 524.0。

EXAMPLE 163 Synthesis of 2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in tetrahydrofuran (2 mL)]Imidazol-6-yl) oxy) quinoxaline (145 mg, 247. Mu. Mol) was added to a solutionPyridine hydrofluoride (244 mg,2.47mmol,0.22 mL) was added. The mixture was stirred at 80℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 4% -34%,10 min) purification to give 2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) quinoxaline (26.4 mg,57.6 μmol, 23%). ¹ H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.78(s,1H),8.43(s,1H),7.84(d,J＝9.2Hz,1H),7.47(d,J＝8.8Hz,1H),7.25(d,J＝9.2Hz,1H),7.07(s,1H),6.88(dd,J＝2.0,8.8Hz,1H),5.09-4.91(m,1H),4.69-4.60(m,1H),3.49(d,J＝11.2Hz,1H),3.14(d,J＝11.2Hz,1H),2.87-2.73(m,2H),2.69(s,3H),2.47(s,3H),2.15(s,2H)；m/z ES+[M+H] ⁺ 458.1。

EXAMPLE 164.8 Synthesis of cyclopropyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

Step 1.4- (4- (8-cyclopropyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid ester

To 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in dioxane (1 mL) and water (0.1 mL)]To a solution of tert-butyl imidazol-6-yl) oxy-quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylate (70 mg, 101. Mu. Mol), cyclopropylboronic acid (87.1 mg,1.01 mmol) was added XPhos Pd G2 (8.0 mg, 10.1. Mu. Mol) and sodium carbonate (21.5 mg, 202. Mu. Mol). The mixture was stirred under nitrogen at 100 ℃ for 5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1 to 0/1) to give 4- (4- (8-cyclopropyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (70 mg, 10.1. Mu. Mol, 99%). M/zES + [ M+H ]] ⁺ 696.4。

Step 2.8-cyclopropyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

4- (4- (8-cyclopropyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (70 mg,100 μmol) was stirred at 25 ℃ for 0.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,7 min) purification to give 8-cyclopropyl-7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (12.5 mg, 26.8. Mu. Mol, 26%). ¹ H NMR(400MHz,CD ₃ OD)δ9.09(s,1H),8.56(s,1H),8.39-8.22(m,2H),7.77(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.28(d,J＝9.0Hz,1H),7.07(s,1H),6.99(d,J＝8.8Hz,1H),4.71(td,J＝4.8,9.6Hz,1H),3.64(d,J＝13.2Hz,2H),3.32-3.18(m,2H),2.86(d,J＝5.6Hz,1H),2.61(s,3H),2.49-2.32(m,4H),1.63(d,J＝3.2Hz,2H),1.06(d,J＝8.8Hz,2H)；m/z ES+[M+H] ⁺ 466.1。

Example 165.Synthesis of 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -1- (3-fluoropyrrolidin-1-yl) ethanone

Step 1.2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] -1- (3-fluoropyrrolidin-1-yl) ethanone

To 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (2 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of acetic acid (100 mg, 177. Mu. Mol), 3-fluoropyrrolidine hydrochloride (33.3 mg, 265. Mu. Mol) and diisopropylethylamine (68.6 mg, 531. Mu. Mol, 92.5. Mu.L) was added 3- (ethyliminomethyleneamino) propyl-dimethylaminoonium; chloride (50.9 mg, 265. Mu. Mol) and hydroxybenzotriazole (35.9 mg, 265. Mu. Mol). The mixture was stirred at 25℃for 12 hours. After completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 ml×2). The combined organic layers were washed with brine (60 ml x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1- (3-fluoropyrrolidin-1-yl) ethanone (113 mg, crude). M/zES + [ M+H ]] ⁺ 636.2。

Step 2.2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] -1- (3-fluoropyrrolidin-1-yl) ethanone

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1.8 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of 1- (3-fluoropyrrolidin-1-yl) ethanone (100 mg, 157. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC (column: phenomenex Synergi C: 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 11% -31%,10 min) purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-1- (3-fluoropyrrolidin-1-yl) ethanone (35.9 mg, 70.9. Mu. Mol, 45%). ¹ H NMR(400MHz,DMSO-d6)δ＝12.66-12.12(m,1H),9.34(s,1H),8.65(d,J＝2.0Hz,1H),8.38(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.95(dd,J＝2.0,8.8Hz,1H),5.55-5.14(m,3H),3.94-3.81(m,1H),3.75-3.44(m,3H),2.50(s,3H),2.31-2.02(m,2H)；m/z ES+[M+H] ⁺ 506.0。

EXAMPLE 166.Synthesis of 2- [1- [ [3- (azetidin-1-yl) cyclobutyl ] methyl ] pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [6- [3- [1- [ [3- (azetidin-1-yl) cyclobutyl ] methyl ] pyrazol-4-yl ] -5-chloro-quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in methanol (1.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of cyclobutanone (160 mg, 272. Mu. Mol), azetidine hydrochloride (140 mg,1.49 mmol) and acetic acid (1.6 mg, 27.2. Mu. Mol) was stirred at 25℃for 0.2 h. Sodium cyanoborohydride (34.1 mg, 543. Mu. Mol) was then added, and the mixture was stirred at 40℃for 2.8 hours. The reaction mixture was diluted with saturated sodium bicarbonate (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 ml x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give 2- [ [6- [3- [1- [ [3- (azetidin-1-yl) cyclobutyl ] as a yellow oil ]Methyl group]Pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (130 mg,206 μmol, 76%). M/zES + [ M+H ]] ⁺ 630.4。

Step 2.2- [1- [ [3- (azetidin-1-yl) cyclobutyl ] methyl ] pyrazol-4-yl ] -8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [6- [3- [1- [ [3- (azetidin-1-yl) cyclobutyl ] in trifluoroacetic acid (1 mL)]Methyl group]Pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A mixture of ethyl-trimethyl-silane (120 mg, 190. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,7 min) purification to give 2- [1- [ [3- (azetidin-1-yl) cyclobutyl ] as a brown solid]Methyl group]Pyrazol-4-yl]-8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (32.7 mg,64.8μmol，34％)。 ¹ H NMR(400MHz,DMSO-d6)δ10.61-10.30(m,1H),9.36(d,J＝2.0Hz,1H),8.71(d,J＝18.0Hz,1H),8.39(s,1H),8.03(d,J＝9.2Hz,1H),7.73(d,J＝8.8Hz,1H),7.52-7.35(m,2H),7.19(dd,J＝2.0,8.8Hz,1H),4.34(br dd,J＝7.2,17.6Hz,2H),4.06(br dd,J＝4.0,18.0Hz,2H),3.88(br d,J＝3.6Hz,2H),2.93-2.83(m,1H),2.69(s,3H),2.39-2.23(m,4H),2.18(br t,J＝7.2Hz,2H),2-1.91(m,1H)；m/z ES+[M+H] ⁺ 500.1。

example 167.8 Synthesis of methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.4- ((4- (8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in dioxane (10 mL) and water (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (1 g,1.40 mmol) and methylboronic acid (850 mg,14.0 mmol) was added sodium carbonate (450 mg,4.30 mmol) and [2- (2-aminophenyl) phenyl ]]-chloro-palladium; di-cyclohexyl- [3- (2, 4, 6-tri-isopropylphenyl) phenyl]Phosphane (170 mg, 210. Mu. Mol). The mixture was stirred under nitrogen at 110 ℃ for 8 hours. After completion, the reaction mixture was filtered. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine (15 ml×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=100:1 to 20:1) to give 4- [ [4- [ 8-methyl-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a white solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (620 mg, 907. Mu. Mol, 65%). M/zES + [ M+H ]] ⁺ 684.2。

Step 2.8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline

4- [ [4- [ 8-methyl-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (6 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of tert-butyl piperidine-1-carboxylate (620 mg, 906. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 1.4g of crude product as a yellow oil. 100mg of the crude product are purified by means of preparative HPLC (neutral conditions; column: waters Xridge 150X 25 mM. Times.5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 23% -53%,10 min) purification to give 8-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy) as a white solid]-2- [1- (4-piperidinylmethyl) pyrazol-4-yl]Quinoxaline (17.7 mg, 39.1. Mu. Mol, 18%). ¹ HNMR(400MHz,DMSO-d6)δ＝12.46-11.82(m,1H),9.22(s,1H),8.66(s,1H),8.33(s,1H),7.84(d,J＝9.2Hz,1H),7.46(d,J＝7.2Hz,1H),7.24(d,J＝8.8Hz,1H),7.06(s,1H),6.87(dd,J＝2.0,8.4Hz,1H),4.08(d,J＝7.2Hz,2H),2.90(s,2H),2.69(s,3H),2.47(s,3H),2.45-2.36(m,3H),2.03-1.89(m,1H),1.45(d,J＝10.8Hz,2H),1.18-1.03(m,2H)；m/z ES+[M+H] ⁺ 454.1。

EXAMPLE 168.8 Synthesis of methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

Step 1.4- (4- (8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid ester

To 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in dioxane (1 mL) and water (0.1 mL) ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (100 mg, 144. Mu. Mol), methyl boronic acid (26.0 mg, 434. Mu. Mol) was added XPhos Pd G2 (11.4 mg, 14.4)Mu mol) and sodium carbonate (46.0 mg,434 mu mol). The mixture was stirred under nitrogen at 110 ℃ for 5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1 to 0/1) to give 4- (4- (8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (90 mg,134 μmol, 93%). M/zES + [ M+H ]] ⁺ 670.4。

Step 2.8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

4- (4- (8-methyl-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (90 mg,134 μmol) was stirred at 25 ℃ for 0.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 7% -37%,10 min) purification to give 8-methyl-7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (35.0 mg, 79.6. Mu. Mol, 59%). ¹ H NMR(400MHz,CD ₃ OD)δ9.18(s,1H),8.64(s,1H),8.40(s,1H),7.93(d,J＝9.2Hz,1H),7.75(d,J＝8.8Hz,1H),7.42(d,J＝9.2Hz,1H),7.30(dd,J＝2.2,8.8Hz,1H),7.23(d,J＝2.0Hz,1H),4.72(dd,J＝5.2,10.0Hz,1H),3.64(d,J＝13.2Hz,2H),3.32-3.24(m,2H),2.84(s,3H),2.74(s,3H),2.51-2.31(m,4H)；m/z ES+[M+H] ⁺ 440.1。

EXAMPLE 169.Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- [1- (oxetan-3-yl) -4-piperidinyl ] ethyl ] pyrazol-4-yl ] quinoxaline

Step 1.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- [1- (oxetan-3-yl) -4-piperidinyl ] ethyl ] pyrazol-4-yl ] quinoxaline

To 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in methanol (5 mL)]-2- [1- [2- (4-piperidinyl) ethyl ]]Pyrazol-4-yl]To a solution of quinoxaline (200 mg, 409. Mu. Mol) was added sodium cyanoborohydride (33.4 mg, 532. Mu. Mol), sodium acetate (43.7 mg, 532. Mu. Mol) and oxetan-3-one (295 mg,4.10 mmol). The mixture was stirred at 20℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 31% -61%,8 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as an off-white solid ]-2- [1- [2- [1- (oxetan-3-yl) -4-piperidinyl]Ethyl group]Pyrazol-4-yl]Quinoxaline (38.7 mg, 71.1. Mu. Mol, 17%). ¹ H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.73(s,1H),8.35(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝1.6Hz,1H),6.96-6.91(m,1H),4.53-4.46(m,2H),4.42-4.36(m,2H),4.31-4.24(m,2H),3.30-3.27(m,1H),2.65(d,J＝10.8Hz,2H),2.48(s,3H),1.88-1.76(m,2H),1.74-1.63(m,4H),1.28-1.14(m,3H)；m/z ES+[M+H] ⁺ 544.1。

Example 170.4 Synthesis of 4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) quinuclidine

Step 1.2- (4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-4-yl) ethanol

To 4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in acetonitrile (3 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (100 mg, 136. Mu. Mol) was added hydrochloric acid (6M, 1 mL). The mixture was stirred at 25℃for 1 hour. Mixing the reactionThe material was diluted with saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (15 mL. Times.3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow oil]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-4-yl ethanol (90 mg, crude). M/zES + [ M+H ] ] ⁺ 634.3。

Step 2.4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) quinuclidine

2- [4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in hydrobromic acid (4.47 g,26.5mmol,3mL, 48%)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-4-piperidinyl]A solution of ethanol (80.0 mg, 126. Mu. Mol) was stirred at 100℃for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: waters Xbridge 150X 25mM X5 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 21% -51%,10 min) purification and purification by preparative HPLC (formic acid conditions; column: shim-pack C18. Times.25.times.10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -10%,10 min) re-purification to give 4- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as an orange gum]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl quinuclidine (13.0 mg,22.7 μmol, 18%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.67(s,1H),9.48-9.36(m,2H),8.37(s,2H),8.06(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.45(d,J＝9.2Hz,1H),7.25(d,J＝2.0Hz,1H),6.96(dd,J＝2.0,8.8Hz,1H),4.80(s,2H),3.16(d,J＝10.4Hz,2H),2.97(t,J＝6.0Hz,2H),2.83-2.70(m,2H),2.49(s,3H),2.23(s,2H),2.06(d,J＝9.2Hz,2H)；m/z ES+[M+H] ⁺ 486.2。

EXAMPLE 171 Synthesis of 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- [1- (2, 2-trifluoroethyl) -4-piperidinyl ] ethyl ] pyrazol-4-yl ] quinoxaline

Step 1.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- [1- (2, 2-trifluoroethyl) -4-piperidinyl ] ethyl ] pyrazol-4-yl ] quinoxaline

To 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in N, N-dimethylformamide (2 mL)]-2- [1- [2- (4-piperidinyl) ethyl ]]Pyrazol-4-yl]To a solution of quinoxaline (200 mg, 409. Mu. Mol) were added diisopropylethylamine (158 mg,1.23 mmol) and 2, 2-trifluoroethyl triflate (142 mg, 614. Mu. Mol). The mixture was stirred at 25℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C18X 30mm X3 um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 10% -40%,7 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as an off-white solid]-2- [1- [2- [1- (2, 2-trifluoroethyl) -4-piperidinyl]Ethyl group]Pyrazol-4-yl]Quinoxaline (31.8 mg, 55.8. Mu. Mol, 13%). ¹ H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.73(s,1H),8.35(s,1H),7.97(d,J＝9.2Hz,1H),7.56(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.26(d,J＝2.4Hz,1H),7.03-6.97(m,1H),4.32-4.24(m,2H),3.11-3.05(m,2H),2.89(d,J＝10.8Hz,2H),2.54(s,3H),2.31-2.20(m,2H),1.80(d,J＝5.2Hz,2H),1.68(d,J＝8.8Hz,2H),1.22(s,3H)；m/z ES+[M+H] ⁺ 570.1。

EXAMPLE 172.Synthesis of 3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -N, N-dimethyl-cyclobutamine

Step 1.3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] oxy-quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -N, N-dimethyl-cyclobutamine

To 3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in methanol (1.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of cyclobutanone (120 mg, 204. Mu. Mol) was added N-methyl methylamine hydrochlorideSalts (94.7 mg,1.16 mmol) and sodium acetate (167 mg,2.04 mmol). The mixture was stirred at 25℃for 0.2 h. Sodium cyanoborohydride (32.0 mg, 509. Mu. Mol) was then added, and the mixture was stirred at 40℃for 1.8 hours. The reaction mixture was quenched with saturated sodium bicarbonate (2 mL) at 25 ℃, then diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 ml x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give 3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-N, N-dimethyl-cyclobutylamine (80 mg,129 μmol, 63%). M/zES + [ M+H ]] ⁺ 618.3。

Step 2.3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -N, N-dimethyl-cyclobutylamine

3- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL) ]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A mixture of N, N-dimethyl-cyclobutylamine (70 mg, 113. Mu. Mol) was stirred at 25℃for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Synergi C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -30%,10 min) purification to give 3- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-N, N-dimethyl-cyclobutylamine (26.7 mg,54.7 μmol, 48%). ¹ H NMR(400MHz,CD ₃ OD)δ9.21(s,1H),8.57(s,1H),8.36(s,1H),8(d,J＝9.2Hz,1H),7.75(d,J＝9.2Hz,1H),7.48(d,J＝9.2Hz,1H),7.35-7.27(m,2H),4.46-4.32(m,2H),3.84-3.56(m,1H),2.82(s,3H),2.80-2.77(m,6H),2.74-2.60(m,1H),2.57-2.44(m,2H),2.16-2.03(m,2H)；m/z ES+[M+H] ⁺ 488.1。

EXAMPLE 173 Synthesis of 2- (1- ((2, 6, 8-trioxaspiro [3.5] nonan-7-yl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((5-methylene-1, 3-dioxan-2-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

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Step 1.8-chloro-2- (1- (2, 2-diethoxyethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (8 mL) ]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Cesium carbonate (964 mg,2.96 mmol) was added to a mixture of ethyl-trimethyl-silane (500 mg, 986. Mu. Mol) and 2-bromo-1, 1-diethoxy-ethane (389 mg,1.97 mmol). The mixture was heated to 100 ℃ and stirred for 4 hours. After completion, the reaction mixture was quenched with water (50 mL) at 20 ℃ and then extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with water (5 ml x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 8-chloro-2- (1- (2, 2-diethoxyethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) quinoxaline (600 mg,866 μmol, 88%). M/zES + [ M+H ]] ⁺ 623.2。

Step 2. (5- (bromomethyl) -2- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -1, 3-dioxan-5-yl) methanol

To 8-chloro-2- (1- (2, 2-diethoxyethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in toluene (5 mL)]Imidazol-6-yl) oxy) quinoxaline (200 mg, 321. Mu. Mol) and 2- (bromomethyl) -2- (hydroxymethyl) propane-1, 3-diol (128 mg, 642. Mu. Mol) or p-toluene sulphonic acid (11.1 mg, 64.2. Mu. Mol) was added. The mixture was then heated to 100 ℃ and stirred for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give [5- (bromomethyl) -2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid ]Quinoxaline-2-yl group]Pyrazol-1-yl]Methyl group]-1, 3-dioxan-5-yl]Methanol (90 mg, 144. Mu. Mol, 45%). M/zES + [ M+H ]] ⁺ 601.3。

Step 3.2- (1- ((2, 6, 8-trioxaspiro [3.5] nonan-7-yl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((5-methylene-1, 3-dioxan-2-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

To a mixture of [5- (bromomethyl) -2- [ [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] methyl ] -1, 3-dioxan-5-yl ] methanol (70 mg,117 μmol) in tetrahydrofuran (4 mL) was added aqueous sodium hydroxide (18.7 mg,468 μmol,60 wt%). The mixture was heated to 60 ℃ and stirred for 2 hours. After completion, the reaction mixture was quenched by addition of water (5 mL) at 0 ℃ and then extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with water (2 ml×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: phenomenex Luna C, 150 x 25mM x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 11% -41%,10 min) and then repurified by prep-HPLC (column: waters Xbridge 150 x 25mM x 5um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile ]; (B%: 27% -57%,10 min) to give 2- (1- ((2, 6, 8-trioxaspiro [3.5] nonan-7-yl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline (8.5 mg,16.4 μmol, 14%) and the compound 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1, 5-methylene-1-pyrazol-4-yl) oxy) 2- (1, 3-dioxa-1, 3-2-yl) pyrazol-4-yl) quinoxaline as a white solid as a yellow solid, 19 mg (40 mg, 35 mg).

¹ H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.66(s,1H),8.38(s,1H),7.97(d,J＝9.2Hz,1H),7.53(br d,J＝8.4Hz,1H),7.33(d,J＝9.2Hz,1H),7.23(br s,1H),6.97(br d,J＝8.4Hz,1H),4.95(t,J＝5.2Hz,1H),4.54(s,2H),4.40-4.27(m,4H),4.11(s,2H),3.75(br d,J＝11.2Hz,2H),2.51(s,3H)；m/zES+[M+H] ⁺ 519.0。

¹ H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.70-8.63(m,1H),8.39(s,1H),8.31(s,1H),7.96(d,J＝9.2Hz,1H),7.51(br d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(br s,1H),6.94(dd,J＝2.4,8.8Hz,1H),5.14(t,J＝5.2Hz,1H),4.97(s,2H),4.41-4.33(m,4H),3.93-3.78(m,2H),2.49(br s,3H)；m/zES+[M+H] ⁺ 489.1。

EXAMPLE 174.Synthesis of 1- [4- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] ethyl ] -1-piperidinyl ] propan-1-one

Step 1.1- [4- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxalin-2-yl ] pyrazol-1-yl ] ethyl ] -1-piperidinyl ] propan-1-one

To 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in tetrahydrofuran (2 mL) and water (1 mL)]-2- [1- [2- (4-piperidinyl) ethyl ]]Pyrazol-4-yl]To a solution of quinoxaline (120 mg, 245. Mu. Mol) were added sodium bicarbonate (61.9 mg, 737. Mu. Mol) and propionyl chloride (45.5 mg, 491. Mu. Mol). The mixture was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 15% -45%,7 min) purification to give 1- [4- [2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]Quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]-1-piperidinyl group]Propan-1-one (44.6 mg, 82.0. Mu. Mol, 33%). ¹ H NMR(400MHz,DMSO-d6)δ12.46-12.05(m,1H),9.30(s,1H),8.74(s,1H),8.35(s,1H),7.95(d,J＝9.2Hz,1H),7.58-7.42(m,1H),7.31(d,J＝8.0Hz,1H),7.25-7.11(m,1H),6.94(d,J＝8.0Hz,1H),4.36(d,J＝13.2Hz,1H),4.32-4.24(m,2H),3.82(d,J＝12.0Hz,1H),2.98-2.87(m,1H),2.54-2.51(m,1H),2.49-2.49(m,3H),2.31-2.24(m,2H),1.89-1.69(m,4H),1.56-1.41(m,1H),1.24-1(m,2H),0.99-0.94(m,3H)；m/z ES+[M+H] ⁺ 544.1。

EXAMPLE 175 Synthesis of 2- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -8-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

Step 1.2- [ [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

To 2- [ [5- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 394. Mu. Mol), (3, 3-difluorocyclobutyl) methyl methanesulfonate (94.8 mg, 473. Mu. Mol) was added potassium carbonate (164 mg,1.18 mmol). The mixture was stirred at 80℃for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with brine (10 ml x 3), dried over sodium sulfate, filtered and concentrated in vacuo to give 2- [ [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow oil]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (250 mg, crude). M/zES + [ M+H ]] ⁺ 611.1。

Step 2.2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] pyrazol-4-yl ] -5-methyl-quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane

Methyl boric acid (245 mg,4.09 mmol), 2- [ [5- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in dioxane (3 mL) and water (0.6 mL) ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A mixture of ethyl-trimethyl-silane (250 mg, 409. Mu. Mol), XPhos Pd G2 (32.2 mg, 40.9. Mu. Mol), sodium carbonate (130 mg,1.23 mmol) was degassed and purged 3 times with nitrogen, then the mixture was stirred under nitrogen atmosphere at 100℃for 2 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2/1 to 0/1) to give 2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow oil]Pyrazol-4-yl]-5-methyl-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (160 mg,261 μmol, 64%). M/zES + [ M+H ]] ⁺ 591.1。

Step 3.2- [1- [ (3, 3-Difluorocyclobutyl) methyl ] pyrazol-4-yl ] -8-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] quinoxaline

2- [ [5- [3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in trifluoroacetic acid (2 mL)]Pyrazol-4-yl]-5-methyl-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (160 mg, 271. Mu. Mol) was stirred at 25℃for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 20% -50%,7 min) purification to give 2- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]-8-methyl-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (59.3 mg, 128. Mu. Mol, 47%). ¹ HNMR(400MHz,DMSO-d6)δ9.27-9.22(m,1H),8.74(s,1H),8.36(s,1H),8.14(s,1H),7.86(d,J＝9.2Hz,1H),7.55(d,J＝8.8Hz,1H),7.28(d,J＝9.2Hz,1H),7.14(d,J＝1.6Hz,1H),6.98(dd,J＝2.0,8.8Hz,1H),4.37(br d,J＝5.2Hz,2H),2.68(s,6H),2.55(s,3H),2.53-2.51(m,2H)；m/z ES+[M+H] ⁺ 461.1。

Example 176.2 Synthesis of- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-bromo-2- [1- [ (3, 3-difluorocyclobutyl) methyl in dioxane (1 mL) and water (0.1 mL)]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (50.0 mg, 95.2. Mu. Mol) and methylboronic acid (57.0 mg, 952. Mu. Mol) were added sodium carbonate (30.3 mg, 286. Mu. Mol) and XPhos Pd G2 (11.2 mg, 1)4.3. Mu. Mol). The mixture was stirred under nitrogen at 110 ℃ for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 17% -47%,10 min) purification to give 2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -8-methyl-7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) quinoxaline (11.0 mg,23.9 μmol, 25%). ¹ H NMR(400MHz,CD ₃ OD)δ＝9.08(s,1H),8.56(s,1H),8.32(s,1H),7.81(d,J＝9.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.29(d,J＝9.2Hz,1H),7.07(d,J＝2.0Hz,1H),6.97(dd,J＝2.4,8.8Hz,1H),4.39(d,J＝6.8Hz,2H),2.76-2.64(m,6H),2.57(s,3H),2.49(dd,J＝6.8,14.0Hz,2H)；m/z ES+[M+H] ⁺ 461.1。

Example 177.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline Synthesis

Step 1.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (50 mg, 84.7. Mu. Mol) was added diisopropylethylamine (21.9 mg, 169. Mu. Mol), 2-trifluoroethyl trifluoromethanesulfonate (23.6 mg, 102. Mu. Mol). The mixture was stirred at 25℃for 16 hours. After completion, the mixture was filtered and the filtrate was purified by reverse phase HPLC (0.1% formic acid conditions) to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil ]Imidazol-6-yl) oxyYl) -2- (1- (1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (50 mg, 74.4. Mu. Mol, 88%). M/zES + [ M+H ]] ⁺ 672.5。

Step 2.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) -2- (1- (1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (50.0 mg, 74.4. Mu. Mol) was stirred at 25℃for 0.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 18% -48%,7 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) -2- (1- (1- (2, 2-trifluoroethyl) piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (20.3 mg,37.4 μmol,49% yield). ¹ H NMR(400MHz,CD ₃ OD)δ9.16(d,J＝3.6Hz,1H),8.63(d,J＝2.4Hz,1H),8.35(d,J＝2.4Hz,1H),7.92(dd,J＝2.4,9.2Hz,1H),7.61(d,J＝8.8Hz,1H),7.38(dd,J＝1.6,9.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.11(dd,J＝2.2,8.8Hz,1H),4.40-4.10(m,1H),3.25-3.06(m,4H),2.71-2.61(m,5H),2.30-2.07(m,4H)；m/z ES+[M+H] ⁺ 542.1。

EXAMPLE 178.8 Synthesis of chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- (4-piperidinyl) ethyl ] pyrazol-4-yl ] quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (10 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (832 mg,1To a solution of 64 mmol) were added potassium carbonate (681 mg,4.93 mmol) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (480 mg,1.64 mmol). The mixture was stirred at 80℃for 2 hours. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]Piperidine-1-carboxylic acid tert-butyl ester (1.20 g, crude). M/zES + [ M+H ]] ⁺ 718.2。

4- [2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Ethyl group]A solution of tert-butyl piperidine-1-carboxylate (100 mg, 139. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 5% -35%,7 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a yellow solid]-2- [1- [2- (4-piperidinyl) ethyl ]]Pyrazol-4-yl]Quinoxaline (26.1 mg,53.6umol, 38%). ¹ H NMR(400MHz,CD ₃ OD)δ9.12(s,1H),8.58(s,1H),8.33(s,1H),7.87(d,J＝9.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.19(d,J＝1.6Hz,1H),7.03(dd,J＝2.0,8.4Hz,1H),4.36(t,J＝6.8Hz,2H),3.35-3.42(m,2H),3.02-2.92(m,2H),2.60(s,3H),2.03-1.93(m,4H),1.70-1.62(m,1H),1.52-1.41(m,2H)；m/z ES+[M+H] ⁺ 488.1。

Example 179.8 Synthesis of chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- (1-methyl-4-piperidinyl) ethyl ] pyrazol-4-yl ] quinoxaline

Step 1.8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] -2- [1- [2- (1-methyl-4-piperidinyl) ethyl ] pyrazol-4-yl ] quinoxaline

To 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy in N, N-dimethylformamide (3 mL)]-2- [1- [2- (4-piperidinyl) ethyl ]]Pyrazol-4-yl]To a solution of quinoxaline (200 mg, 409. Mu. Mol) were added paraformaldehyde (123 mg,4.10 mmol) and formic acid (196 mg,4.10 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Synergi C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -30%,10 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a yellow gum]-2- [1- [2- (1-methyl-4-piperidinyl) ethyl group ]Pyrazol-4-yl]Quinoxaline (26.6 mg,53.0 mu mol, 12%). ¹ H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.74(s,1H),8.36(s,1H),8.20(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.97-6.91(m,1H),4.31-4.26(m,2H),3.54-3.29(m,2H),3.13(d,J＝11.6Hz,2H),2.50(s,3H),2.49(s,3H),1.83(d,J＝6.0Hz,4H),1.42-1.27(m,3H),4.17-4.14(m,3H),3(s,3H),2.75-2.61(m,2H),1.70-1.64(m,4H),1.53-1.46(m,1H),1.43(s,9H),1.41-1.34(m,1H),1.18-1.08(m,2H)；m/z ES+[M+H] ⁺ 502.1。

Example 180.8 Synthesis of chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

Step 1.4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (5 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (500 mg, 986. Mu. Mol), 4-iodopiperidine-1-carboxylic acid tert-butyl esterA solution of (1.53 g,4.93 mmol) cesium carbonate (640 mg,1.97 mmol) was stirred at 100℃for 1 hour. Tert-butyl 4-iodopiperidine-1-carboxylate (920 mg,2.96 mmol) was then added and the mixture stirred at 100℃for 1 hour. Further, tert-butyl 4-iodopiperidine-1-carboxylate (920 mg,2.96 mmol) was added, and the mixture was stirred at 100℃for 1 hour. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give 4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid ]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (320 mg,463 μmol, 47%). M/zES + [ M+H ]] ⁺ 690.2。

Step 2.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

4- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (5 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (320 mg, 463. Mu. Mol) was stirred at 25℃for 10min. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,10 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (150 mg,0.324mmol, 70%). ¹ H NMR(400MHz,CD ₃ OD)δ9.24(s,1H),8.67(s,1H),8.42(s,1H),8.01(d,J＝9.2Hz,1H),7.74(d,J＝8.8Hz,1H),7.49(d,J＝9.2Hz,1H),7.36-7.24(m,2H),4.73(tt,J＝4.8,10.0Hz,1H),3.64(d,J＝13.2Hz,2H),3.32-3.22(m,2H),2.81(s,3H),2.53-2.29(m,4H)；m/z ES+[M+H] ⁺ 460.1。

Step 3.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline

To 8-chloro-7- ((2-methyl-1H-benzo [ d) in N, N-dimethylformamide (1 mL)]Imidazol-6-yl) oxy) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinol ine To a solution of quinoxaline (50 mg, 109. Mu. Mol) were added paraformaldehyde (32.6 mg,1.09 mmol) and formic acid (52.2 mg,1.09 mmol). The mixture was stirred at 60℃for 16 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Synergi C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 0% -29%,10 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) quinoxaline (36.2 mg,0.076mmol, 70%). ¹ H NMR(400MHz,CD ₃ OD)δ9.15(s,1H),8.64(s,1H),8.38(s,1H),7.89(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.18(s,1H),7.01(d,J＝8.8Hz,1H),4.70-4.54(m,1H),3.60(d,J＝12.4Hz,2H),3.25–3.10(m,2H),2.88(s,3H),2.58(s,3H),2.45–2.35(m,4H)；m/z ES+[M+H] ⁺ 474.1。

Example 181.8 Synthesis of chloro-2- (1- (1- (ethylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (4 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 394. Mu. Mol) and tert-butyl 3-iodoazetidine-1-carboxylate (123 mg, 433. Mu. Mol) was added cesium carbonate (257 mg, 789. Mu. Mol). The mixture was stirred at 50℃for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=100/1 to 50/1) to give 3- (4- (8-chloro) as a yellow solid -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ]]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl-azetidine-1-carboxylic acid tert-butyl ester (210 mg,314 μmol, 80%). M/zES + [ M+H ]] ⁺ 662.3。

To 3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in dichloromethane (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of tert-butyl azetidine-1-carboxylate (190 mg, 287. Mu. Mol) was added trifluoroacetic acid (770 mg,6.75mmol,0.5 mL). The mixture was stirred at 25℃for 2 hours. The reaction mixture was diluted with sodium bicarbonate (30 mL) and extracted with dichloromethane (20 ml×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid]Imidazol-6-yl) oxy) quinoxaline (300 mg, crude). M/zES + [ M+H ] ] ⁺ 562.2。

Step 3.8-chloro-2- (1- (1- (ethylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [3- [1- (azetidin-3-yl) pyrazol-4-yl ] in dichloromethane (5 mL)]-5-chloro-quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (300 mg, 534. Mu. Mol) was added diisopropylethylamine (207 mg,1.60mmol, 279. Mu.L). Then ethanesulfonyl chloride (103 mg, 800. Mu. Mol, 75.7. Mu.L) was added at 0deg.C. The mixture was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure to give 8-chloro-2- (1- (1- (ethylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) quinoxaline (350 mg, crude). M/zES + [ M+H ]] ⁺ 654.3。

Step 4.8-chloro-2- (1- (1- (ethylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-chloro-3- [1- (1-ethylsulfonylazetidin-3-yl) pyrazol-4-yl ] in trifluoroacetic acid (5 mL) ]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (350 mg, 535. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,10 min) purification to give 8-chloro-2- (1- (1- (ethylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) quinoxaline (48.0 mg,91.2 μmol, 17%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.35(s,1H),8.84(s,1H),8.51(s,1H),7.97(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.22(s,1H),6.94(dd,J＝2.4,8.8Hz,1H),5.55–5.45(m,1H),4.42-4.29(m,4H),3.26(dd,J＝14.8,7.2Hz,2H),2.49(s,3H),1.29(t,J＝7.2Hz,3H)；m/z ES+[M+H] ⁺ 524.0。

EXAMPLE 182.Synthesis of 1- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) ethan-1-one

Step 1.3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in dimethyl sulfoxide (10 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (500 mg, 986. Mu. Mol) and tert-butyl 3- ((methylsulfonyl) oxy) piperidine-1-carboxylate (551 mg,1.97 mmol) was added cesium carbonate (964 mg,2.96 mmol) and potassium iodide (164 mg, 98) 6. Mu. Mol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was quenched by addition of water (0.2 mL) and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 80-90% acetonitrile, 8 min) to give 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as an orange solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (430 mg,0.62mmol, 57%). M/zES + [ M+H ]] ⁺ 690.3。

Step 2.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline

3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (165 mg,239 μmol) was stirred at 30 ℃ for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as an orange oil]Imidazol-6-yl) oxy) -2- (1- (piperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline (110 mg, crude). M/zES + [ M+H ]] ⁺ 460.1。

Step 3.1- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl) ethan-1-one

To 8-chloro-7- ((2-methyl-1H-benzo [ d) in dichloromethane (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1- (piperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline (100 mg, 217. Mu. Mol) was added triethylamine (66.0 mg, 652. Mu. Mol, 90.8. Mu. L) and acetyl chloride (15.4 mg, 196. Mu. Mol, 14.0. Mu. L). The mixture was stirred at 0deg.C for 20min. Acetyl chloride (17.0 mg, 217. Mu. Mol, 15.5. Mu.L) was then added and the mixture was stirred at 0deg.C for 10min. Furthermore, acetyl chloride (17.0 mg, 217. Mu. Mol, 15.5. Mu.L) was added and the mixture was stirred at 0deg.C for 10min. After completion, the reaction mixture was quenched with methanol (0.2 mL) and then concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 13% -43%,10 min) purification to obtainOff-white 1- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo) d)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidin-1-yl ethanone (45.6 mg,0.091mmol, 42%). ¹ H NMR(400MHz,DMSO-d6)δ12.32(br s,1H),9.33(d,J＝6.8Hz,1H),8.80(d,J＝7.2Hz,1H),8.41(d,J＝11.6Hz,1H),7.96(d,J＝9.2Hz,1H),7.51(br d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝2.0,8.8Hz,1H),4.68-4.43(m,1H),4.36-4.16(m,1H),4.08(dd,J＝3.6,12.8Hz,0.5H),3.82(d,J＝13.6Hz,0.5H),3.54(dd,J＝13.2,10.0Hz,0.5H),3.16–3(m,1H),2.85-2.77(m,0.5H),2.49(s,3H),2.26-2.12(m,2H),2.06(d,J＝4.4Hz,3H),1.88-1.77(m,1H),1.68-1.46(m,1H)；m/z ES+[M+H] ⁺ 502.1。

EXAMPLE 183.Synthesis of 2- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (ethylsulfonyl) azetidin-3-yl) acetonitrile

Step 1.2- (3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (ethylsulfonyl) azetidin-3-yl) acetonitrile

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in acetonitrile (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (100 mg, 197. Mu. Mol) was added 2,3,4,6,7,8,9, 10-octahydropyrimido [1,2-a ]]Aza-compounds(30.0 mg, 197. Mu. Mol) and 2- (1-ethylsulfonylazetidin-3-ylidene) acetonitrile (40.0 mg, 214. Mu. Mol). The mixture was stirred at 30℃for 12 hours. After completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- [3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzo as a yellow solidImidazol-5-yl]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1-ethylsulfonyl-azetidin-3-yl]Acetonitrile (120 mg, crude). M/zES + [ M+H ]] ⁺ 693.1。

Step 2.2- (3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (ethylsulfonyl) azetidin-3-yl) acetonitrile

2- [3- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1-ethylsulfonyl-azetidin-3-yl]A solution of acetonitrile (70.0 mg, 100. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18X 30mM 3um; mobile phase [ water (10 mM ammonium bicarbonate) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -52%,8 min) purification to give 2- [3- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as a gray solid]Quinoxalin-2-yl]Pyrazol-1-yl]-1-ethylsulfonyl-azetidin-3-yl]Acetonitrile (18.7 mg,0.033mmol, 32%). ¹ H NMR(400MHz,DMSO-d6)δ12.31(br s,1H),9.38(s,1H),9.11(s,1H),8.56(s,1H),7.99(d,J＝9.2Hz,1H),7.51(d,J＝8.0Hz,1H),7.35(d,J＝9.2Hz,1H),7.23(s,1H),6.92(dd,J＝8.4,2.0Hz,1H),4.57(d,J＝9.2Hz,2H),4.28(d,J＝9.2Hz,2H),3.71(s,2H),3.40-3.20(m,2H),2.51(s,3H),1.25(t,J＝7.2Hz,3H)；m/z ES+[M+H] ⁺ 563.0。

EXAMPLE 184.Synthesis of 8-chloro-2- (1- (2, 5-dihydrofuran-2-yl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.2- (2, 5-Dihydrofuran-2-yl) ethylmethanesulfonate

To a solution of 2- (2, 5-dihydrofuran-2-yl) ethan-1-ol (260 mg,2.28 mmol) in dichloromethane (1 mL) was added triethylamine (921 mg,9.11 mmol) and methanesulfonyl chloride (782 mg,6.83 mmol). The mixture was stirred at 25℃for 1 hour. Will be mixed The material was poured into water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to give 2- (2, 5-dihydrofuran-2-yl) ethylmethanesulfonate (100 mg,520 μmol, 22%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ6.04-5.92(m,1H),5.84-5.81(m,1H),5.10-4.91(m,1H),4.75-4.61(m,2H),4.39(dd,J＝5.6,7.2Hz,2H),3.04(s,3H),2.21-2.09(m,1H),2-1.83(m,1H)。

Step 2.8-chloro-2- (1- (2, 5-dihydrofuran-2-yl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in N, N-dimethylformamide (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1H-pyrazol-4-yl) quinoxaline (100 mg, 197. Mu. Mol) was added 2- (2, 5-dihydrofuran-2-yl) ethylmethanesulfonate (53.0 mg, 276. Mu. Mol) and potassium carbonate (81.7 mg, 591. Mu. Mol). The mixture was stirred at 80℃for 12 hours. After completion, the mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (30 ml x 3), filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane/methanol=20/1) to give 8-chloro-2- (1- (2, 5-dihydrofuran-2-yl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a white solid ]Imidazol-6-yl) oxy) quinoxaline (80 mg,132 μmol, 67%). M/zES + [ M+H ]] ⁺ 603.2。

Step 3.8-chloro-2- (1- (2, 5-dihydrofuran-2-yl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

8-chloro-2- (1- (2, 5-dihydrofuran-2-yl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (2 mL)]Imidazol-6-yl) oxy) quinoxaline (80 mg,132 mu mol) was stirred at 25 ℃ for 0.5 hours. After completion, willThe mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Synergi C18:18:150.25 mm.10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 14% -44%,10 min) purification to give 8-chloro-2- (1- (2, 5-dihydrofuran-2-yl) ethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) quinoxaline (38.9 mg,82.1 μmol, 61%). ¹ H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.74(s,1H),8.36(s,1H),8(d,J＝9.2Hz,1H),7.68(d,J＝8.8Hz,1H),7.50-7.33(m,2H),7.14(dd,J＝2.0,8.8Hz,1H),6.02(dd,J＝1.6,6.2Hz,1H),5.95-5.82(m,1H),4.85–4.75(m,1H),4.67-4.45(m,2H),4.32(t,J＝7.2Hz,2H),2.65(s,3H),2.25-2.10(m,1H),2.07-1.89(m,1H)；m/z ES+[M+H] ⁺ 473.1。

EXAMPLE 185.4 Synthesis of- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydro-2H-thiopyran 1, 1-dioxide

Step 1.4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydro-2H-thiopyran 1, 1-dioxide

To 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in dichloromethane (4 mL) at 0deg.C]Imidazol-6-yl) oxy) -2- (1- ((tetrahydro-2H-thiopyran-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (0.20 g, 322. Mu. Mol) 3-chloroperoxybenzoic acid (144 mg, 708. Mu. Mol,85% purity) was added to a mixture. The mixture was then stirred at 25 ℃ for 2 hours. After completion, the mixture was poured into aqueous sodium sulfite solution (20 mL) and extracted with dichloromethane (15 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=60/1 to 20/1) to give a solid4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) of white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl-tetrahydro-2H-thiopyran 1, 1-dioxide (170 mg,0.26mmol, 64%). M/zES + [ M+H ] ] ⁺ 653.3。

Step 2.4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydro-2H-thiopyran 1, 1-dioxide

4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) in trifluoroacetic acid (2 mL)]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) tetrahydro-2H-thiopyran 1, 1-dioxide (0.17 g,260 μmol) was stirred at 15 ℃ for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: phenomenex Luna C, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 11% -41%,10 min) purification to give 4- ((4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a white solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl-tetrahydro-2H-thiopyran 1, 1-dioxide (40.0 mg, 76.5. Mu. Mol, 29%). ¹ H NMR(400MHz,CD ₃ OD)ppm 9.21(s,1H),8.64(s,1H),8.39(s,1H),7.97(d,J＝9.2Hz,1H),7.67(d,J＝8.8Hz,1H),7.44(d,J＝9.2Hz,1H),7.27(d,J＝2.4Hz,1H),7.17(dd,J＝8.4,2.4Hz,1H),4.36(t,J＝6.8Hz,2H),3.30-3.20(m,2H),3.12-3.03(m,1H),2.82-2.76(m,1H),2.73(s,3H),2.51-2.40(m,2H),2.26-2.13(m,2H),1.98-1.87(m,1H)；m/z ES+[M+H] ⁺ 523.0。

EXAMPLE 186.8 Synthesis of chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((tetrahydro-2H-thiopyran-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((tetrahydro-2H-thiopyran-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

Will be in trifluoroacetic acid (1 mL)2- [ [6- [ 5-chloro-3- [1- (tetrahydrothiopyran-4-ylmethyl) pyrazol-4-yl ] of (e.g., a) amino group]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (60 mg, 96.5. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna C18, 150X 25mm X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 20% -50%,10 min) purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy as a white solid]-2- [1- (tetrahydrothiopyran-4-ylmethyl) pyrazol-4-yl]Quinoxaline (18.04 mg,0.037mmol, 37%). ¹ H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.76(s,1H),8.37(s,1H),8(d,J＝9.2Hz,1H),7.66(d,J＝8.8Hz,1H),7.39(d,J＝9.2Hz,1H),7.35(d,J＝2.4Hz,1H),7.11(dd,J＝8.8,2.4Hz,1H),4.31-4.12(m,2H),2.88-2.75(m,3H),2.63(s,3H),2.60-2.58(m,1H),2.16-1.92(m,3H),1.96-1.86(m,1H),1.65-1.26(m,1H)；m/z ES+[M+H] ⁺ 491.0。

EXAMPLE 187 Synthesis of 8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To (3S, 4S) -4- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl in tetrahydrofuran (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]To a solution of tert-butyl 3-fluoro-piperidine-1-carboxylate (200 mg, 282. Mu. Mol) was added pyridine hydrofluoride (1.10 g,11.1mmol,1 mL). The mixture was stirred at 80℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 8-chloro-2- (1- ((3S, 4S) -3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo) as an off-white solid[d]Imidazol-6-yl) oxy) quinoxaline (67.1 mg, 127. Mu. Mol,45%, formate). ¹ H NMR(400MHz,DMSO-d6)δ＝9.33(s,1H),8.79(s,1H),8.45(s,1H),8.14(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(d,J＝2.0Hz,1H),6.94(dd,J＝2.4,8.8Hz,1H),5.12-4.89(m,1H),4.75-4.64(m,1H),3.56-3.47(m,1H),3.17(d,J＝10.4Hz,1H),2.91-2.74(m,2H),2.48(s,3H),2.20–2.12(m,2H)；m/z ES+[M+H] ⁺ 478.1。

Example 188.8 Synthesis of 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((4- (methylsulfanyl) cyclohexyl) methyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((4- (methylsulfanyl) cyclohexyl) methyl) -1H-pyrazol-4-yl) quinoxaline

2- [ [6- [ 5-chloro-3- [1- [ (4-methylsulfanyl cyclohexyl) methyl ] in trifluoroacetic acid (2 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (20 mg, 30.8. Mu. Mol) was stirred at 25℃for 10min. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Synergi C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 22% -52%,10 min) t purification to give 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy) as a white solid]-2- [1- [ (4-methylsulfanyl-cyclohexyl) methyl group ]Pyrazol-4-yl]Quinoxaline (9.6 mg, 18.5. Mu. Mol, 60%). ¹ H NMR(400MHz,CD ₃ OD)δ9.15(s,1H),8.61-8.48(m,1H),8.41-8.28(m,1H),7.89(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.18(d,J＝2.4Hz,1H),7.01(dd,J＝2.4,8.8Hz,1H),4.23-4.04(m,2H),2.58(s,3H),2.13–2.08(m,1H),2.06(s,3H),2.04–1.97(m,1H),1.95-1.66(m,4H),1.61-1.42(m,3H),1.28-1.11(m,1H)；m/z ES+[M+H] ⁺ 519.1。

EXAMPLE 189.8 Synthesis of chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1-methylpiperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline

Step 1.3- ((methylsulfonyl) oxy) piperidine-1-carboxylic acid tert-butyl ester

Methanesulfonyl chloride (3.13 g,27.3mmol,2.12 mL) was added to a mixture of tert-butyl 3-hydroxypiperidine-1-carboxylate (5 g,24.84 mmol) and triethylamine (5.03 g,49.7mmol,6.92 mL) in dichloromethane (30 mL) at 0deg.C. The mixture was then stirred at 25 ℃ for 2 hours. After completion, the reaction mixture was quenched by addition of water (50 mL) at 0 ℃ and then diluted with water (50 mL) and extracted with dichloromethane (100 ml×3). The combined organic layers were washed with brine (300 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 3- ((methylsulfonyl) oxy) piperidine-1-carboxylate (6.9 g, crude) as a yellow solid.

Step 2.3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

To 8-chloro-2- (1H-pyrazol-4-yl) -7- ((1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in dimethyl sulfoxide (10 mL) ]To a solution of imidazol-6-yl) oxy quinoxaline (500 mg,0.99 mmol) and tert-butyl 3- ((methylsulfonyl) oxy) piperidine-1-carboxylate (553mg, 1.97 mmol) was added cesium carbonate (964 mg,2.96 mmol) and potassium iodide (164 mg,0.99 mmol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was quenched by addition of water (0.2 mL) and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 80-90% acetonitrile, 8 min) to give 3- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d)) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl piperidine-1-carboxylic acid tert-butyl ester (430 mg,0.56mmol, 57%). M/zES + [ M+H ]] ⁺ 690.4。

Step 3.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline

A solution of tert-butyl 3- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (100 mg, 145. Mu. Mol) in trifluoroacetic acid (1 mL) was stirred at 30℃for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (piperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline (67 mg, crude) as an orange oil.

Step 4.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (1-methylpiperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline

To 8-chloro-7- ((2-methyl-1H-benzo [ d) in N, N-dimethylformamide (1 mL)]To a solution of imidazol-6-yl) oxy) -2- (1- (piperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline (67.0 mg, 146. Mu. Mol) was added formic acid (140 mg,2.91 mmol) and paraformaldehyde (87.5 mg,2.91 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C18150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,10 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (1-methylpiperidin-3-yl) -1H-pyrazol-4-yl) quinoxaline (46.4 mg,0.098mmol, 67%). ¹ H NMR(400MHz,CD ₃ OD)δ9.18(s,1H),8.71(s,1H),8.44(s,1H),8.20(s,1H),7.93(d,J＝9.2Hz,1H),7.58(d,J＝8.8Hz,1H),7.39(d,J＝9.2Hz,1H),7.23(d,J＝2.4Hz,1H),7.07(dd,J＝2.4,8.8Hz,1H),4.94-4.91(m,1H),3.80-3.65(m,2H),3.45–3.35(m,1H),3.32–3.20(m,1H),2.97(s,3H),2.63(s,3H),2.35-2.19(m,2H),2.20–2.10(m,1H),2.05-1.91(m,1H)；m/zES+[M+H] ⁺ 474.1。

Example 190.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((2-methyl-2-azabicyclo [2.2.1] heptan-5-yl) methyl) -1H-pyrazol-4-yl) quinoxaline Synthesis

Step 1.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((2-methyl-2-azabicyclo [2.2.1] heptan-5-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

To 2- (1- (2-azabicyclo [ 2.2.1) in N, N-dimethylformamide (1 mL)]Heptane-5-ylmethyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d]To a solution of imidazol-6-yl) oxy quinoxaline (70.0 mg, 114. Mu. Mol) was added formic acid (109 mg,2.27 mmol) and paraformaldehyde (68.2 mg,2.27 mmol). The mixture was stirred at 60℃for 2 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) -2- (1- ((2-methyl-2-azabicyclo [ 2.2.1)]Heptane-5-yl) methyl) -1H-pyrazol-4-yl quinoxaline (70.0 mg, crude). M/zES + [ M+H ]] ⁺ 630.2。

Step 2.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((2-methyl-2-azabicyclo [2.2.1] heptan-5-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] in trifluoroacetic acid (1 mL)]Imidazol-6-yl) oxy) -2- (1- ((2-methyl-2-azabicyclo [ 2.2.1)]A solution of heptane-5-yl-methyl) -1H-pyrazol-4-yl-quinoxaline (70.0 mg, 111. Mu. Mol) was stirred at 20℃for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 3% -33%,10 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -2- (1- ((2-methyl-2-azabicyclo [ 2.2.1)]Heptane-5-yl) methyl) -1H-pyrazol-4-yl quinoxaline (44.1 mg,0.088mmol, 79%). ¹ H NMR(400MHz,CD ₃ OD)δ9.17(s,1H),8.62(s,1H),8.37(s,1H),7.93(d,J＝9.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.39(d,J＝9.2Hz,1H),7.23(s,1H),7.09(dd,J＝2.0,8.8Hz,1H),4.53-4.43(m,1H),4.42–4.25(m,1H),4.20–3.95(m,2H),3.19-2.98(m,1H),2.94(s,3H),2.87-2.78(m,1H),2.65(s,3H),2.64-2.62(m,1H),2.26-2.10(m,2H),2–1.85(m,1H),1.75-1.48(m,1H)；m/z ES+[M+H] ⁺ 500.1。

EXAMPLE 191 Synthesis of 8-chloro-2- (1- ((3, 3-difluoropiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 8-chloro-2- (1- ((3, 3-difluoro-1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.3, 3-difluoro-4- (((methylsulfonyl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 3, 3-difluoro-4- (hydroxymethyl) piperidine-1-carboxylate (500 mg,1.99 mmol) in dichloromethane (10 mL) was added triethylamine (604 mg,5.97 mmol) and methanesulfonyl chloride (3411 mg,2.98 mmol). The mixture was stirred at 0 ℃ for 1 hour. After completion, the reaction mixture was diluted with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 3, 3-difluoro-4- (methylsulfonyloxymethyl) piperidine-1-carboxylate (1 g, crude) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ4.58-4.52(m,1H),4.35-4.15(m,3H),3.04(s,3H),2.85–2.75(m,1H),2.44-2.24(m,1H),2.01-1.91(m,1H),1.68-1.54(m,1H),1.46(s,9H),1.43-1.38(m,1H)。

Step 2.4- ((4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) -3, 3-difluoropiperidine-1-carboxylic acid tert-butyl ester

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (3 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (200 mg, 394. Mu. Mol) was added potassium carbonate (163 mg,1.18 mmol) and 3, 3-difluoro-4- (methylsulfonyloxymethyl)) Tert-butyl piperidine-1-carboxylate (155 mg, 473. Mu. Mol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane: methanol=10:1) to give 4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] as a yellow solid]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]-3, 3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (80.0 mg,0.11mmol, 20%). M/zES + [ M+H ]] ⁺ 740.3。

Step 3.8-chloro-2- (1- ((3, 3-difluoropiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

4- [ [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (4 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of tert-butyl 3, 3-difluoro-piperidine-1-carboxylate (70.0 mg, 94.5. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,7 min) purification to give 8-chloro-2- [1- [ (3, 3-difluoro-4-piperidinyl) methyl ] as an off-white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (22.2 mg,0.044mmol,42% formate). ¹ H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.79(s,1H),8.43(s,1H),8.13(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.33(d,J＝9.2Hz,1H),7.21(s,1H),6.98-6.89(m,1H),4.65-4.55(m,1H),4.36-4.24(m,1H),3.50-3.41(m,1H),3.19-3.03(m,2H),2.87-2.64(m,2H),2.49(s,3H),1.72-1.44(m,2H)；m/z ES+[M+H] ⁺ 510.0。

Step 4.8-chloro-2- (1- ((3, 3-difluoro-1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 8-chloro-2- [1- [ (3, 3-difluoro-4-piperidinyl) methyl in N, N-dimethylformamide (1 mL)]Pyrazol-4-yl]7- [ (2-methyl-)3H-benzimidazol-5-yl) oxy]To a solution of quinoxaline (80.0 mg, 156. Mu. Mol) were added formic acid (75.3 mg,1.57 mmol) and paraformaldehyde (47.11 mg,1.57 mmol). The mixture was stirred at 60℃for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX C1875 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,7 min) purification to give 8-chloro-2- [1- [ (3, 3-difluoro-1-methyl-4-piperidinyl) methyl as an off-white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (28.5 mg,0.054mmol, 34%). ¹ H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.77(s,1H),8.40(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(s,1H),6.98-6.89(m,1H),4.64-4.53(m,1H),4.29-4.18(m,1H),3.32–3.28(m,1H),3.07-2.97(m,1H),2.74(d,J＝11.2Hz,1H),2.49(s,3H),2.37-2.24(m,1H),2.22(s,3H),2.04-1.87(m,1H),1.60-1.38(m,2H)；m/z ES+[M+H] ⁺ 524.1。

Example 192.8 Synthesis of chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-4-yl) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (170 mg,335 umol) was added potassium carbonate (139 mg,1.01 mmol) and 1- (2-chloroethyl) pyrrolidine hydrochloride (57 mg,335 umol). The mixture was stirred at 80℃for 12 hours. After completion, the mixture was quenched with water (8 mL) and extracted with ethyl acetate (10 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 2- [ [6- [ 5-chloro-3- [1- (2-pyrrolidin-1-ylethyl) pyridine as a yellow oil Azol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (300 mg, crude). M/z ES+ [ M+H ]] ⁺ 604.1。

Step 2.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-4-yl) quinoxaline

2- [ [6- [ 5-chloro-3- [1- (2-pyrrolidin-1-ylethyl) pyrazol-4-yl ] in trifluoroacetic acid (2 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (100 mg, 165. Mu. Mol) was stirred at 25℃for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 2% -32%,7 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -2- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-pyrazol-4-yl) quinoxaline (30 mg,0.063mmol, 38%). ¹ H NMR(400MHz,CDCl ₃ )δ8.97(s,1H),8.42(s,1H),8.31(s,1H),7.84(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.29(s,1H),7.22(d,J＝2.4Hz,1H),7.05-7(m,1H),4.70(t,J＝6.0Hz,2H),3.65(t,J＝6.0Hz,2H),3.15–3(m,4H),2.66(s,3H),2(br t,J＝6.4Hz,4H)；m/z ES+[M+H] ⁺ 474.1。

EXAMPLE 193.6 Synthesis of- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -3- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline-5-carbonitrile

Step 1.4- [ [4- (7-bromoquinoxalin-2-yl) pyrazol-1-yl ] methyl ] piperidine-1-carboxylic acid tert-butyl ester

To 7-bromo-2-chloro-quinoxaline (0.250 g,1.03 mmol) and 4- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl in dioxane (10 mL) and water (2 mL)]Methyl group]To a mixture of tert-butyl piperidine-1-carboxylate (430 mg,1.10 mmol) was added potassium acetate (302 mg,3.08 mmol) and cyclopent-2, 4-dien-1-yl (diphenyl) phosphine; palladium dichloride; iroN (ii) (75).1mg,103 umol). The mixture was stirred under nitrogen at 60 ℃ for 12 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1 to 1:2) to give 4- [ [4- (7-bromoquinoxalin-2-yl) pyrazol-1-yl ] as a yellow solid]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (220 mg, 470. Mu. Mol, 43%). ¹ H NMR(400MHz,CDCl ₃ )δ9.09(s,1H),8.41-8.04(m,3H),7.94(d,J＝8.8Hz,1H),7.78(d,J＝8.8Hz,1H),4.21-4.08(m,4H),2.79-2.64(m,2H),2.26-2.14(m,1H),1.68-1.59(m,2H),1.46(s,9H),1.31-1.26(m,2H)；m/z ES+[M+H] ⁺ 472.1。

Step 2.4- ((4- (7-Hydroxyquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To 4- [ [4- (7-bromoquinoxalin-2-yl) pyrazol-1-yl ] in dioxane (280 mL) and water (140 mL)]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (27.0 g,58.0 mmol) was added tris (dibenzylideneacetone) dipalladium (5.30 g,5.8 mmol), 2-di-tert-butylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl (2.50 g,5.80 mmol) and potassium hydroxide (32.0 g,0.58 mol). The mixture was degassed and purged 3 times with nitrogen and then stirred under nitrogen at 100 ℃ for 3 hours. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (300 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1 to dichloromethane/methanol=20/1) to give tert-butyl 4- ((4- (7-hydroxyquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (20.0 g,48.9mmol, 84%) as a yellow solid. m/zES ⁺ [M+H] ⁺ 410.0。

Step 3.4- ((4- (8-bromo-7-hydroxyquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To 4- [ [4- (7-hydroxyquinoxalin-2-yl) pyrazol-1-yl ] in acetonitrile (10 mL) at 0deg.C]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (500 mg,1.22 mmol) was added N-bromosuccinimide (196 mg,1.10 mmol) in portions. The mixture was stirred at 80 ℃And 12 hours. The reaction mixture was filtered and carefully concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1 to 1/1) to give tert-butyl 4- ((4- (8-bromo-7-hydroxyquinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (490 mg,0.97mmol, 79%) as a yellow solid. M/zES + [ M+H ]] ⁺ 488.0。

Step 4.4- ((4- (8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To 4- [ [4- (8-bromo-7-hydroxy-quinoxalin-2-yl) pyrazol-1-yl ] in 1, 2-dichloroethane (6 mL)]Methyl group]Piperidine-1-carboxylic acid tert-butyl ester (245 mg, 502. Mu. Mol) and [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl]To a solution of boric acid (307 mg,1 mmol) was added copper acetate (109 mg, 602. Mu. Mol), Molecular sieves (500 mg) and cesium carbonate (169 mg,1.25 mmol). The mixture was stirred under nitrogen at 15psi at 60℃for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=1/0 to 40/1) to give 4- ((4- (8-bromo-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl piperidine-1-carboxylic acid tert-butyl ester (230 mg,285 μmol, 28%). M/zES + [ M+H ]] ⁺ 750.1。

[/g1]4- ((4- (8-cyano-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

To 4- [ [4- [ 8-bromo-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in N, N-dimethylformamide (5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]To a solution of tert-butyl piperidine-1-carboxylate (100 mg, 134. Mu. Mol) and malononitrile (17.64 mg, 267. Mu. Mol, 16.8. Mu.L) was added copper iodide (12.7 mg, 66.8. Mu. Mol), 4-di-tert-butylphosphino-N, N-dimethyl-aniline; palladium dichloride (1.89 mg, 2.67. Mu. Mol), 1, 10-phenanthroline (6.02 mg, 33.39. Mu. Mol), sodium tert-butoxide (25.7 mg, 267. Mu. Mol) and potassium fluoride (15.5 mg, 267. Mu. Mol). The mixture was stirred under nitrogen at 130 ℃ for 12 hours. The reaction mixture was treated with H ₂ O (30 mL) was diluted and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane: methanol=100/1 to 20/1) to give 8-chloro-7- ((2-methoxypyridin-4-yl) oxy) -2- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (50 mg,60.3 μmol, 45%) as a yellow oil. M/zES + [ M+H ]] ⁺ 695.1。

Step 6.6- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -3- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline-5-carbonitrile

4- [ [4- [ 8-cyano-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (1 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]Methyl group]A solution of tert-butyl piperidine-1-carboxylate (50 mg, 60.3. Mu. Mol) was stirred at 25℃for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 6- ((2-methyl-1H-benzo [ d ] as a yellow oil]Imidazol-6-yl) oxy) -3- (1- (piperidin-4-ylmethyl) -1H-pyrazol-4-yl) quinoxaline-5-carbonitrile (40 mg, crude, trifluoroacetic acid). M/zES + [ M+H ]] ⁺ 465.0。

Step 7.6- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -3- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline-5-carbonitrile

To 6- [ (2-methyl-3H-benzimidazol-5-yl) oxy in N, N-dimethylformamide (1 mL)]-3- [1- (4-piperidinylmethyl) pyrazol-4-yl]To a solution of quinoxaline-5-carbonitrile (40 mg, 69.14. Mu. Mol, trifluoroacetic acid) was added aqueous formaldehyde (56.1 mg, 691. Mu. Mol, 51. Mu.L, 37%). The mixture was stirred at 25℃for 0.5 h. Sodium triacetoxyborohydride (73.3 mg, 346. Mu. Mol) was then added. The mixture was stirred at 25℃for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressureConcentrating. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 1% -30%,10 min) purification to give 6- ((2-methyl-1H-benzo [ d) as a yellow solid]Imidazol-6-yl) oxy) -3- (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline-5-carbonitrile (9.0 mg, 18.8. Mu. Mol, 27%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.34(s,1H),8.71(s,1H),8.38(s,1H),8.19(d,J＝9.6Hz,1H),7.58(d,J＝8.4Hz,1H),7.43(s,1H),7.17(d,J＝9.2Hz,1H),7.06(d,J＝7.2Hz,1H),4.17(d,J＝7.2Hz,2H),2.89(d,J＝11.2Hz,2H),2.49(s,3H),2.26(s,3H),2.06(t,J＝10.4Hz,2H),1.97-1.87(m,1H),1.54(d,J＝11.6Hz,2H),1.39-1.26(m,2H)；m/z ES+[M+H] ⁺ 479.2。

EXAMPLE 194.Synthesis of 2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one

Step 1.2- (4- (8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (150 mg, 295. Mu. Mol) was added potassium carbonate (122 mg, 887. Mu. Mol) and 2-chloro-1-pyrrolidin-1-yl-ethanone (50.0 mg, 338. Mu. Mol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl as a yellow oil]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone (200 mg, crude). M/zES + [ M+H ]] ⁺ 618.2。

Step 2.2- (4- (8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one

2- [4- [ 8-chloro-7- [ 2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl ] in trifluoroacetic acid (5.5 mL)]Oxy-quinoxalin-2-yl]Pyrazol-1-yl]A solution of-1-pyrrolidin-1-yl-ethanone (200 mg, 323. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 12% -42%,7 min) purification to give 2- [4- [ 8-chloro-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] as an off-white solid]Quinoxalin-2-yl]Pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone (39.3 mg,0.081mmol, 24%). ¹ H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.63(s,1H),8.36(s,1H),7.98(d,J＝9.2Hz,1H),7.58(d,J＝8.8Hz,1H),7.35(d,J＝9.2Hz,1H),7.28(d,J＝2.0Hz,1H),7.06-7(m,1H),5.19(s,2H),3.54(t,J＝6.8Hz,2H),3.35(t,J＝6.8Hz,2H),2.55(s,3H),2.01-1.88(m,2H),1.85-1.76(m,2H)；m/z ES+[M+H] ⁺ 488.1。

Example 195.8 Synthesis of chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1- (vinylsulfonyl) piperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

Step 1.8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1- (vinylsulfonyl) piperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

To 2- [ [6- [ 5-chloro-3- [1- (4-piperidinylmethyl) pyrazol-4-yl ] in dichloromethane (1 mL)]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (50 mg, 82.8. Mu. Mol) was added diisopropylethylamine (53.48 mg, 414. Mu. Mol, 72. Mu.L). Then, 2-chloroethanesulfonyl chloride (13.49 mg, 82.8. Mu. Mol, 9. Mu.L) was added at 0deg.C. The mixture was subjected to a temperature of 25 ℃Stirring is carried out for 1 hour. The reaction mixture was concentrated under reduced pressure to give 8-chloro-7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] as a yellow solid ]Imidazol-6-yl) oxy) -2- (1- ((1- (vinylsulfonyl) piperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (60 mg, crude). M/zES + [ M+H ]] ⁺ 694.2。

Step 2.8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) -2- (1- ((1- (vinylsulfonyl) piperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline

2- [ [6- [ 5-chloro-3- [1- [ (1-vinylsulfonyl-4-piperidinyl) methyl ] in trifluoroacetic acid (1 mL)]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (60 mg, 86.42. Mu. Mol) was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column Phenomenex Luna C, 150 x 25mm x 10um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 17% -47%,10 min) purification to give 8-chloro-7- ((2-methyl-1H-benzo [ d) as an off-white solid]Imidazol-6-yl) oxy) -2- (1- ((1- (vinylsulfonyl) piperidin-4-yl) methyl) -1H-pyrazol-4-yl) quinoxaline (6.4 mg,11.3 μmol, 13%). ¹ H NMR(400MHz,DMSO-d6)δ＝9.31(s,1H),8.69(s,1H),8.38(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(s,1H),6.94(dd,J＝2.4,8.8Hz,1H),6.78(dd,J＝10.0,16.4Hz,1H),6.16-6.05(m,2H),4.19(d,J＝7.2Hz,2H),3.54(d,J＝12.0Hz,2H),2.64-2.55(m,2H),2.49(s,3H),2.10-1.96(m,1H),1.64(d,J＝11.2Hz,2H),1.38-1.24(m,2H)；m/z ES+[M+H] ⁺ 564.1。

Example 196.8 Synthesis of chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

Step 1.8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (2 mL)]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]To a solution of ethyl-trimethyl-silane (150 mg, 295. Mu. Mol) was added potassium carbonate (122 mg, 887. Mu. Mol) and 3- (bromomethyl) -1, 1-difluoro-cyclobutane (60.0 mg, 324. Mu. Mol). The mixture was stirred at 80℃for 12 hours. After completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 ml×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- [ [6- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] as a yellow solid]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (180 mg, crude). M/zES + [ M+H ]] ⁺ 611.2。

Step 2.8-chloro-2- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

2- [ [6- [ 5-chloro-3- [1- [ (3, 3-difluorocyclobutyl) methyl ] in trifluoroacetic acid (2 mL) ]Pyrazol-4-yl]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]A solution of ethyl-trimethyl-silane (140 mg, 229. Mu. Mol) was stirred at 25℃for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Gemini-NX 18 x 75 x 30mm x 3um; mobile phase: [ water (0.225% formic acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the (B%: 20% -50%,7 min) purification to give 8-chloro-2- [1- [ (3, 3-difluorocyclobutyl) methyl ] as an off-white solid]Pyrazol-4-yl]-7- [ (2-methyl-3H-benzimidazol-5-yl) oxy]Quinoxaline (71.3 mg,0.15mmol, 64%). ¹ H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.77(s,1H),8.38(s,1H),7.99(d,J＝9.2Hz,1H),7.63(d,J＝8.8Hz,1H),7.38(d,J＝9.2Hz,1H),7.33(s,1H),7.09(d,J＝8.4Hz,1H),4.39(d,J＝4.8Hz,2H),2.76–2.58(m,3H),2.60(s,3H),2.57-2.53(m,1H),2.48-2.41(m,1H)；m/z ES+[M+H] ⁺ 481.1。

Example 197.8 Synthesis of 8-chloro-2- (1- (2, 2-diethoxyethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 2- (1- ((1, 3-dioxan-2-yl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To 2- [ [6- [ 5-chloro-3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] in N, N-dimethylformamide (3 mL) at 20 ℃C ]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Cesium carbonate (3864 mg,1.18 mmol) was added in one portion to a mixture of ethyl-trimethyl-silane (200 mg, 394. Mu. Mol) and 2-bromo-1, 1-diethoxy-ethane (155 mg, 789. Mu. Mol, 119. Mu.L). The mixture was then heated to 100 ℃ and stirred for 4 hours. After completion, the reaction mixture was quenched by addition of water (20 mL) at 20 ℃ and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (20 ml x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- [ [6- [ 5-chloro-3- [1- (2, 2-diethoxyethyl) pyrazol-4-yl ] as a yellow oil]Quinoxalin-6-yl]Oxy-2-methyl-benzimidazol-1-yl]Methoxy group]Ethyl-trimethyl-silane (0.25 g,0.40mmol, 97%). M/zES + [ M+H ]] ⁺ 623.4。

Step 2.8-chloro-2- (1- (2, 2-diethoxyethyl) -1H-pyrazol-4-yl) -7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline and 2- (1- ((1, 3-dioxan-2-yl) methyl) -1H-pyrazol-4-yl) -8-chloro-7- ((2-methyl-1H-benzo [ d ] imidazol-6-yl) oxy) quinoxaline

To a mixture of 2- [ [6- [ 5-chloro-3- [1- (2, 2-diethoxyethyl) pyrazol-4-yl ] quinoxalin-6-yl ] oxy-2-methyl-benzoimidazol-1-yl ] methoxy ] ethyl-trimethyl-silane (250 mg,401 μmol) and propane-1, 3-diol (61.0 mg,802 μmol,58 μL) in toluene (5 mL) was added p-toluenesulfonic acid monohydrate (7.6 mg,40.1 μmol) at once. The mixture was then heated to 120 ℃ and stirred for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: phenomenex Luna C18.150X 25mM X10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; (B%: 15% -45%,10 min) and by preparative HPLC (column: phenomenex Gemini-NX 18X 30mM X3 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile ]; (B%: 20% -50%,8 min)), the impure product was further purified by preparative HPLC (column: phenomenex Gemini-NX 18.75X 30mM X3 um; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile ]; (B%: 28% -58%,8 min) to give 8-chloro-2- [1- (2, 2-diethoxyethyl) pyrazol-4-yl ] -7- [ (2-methyl-3H-benzimidazol-5-yl) oxy ] (quinoxaline (8.2 mg,0.017mmol, 4.1%) and 1- (1-dioxan-1, 3-5-yl) as yellow gum- ((1, 2-chloro-2- [1- (2, 2-diethoxyethyl) pyrazol-4-yl) -7- [ (2, 2-methyl-5-imidazolyl) oxy ] (-quinoxaline) as yellow gum.

¹ H NMR(400MHz,DMSO-d6)δ12.28(br s,1H),9.32(s,1H),8.69(s,1H),8.38(s,1H),7.96(d,J＝9.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.32(d,J＝8.8Hz,1H),7.21(s,1H),6.94(d,J＝9.2Hz,1H),4.91(t,J＝5.6Hz,1H),4.33(d,J＝5.6Hz,2H),3.75-3.56(m,2H),3.51-3.40(m,2H),2.49(s,3H),1.08(t,J＝7.2Hz,6H)；m/z ES+[M+H] ⁺ 493.1。

¹ H NMR(400MHz,DMSO-d6)9.31(s,1H),8.64(s,1H),8.37(s,1H),7.95(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.94(dd,J＝2.4,8.4Hz,1H),4.98(t,J＝4.8Hz,1H),4.32(d,J＝4.8Hz,2H),4.05(dd,J＝4.8,11.2Hz,2H),3.86-3.68(m,2H),2.49(s,3H),2.02-1.77(m,1H),1.38(d,J＝13.6Hz,1H)；m/z ES+[M+H] ⁺ 477.0。

EXAMPLE 198.1- [ (4- {7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (oxolan-3-yl) quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclopropan-1-ol

m/z ES+[M+H] ⁺ 501.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.13(s,1H),8.64(s,1H),8.47(br,1H),8.36(s,1H),7.84(d,J＝9.6Hz,1H),7.35(d,J＝8.8Hz,1H),7.20(d,J＝9.2Hz,1H),7.08(m,2H),5.06(quint,J＝9.2Hz,1H),4.41(dd,J＝7.6,8.8Hz,1H),4.37(s,2H),4.31(m,1H),4.22(t,J＝8.4Hz,1H),4.11(q,J＝8.0Hz,1H),2.82(m,1H),2.62(s,3H),2.40(m,1H),0.90(m,4H)。

Example 199.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -8- (2, 2-dimethyl-2, 5-dihydrofuran-3-yl) -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 543.0； ¹ H NMR(400MHz,DMSO)δ12.10(br,1H),9.20(s,1H),8.62(s,1H),8.25(s,1H),7.93(d,J＝9.2Hz,1H),7.47(d,J＝8.0Hz,1H),7.24(d,J＝9.2Hz,1H),7.11(s,1H),6.87(d,J＝8.8Hz,1H),5.86(s,1H),4.74(s,2H),4.38(d,J＝5.2Hz,1H),2.67(m,4H),2.50(m,1H),2.53(m,1H),2.47(s,3H),1.35(s,6H)。

Example 200.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (oxolan-3-yl) quinoxaline

m/z ES+[M+H] ⁺ 535.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.12(s,1H),8.58(s,1H),8.34(s,1H),7.86(d,J＝9.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.27(m,2H),5.00(quint,J＝9.2Hz,1H),2.80(s,3H),2.79-2.60(m,4H),2.58–2.43(m,2H),2.43–2.35(m,1H)。

Example 201.1- ({ 4- [8- (5, 5-dimethyl-2, 5-dihydrofuran-3-yl) -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl ] -1H-pyrazol-1-yl } methyl) cyclopropan-1-ol

m/z ES+[M+H] ⁺ 527.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.12(s,1H),8.56(s,1H),8.27(s,1H),7.88(d,J＝9.2Hz,1H),7.28(m,2H),7.00(t,J＝8.0Hz,1H),6.49(s,1H),5.27(d,J＝2.0Hz,2H),4.34(s,2H),2.60(s,3H),1.46(s,6H),0.86(d,J＝6.4Hz,4H)。

Example 202.3- {6- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -3- {1- [ (1-hydroxycyclopropyl) methyl ] -1H-pyrazol-4-yl } quinoxalin-5-yl } -1, 3-oxazolidin-2-one

m/z ES+[M+H] ⁺ 516.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.19(s,1H),8.62(s,1H),8.34(s,1H),8.02(d,J＝9.6Hz,1H),7.35(m,2H),7.17(dd,J＝8.8,9.2Hz,1H),4.81(m,1H),4.64(q,J＝8.4Hz,1H),4.45–4.32(m,3H),4.16(m,1H),2.62(s,3H),0.86(m,4H)。

EXAMPLE 203.1- [ (4- {7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (morpholin-4-yl) quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclopropan-1-ol

m/z ES+[M+H] ⁺ 498.0； ¹ H NMR(400MHz,CD ₃ OD)δ8.98(s,1H),8.46(s,1H),8.18(s,1H),7.61(d,J＝9.2Hz,1H),7.36(d,J＝8.8Hz,1H),7.26(d,J＝9.2Hz,1H),6.89(d,J＝2.0Hz,1H),6.83(dd,J＝2.0,8.4Hz,1H),4.20(s,2H),3.63(m,4H),3.39(m,4H),2.44(s,3H),0.76(m,4H)。

Example 204.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -8- (5, 5-dimethyl-2, 5-dihydrofuran-3-yl) -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

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m/z ES+[M+H] ⁺ 543.0； ¹ H NMR(400MHz,DMSO)δ9.24(s,1H),8.64(s,1H),8.25(s,1H),7.93(d,J＝9.2Hz,1H),7.50(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.11(d,J＝2.4Hz,1H),6.90(dd,J＝2.4,8.8Hz,1H),6.52(t,J＝2.0Hz,1H),5.12(d,J＝2.0Hz,2H),4.39(d,J＝5.2Hz,2H),2.68(m,4H),2.55(m,1H),2.50(s,3H),1.33(s,6H)。

Example 205.1- ({ 4- [8- (2, 5-Dihydrofuran-3-yl) -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl ] -1H-pyrazol-1-yl } methyl) cyclopropan-1-ol

m/z ES+[M+H] ⁺ 499.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.14(s,1H),8.58(s,1H),8.26(s,1H),7.83(d,J＝8.8Hz,1H),7.30(br,1H),7.27(d,J＝9.2Hz,1H),7.05(t,J＝7.2Hz,1H),6.72(t,J＝2.0Hz,1H),5.34(m,2H),5.00–4.95(m,2H),2.60(s,3H),0.89(m,4H)。

Example 206.1- [3- (3- {1- [ (3, 3-difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -6- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-5-yl) -2, 5-dihydro-1H-pyrrol-1-yl ] ethan-1-one

m/z ES+[M+H] ⁺ 556.1； ¹ H NMR(400MHz,DMSO)δ9.24(d,J＝6.8Hz,1H),8.67(d,J＝8.4Hz,1H),8.30(d,J＝24.8Hz,1H),7.93(dd,J＝3.2,9.2Hz,1H),7.48(d,J＝8.4Hz,1H),7.27(dd,J＝6.8,9.2Hz,1H),7.15(m,1H),6.90(td,J＝2.8,8.8Hz,1H),6.45(td,J＝1.6,10.8Hz,1H),4.93(s,1H),4.73(s,1H),4.54(s,1H),4.37(s,2H),4.32(s,1H),2.68(m,3H),2.54(m,2H),2.47(s,3H),2.01(d,J＝8.4Hz,3H)。

EXAMPLE 207.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -8- (5, 5-dimethyl-2, 5-dihydrofuran-3-yl) -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 561.0； ¹ H NMR(400MHz,DMSO)δ12.70(br,1H),9.22(s,1H),8.64(s,1H),8.25(s,1H),7.90(d,J＝9.6Hz,1H),7.27(m,1H),7.21(d,J＝9.2Hz,1H),6.97(m,1H),6.55(s,1H),5.17(d,J＝2.0Hz,2H),4.39(d,J＝5.2Hz,2H),2.69(m,4H),2.51(m,1H),2.50(s,3H),1.38(s,6H)。

Example 208.4- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy)]Quinoxalin-2-yl } -1H-pyrazol-1-yl) -1- (methylimino) -1 lambda ⁶ Thiopyran-1-ones

m/z ES+[M+H] ⁺ 521.9； ¹ H NMR(400MHz,DMSO)δ12.32(br,1H),9.33(s,1H),8.78(s,1H),8.37(s,1H),7.95(d,J＝9.6Hz,1H),7.51(m,1H),7.32(d,J＝8.8Hz,1H),7.21(m,1H),6.94(d,J＝8.0Hz,1H),4.6(m,1H),2.67(s,3H),2.55(m,2H),2.50(s,3H),2.45–2.20(m,6H)。

EXAMPLE 209.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (furan-3-yl) quinoxaline

m/z ES+[M+H] ⁺ 531.1； ¹ H NMR(400MHz,DMSO)δ12.72(br,1H),9.25(s,1H),8.64(s,1H),8.44(s,1H),8.31(s,1H),7.90(d,J＝9.6Hz,1H),7.82(t,J＝1.6Hz,1H),7.31(d,J＝8.4Hz,1H),7.26(s,1H),7.23(d,J＝9.2Hz,1H),7.03(t,J＝7.6Hz,1H),4.39(d,J＝5.6Hz,2H),2.70(m,4H),2.52(s,3H)。

EXAMPLE 210 [4- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ]]Quinoxalin-2-yl } -1H-pyrazol-1-yl) piperidin-1-yl](imino) methyl-lambda ⁶ Thioketone

m/z ES+[M+H] ⁺ 537.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.13(s,1H),8.62(s,1H),8.35(s,1H),7.86(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.32(d,J＝9.2Hz,1H),7.18(s,1H),7.00(dd,J＝2.0,8.8Hz,1H),4.45(m,1H),3.99(m,2H),2.98(m,2H),2.91(s,3H),2.57(s,3H),2.35-2.19(m,4H)。

EXAMPLE 211.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -8- (2, 5-dihydro-1H-pyrrol-3-yl) -7- [ (2-methyl-1H-1, 3-benzooxadiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 514.0； ¹ H NMR(400MHz,DMSO)δ9.25(s,1H),8.80(s,1H),8.42(s,1H),8.32(s,1H),7.95(d,J＝9.6Hz,1H),7.50(d,J＝8.4Hz,1H),7.25(d,J＝9.2Hz,1H),7.18(d,J＝2.0Hz,1H),6.91(dd,J＝2.0,8.4Hz,1H),6.50(s,1H),4.69(s,2H),4.38(d,J＝5.2Hz,2H),4.19(s,2h),3.43(m,1H),2.69(m,4H),2.48(s,3H)。

EXAMPLE 212.3- (3- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -6- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-5-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester

m/z ES+[M+H] ⁺ 614.1； ¹ H NMR(400MHz,CD ₃ OD)δ9.10(s,1H),8.50(d,J＝6.4Hz,1H),8.25(d,J＝3.6Hz,1H),7.92(d,J＝9.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.36(dd,J＝6.0,8.8Hz,1H),7.13(s,1H),7.01(d,J＝8.8Hz,1H),6.33(d,J＝16Hz,1H),4.74(s,2H),4.38(d,J＝6.8Hz,2H),4.31(br,2H),2.80–2.65(m,3H),2.62(s,3H),2.49(m,2H),1.48(s,9H)。

EXAMPLE 213.4- (4- { 8-chloro)-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy)]Quinoxalin-2-yl } -1H-pyrazol-1-yl) -1-imino-1 lambda ⁶ Thiopyran-1-ones

m/z ES+[M+H] ⁺ 507.9； ¹ H NMR(400MHz,DMSO)δ9.33(s,1H),8.78(s,1H),8.37(s,1H),7.95(d,J＝9.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.94(dd,J＝2.4,8.4Hz,2H),4.74(m,1H),3.34(m,3H),3.16(d,J＝12.4Hz,2H),2.53(m,2H),2.48(s,3H),2.33(d,J＝11.2Hz,2H)。

EXAMPLE 214 { 4- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy } -)]Quinoxalin-2-yl } -1H-pyrazol-1-yl) piperidin-1-yl](methyl) oxo-lambda ⁶ -thioalkylene } (meth) amines

m/z ES+[M+H] ⁺ 551.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.15(s,1H),8.66(s,1H),8.37(s,1H),7.89(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.18(d,J＝2.0Hz,1H),7.00(dd,J＝2.4,8.8Hz,1H),4.46(m,1H),3.83–3.75(m,2H),3.01(m,2H),2.91(s,3H),2.66(s,3H),2.66(s,3H),2.30–2.15(m,4H)。

Example 215.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (oxa-n-3-yl) quinoxaline

m/z ES+[M+H] ⁺ 531.0； ¹ H NMR(400MHz,CD ₃ OD)δ8.20(s,1H),8.51(s,1H),8.00(d,J＝9.2Hz,1H),7.97(s,1H),7.60–7.53(m,2H),7.28(s,1H),7.18(d,J＝2.4Hz,1H),7.05(d,J＝8.8Hz,1H),4.36(d,J＝6.8Hz,1H),4.05(ddd,J＝2.8,10.8,28Hz,2H),3.80(t,J＝10.4Hz,2H),3.68–3.50(m,2H),2.80–2.65(m,3H),2.59(s,3H),2.50–2.35(m,2H),2.15(br,2H),1.8(br,2H)。

EXAMPLE 216.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (2, 5-tetramethyl-2, 5-dihydrofuran-3-yl) quinoxaline

m/z ES+[M+H] ⁺ 589.0； ¹ H NMR(400MHz,DMSO)δ9.19(s,1H),8.60(s,1H),8.21(s,1H),7.93(d,J＝9.2Hz,1H),7.28(d,J＝8.4Hz,1H),7.19(d,J＝9.2Hz,1H),6.94(t,J＝7.6Hz,1H),5.74(s,1H),4.37(d,J＝5.6Hz,2H),2.68(m,4H),2.52(s,3H),1.40(s,6H),1.36(s,6H)。

EXAMPLE 217.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -8- (2, 5-dihydrofuran-3-yl) -7- [ (7-fluoro-2-methyl-1H-1, 3-benzooxadiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 533.2； ¹ H NMR(400MHz,DMSO)δ12.57(br,1H),9.20(d,J＝5.6Hz,1H),8.65(s,1H),8.28(s,1H),7.87(d,J＝9.2Hz,1H),7.27(d,J＝8.8Hz,1H),7.15(d,J＝8.8Hz,1H),7.00(t,J＝7.6Hz,1H),6.73(t,J＝1.6Hz,1H),5.20(m,2H),4.80(m,2H),4.37(d,J＝5.0Hz,2H),2.75-2.65(m,4H),2.55-2.51(m,1H),2.50(s,3H)。

Example 218.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (2, 5-tetramethyl-2, 5-dihydrofuran-3-yl) quinoxaline

m/z ES+[M+H] ⁺ 571.1； ¹ H NMR(400MHz,DMSO)δ9.20(s,1H),8.60(s,1H),8.21(s,1H),7.95(d,J＝9.2Hz,1H),7.45(d,J＝8.4Hz,1H),7.30(d,J＝9.2Hz,1H),7.06(s,1H),6.86(dd,J＝2.4,8.4Hz,1H),5.68(s,1H),4.37(t,J＝5.6Hz,2H),2.68(m,3H),2.46(s,3H),1.36(s,6H),1.34(s,6H)。

Example 219.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -8- (5, 6-dihydro-2H-pyran-3-yl) -7- [ (2-methyl-1H-1, 3-benzooxadiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 529.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.08(s,1H),8.51(s,1H),8.27(s,1H),7.91(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.37(d,J＝9.2Hz,1H),7.09(d,J＝2.0Hz,1H),6.99(dd,J＝2.0,8.4Hz,1H),5.96(br,1H),4.44(d,J＝2.0Hz,2H),4.37(d,J＝7.2Hz,2H),3.86(t,J＝5.6Hz,2H),2.80–2.60(m,3H),2.65(s,3H),2.55-2.40(m,2H),2.34(br,2H),2.53–2.35(m,2H)2.14(m,2H),1.81(d,J＝13.6Hz,2H)。

Example 220.8-chloro-2- [1- (3, 3-difluoropropyl) -1H-pyrazol-4-yl ] -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 454.9； ¹ H NMR(400MHz,DMSO)δ9.36(s,1H),8.77(s,1H),8.40(s,1H),8.04(d,J＝9.2Hz,1H),7.78(d,J＝8.8Hz,1H),7.47–7.45(m,2H),7.26(dd,J＝2.0,8.8Hz,1H),6.20(tt,J＝4.4,56.4Hz,1H),4.43(t,J＝6.8Hz,2H),2.74(s,3H),2.52(m,2H)。

Example 221.1- [ (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclopropan-1-amine

m/z ES+[M+H] ⁺ 445.9； ¹ H NMR(400MHz,DMSO)δ9.33(s,1H),8.81(s,1H),8.41(s,1H),7.95(d,J＝8.8Hz,1H),7.28(d,J＝8.8Hz,1H),7.51(d,J＝8.8Hz,1H),7.31(d,J＝9.6Hz,1H),7.21(d,J＝1.6Hz,1H),6.94(dd,J＝2.0,8.8Hz,1H),4.44(s,2H),3.36(t,J＝6.4Hz,1H),3.32(t,J＝6.4Hz,1H),2.50(s,3H),1.97–1.87(m,4H)。

EXAMPLE 222.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (oxetan-4-yl) quinoxaline

m/z ES+[M+H] ⁺ 531.0； ¹ H NMR(400MHz,CD ₃ OD)δ8.19(s,1H),8.02(d,J＝9.2Hz,1H),7.96(s,1H),7.57–7.53(m,2H),7.28(d,J＝1.6Hz,1H),7.19(d,J＝2.4Hz,1H),7.05(dd,J＝2.0,8.8Hz,1H),4.35(d,J＝6.4Hz,2H),4.07(dd,J＝2.4,10.8Hz,2H),3.60(m,2H),3.31(s,3H),2.75-2.58(m,3H),2.59(s,3H),2.53–2.35(m,2H)2.14(m,2H),1.81(d,J＝13.6Hz,2H)。

Example 223.3- (3- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -6- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-5-yl) -1, 3-oxazolidin-2-one

m/z ES+[M+H] ⁺ 550.3； ¹ H NMR(400MHz,DMSO)δ12.60(s,1H),9.25(s,1H),8.73(s,1H),8.33(s,1H),7.98(d,J＝9.6Hz,1H),7.28(d,J＝8.8Hz,1H),7.20(d,J＝9.2Hz,1H),7.05(m,1H),4.72(dd,J＝2.4,6.4Hz,1H),4.51(m,1H),4.36(d,J＝5.6Hz,2H),4.30(m,1H),3.93(m,1H),2.73-2.57(m,4H),5.58-2.50(m,1H),2.50(s,3H)。

EXAMPLE 224.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (1H-imidazo l-1-yl) quinoxaline

m/z ES+[M+H] ⁺ 531.1； ¹ H NMR(400MHz,DMSO)δ12.66(br,1H),9.30(m,1H),8.54(s,1H),8.20–8.10(m,1H),8.16(s,1H),8.06(d,J＝9.2Hz,1H),7.62(d,J＝6.4Hz,1H),7.35–7.05(m,4H),4.36(d,J＝4.8Hz,2H),2.70–2.60(m,2H),2.52(s,3H)。

Example 225.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (oxetan-3-yl) quinoxaline

m/z ES+[M+H] ⁺ 503.0； ¹ H NMR(400MHz,DMSO)δ9.81(m,1H),9.22(s,1H),8.71(s,1H),8.35(s,1H),7.86(d,J＝9.2Hz,1H),7.48(d,J＝8.4Hz,1H),7.20(d,J＝9.2Hz,1H),6.89(dd,J＝2.4,8.8Hz,1H),6.53(s,1H),4.37(d,J＝5.6Hz,2H),3.57(m,2H),2.83(m,2H),2.75-2.65(m,4H),2.55-2.51(m,2H),2.48(s,3H)。

EXAMPLE 226N- {1- [ (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclopropyl } acetamide

m/z ES+[M+H] ⁺ 488.0； ¹ H NMR(400MHz,DMSO)δ9.34(s,1H),8.65(s,2H),8.34(s,1H),8.12(s,1H),7.96(d,J＝9.6Hz,1H),7.51(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(d,J＝2.0Hz,1H),6.94(dd,J＝2.4,8.4Hz,1H),4.35(s,2H),2.50(s,3H),1.75(s,3H),0.98(m,2H),0.71(m,2H)。

EXAMPLE 227N- {1- [ (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclopropyl } methanesulfonamide

m/z ES+[M+H] ⁺ 523.9； ¹ H NMR(400MHz,DMSO)δ9.41(s,1H),8.68(s,2H),8.40(s,1H),8.06(d,J＝9.2Hz,1H),7.82(d,J＝8.8Hz,1H),7.64(s,1H),7.49(d,J＝9.2Hz,1H),7.45(d,J＝2.4Hz,1H),7.31(dd,J＝2.4,9.2Hz,1H),4.37(s,2H),2.96(s,3H),2.79(s,3H),1.01(s,4H)。

Example 228.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -8- (3.6 dihydro-2H-pyran-4-yl) -7- [ (2-methyl-1H-1, 3-benzooxadiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 529.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.11(s,1H),8.50(s,1H),8.25(s,1H),7.95(d,J＝9.2Hz,1H),7.62(d,J＝8.8Hz,1H),7.43(d,J＝9.2Hz,1H),7.15(d,J＝1.6Hz,1H),7.12(dd,J＝2.0,8.8Hz,1H),5.83(s,1H),4.38(d,J＝6.8Hz,2H),4.27(d,J＝2.4Hz,2H),3.84(t,J＝5.2Hz,2H),2.72(s,3H),2.80-2.60(m,3H),2.55–2.40(m,4H)。

EXAMPLE 229.8-chloro-2- (1- {6, 6-difluorospiro [3.3] heptan-2-yl } -1H-pyrazol-4-yl) -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 506.9； ¹ H NMR(400MHz,DMSO)δ9.31(s,1H),8.78(s,2H),8.38(s,1H),7.96(d,J＝9.2Hz,1H),7.53(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.23(d,J＝2.0Hz,1H),6.97(dd,J＝2.4,8.8Hz,1H),4.98(quint,J＝8.4Hz,1H),2.64(m,8H),2.51(s,3H)。

Example 230.1- [ (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclobutane-1, 3-diol

m/z ES+[M+H] ⁺ 494.9； ¹ H NMR(400MHz,DMSO)δ9.31(s,1H),8.56(s,2H),8.44(s,1H),8.35(s,1H),7.93(d,J＝9.6Hz,1H),7.34(d,J＝8.8Hz,1H),7.09(t,J＝8.0Hz,1H),4.31(s,2H),4.28(m,1H),2.52(s,3H),2.16(m,2H),2.04(m,2H)。

Example 231.1- [ (4- {7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (1H-imidazo l-1-yl) quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclopropan-1-ol

m/z ES+[M+H] ⁺ 497.2； ¹ H NMR(400MHz,DMSO)δ9.36(s,1H),8.50(s,2H),8.15(s,1H),8.11(d,J＝9.6Hz,1H),7.76(br,1H),7.42(m,1H),7.34(d,J＝8.4Hz,1H),7.30(d,J＝9.6Hz,1H),7.17(t,J＝8.0Hz,1H),5.61(s,1H),4.26(s,2H),2.52(s,3H),0.71(m,4H)。

EXAMPLE 232.8-chloro-2- {1- [ (1S) -1- (4, 4-difluorocyclohexyl) ethyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 523.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.12(s,1H),8.57(s,1H),8.35(s,1H),7.86(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.18(d,J＝2.4Hz,1H),7.00(dd,J＝2.4,8.8Hz,1H),4.28(m,1H),2.56(s,3H),2.10–1.76(m,5H),1.60(d,J＝6.8Hz,3H),1.45–1.20(m,4H)。

Example 233.8-chloro-2- {1- [ (1R) -1- (4, 4-difluorocyclohexyl) ethyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 523.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.13(s,1H),8.57(s,1H),8.36(s,1H),7.86(d,J＝9.2Hz,1H),7.52(d,J＝8.8Hz,1H),7.31(d,J＝9.2Hz,1H),7.18(d,J＝2.4Hz,1H),7.00(dd,J＝2.4,8.8Hz,1H),4.28(m,1H),2.56(s,3H),2.10–1.76(m,5H),1.60(d,J＝63.8Hz,3H),1.42–1.24(m,3H),2.15(s,4H)。

EXAMPLE 234 (2S) -2- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propan-1-ol

m/z ES+[M+H] ⁺ 452.9； ¹ H NMR(400MHz,DMSO)δ9.31(s,1H),8.69(s,1H),8.36(s,1H),7.93(d,J＝9.2Hz,1H),7.34(d,J＝8.4Hz,1H),7.21(d,J＝9.2Hz,1H),7.09(t,J＝8.4Hz,1H),5.04(m,1H),4.50(m,1H),3.71(m,2H),2.52(s,3H),1.46(d,J＝6.8Hz,3H)。

EXAMPLE 235 (2R) -2- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propan-1-ol

m/z ES+[M+H] ⁺ 452.9； ¹ H NMR(400MHz,DMSO)δ12.70(br,1H),9.31(s,1H),8.69(s,1H),8.36(s,1H),7.93(d,J＝9.2Hz,1H),7.34(d,J＝8.4Hz,1H),7.21(d,J＝8.8Hz,1H),7.09(t,J＝8.4Hz,1H),5.04(m,1H),4.50(m,1H),3.72(m,2H),2.53(s,3H),1.47(d,J＝6.8Hz,3H)。

Example 236.8-chloro-2- {1- [ (1S) -1- (3, 3-difluorocyclobutyl) ethyl ] -1H-pyrazol-4-yl } -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 512.9； ¹ H NMR(400MHz,DMSO)δ12.68(br,1H),9.31(s,1H),8.80(s,1H),8.38(s,1H),7.94(d,J＝9.2Hz,1H),7.34(d,J＝8.0Hz,1H),7.22(d,J＝9.2Hz,1H),7.09(t,J＝8.0Hz,1H),4.56(quint,J＝6.0Hz,1H),2.8–2.61(m,4H),2.53(s,3H),2.43(m,1H),1.48(d,J＝6.4Hz,3H)。

Example 237.8-chloro-2- {1- [ (1R) -1- (3, 3-difluorocyclobutyl) ethyl ] -1H-pyrazol-4-yl } -7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 512.9； ¹ H NMR(400MHz,DMSO)δ12.70(br,1H),9.31(s,1H),8.80(s,1H),8.38(s,1H),7.94(d,J＝9.2Hz,1H),7.34(d,J＝4.0Hz,1H),7.22(d,J＝9.2Hz,1H),7.09(dd,J＝2.8,8.0Hz,1H),4.56(m,1H),2.8–2.61(m,4H),2.59(s,3H),2.43(m,1H),1.48(d,J＝6.4Hz,3H)。

EXAMPLE 238.8-chloro-2- {1- [ (1-methoxycyclopropyl) methyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 460.9； ¹ H NMR(400MHz,DMSO)δ9.34(s,1H),8.71(s,1H),8.36(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(d,J＝2.0Hz,1H),6.96(dd,J＝2.0,8.4Hz,1H),4.43(s,2H),3.27(s,3H),0.84(s,4H)。

Example 239.8-chloro-2- {1- [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzooxadiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 473.3； ¹ H NMR(400MHz,DMSO)δ12.28(d,J＝39.9Hz,1H),9.35(d,J＝4.2Hz,1H),8.89(s,1H),8.45(s,1H),7.97(dd,J＝5.4,9.2Hz,1H),7.51(dd,J＝8.6,31.8Hz,1H),7.34(dd,J＝9.2,20.5Hz,1H),7.22(dd,J＝2.0,36.3Hz,1H),6.94(ddd,J＝2.2,8.6,13.4Hz,1H),5.84(s,2H),2.51(s,3H),2.48(s,3H)。

EXAMPLE 240.2- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -2-methylpropanoic acid methyl ester

m/z ES+[M+H] ⁺ 495.2； ¹ H NMR(400MHz,DMSO)δ12.66(s,1H),9.38(s,1H),8.92(s,1H),8.39(s,1H),7.95(d,J＝9.3Hz,1H),7.33(d,J＝7.3Hz,1H),7.23(d,J＝8.7Hz,1H),7.11(t,J＝7.7Hz,1H),3.67(s,3H),2.53(s,3H),1.89(s,6H)。

Example 241.2- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -1- (4-methoxypiperidin-1-yl) ethan-1-one

m/z ES+[M+H] ⁺ 532.3； ¹ H NMR(400MHz,DMSO)δ12.33(s,1H),9.33(s,1H),8.63(s,1H),8.36(s,1H),7.96(d,J＝9.2Hz,1H),7.51(d,J＝8.6Hz,1H),7.32(d,J＝9.2Hz,1H),7.22(s,1H),6.95(dd,J＝2.3,8.6Hz,1H),5.31(s,2H),4.04(s,3H),3.89–3.77(m,1H),3.77–3.66(m,1H),3.53–3.39(m,1H),3.28(s,3H),3.24–3.01(m,2H),1.99–1.86(m,1H),1.86–1.73(m,1H),1.63–1.44(m,1H),1.44-1.27(m,1H)。

Example 242.1- (4-Acetylpiperazin-1-yl) -2- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) ethan-1-one

m/z ES+[M+H] ⁺ 545.5； ¹ H NMR(400MHz,CD ₃ OD)δ9.10(s,1H),8.53(s,1H),8.34(s,1H),7.52(d,J＝9.2Hz,1H),7.19(s,1H),7.02(dd,J＝1.8,8.6Hz,1H),5.32(s,2H),3.65(dd,J＝10.3,22.5Hz,8H),2.58(s,3H),2.15(s,3H)。

Example 243.2- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -2-methylpropanoic acid

m/z ES+[M+H] ⁺ 481.3； ¹ H NMR(400MHz,DMSO)δ9.37(s,1H),8.88(s,1H),8.36(s,1H),7.94(d,J＝9.3Hz,1H),7.34(d,J＝8.3Hz,1H),7.22(d,J＝9.2Hz,1H),7.09(d,J＝8.0Hz,1H),2.53(s,3H),1.85(s,6H)。

EXAMPLE 244.4- [ (4- { 8-methanesulfonyl-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy)]Quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl]-1λ ⁶ -thiane-1, 1-diones

m/z ES+[M+H] ⁺ 567.1； ¹ H NMR(500MHz,DMSO)δ9.35(s,1H),8.71(s,1H),8.40(d,J＝0.5Hz,1H),8.20(d,J＝9.3Hz,1H),7.59–7.50(m,1H),7.30(d,J＝9.3Hz,1H),7.28–7.24(m,1H),6.99–6.95(m,1H),4.28(d,J＝7.1Hz,2H),3.73(s,3H),3.31(s,3H),3.17(td,J＝13.6,3.4Hz,2H),3.12–3.04(m,2H),2.34–2.26(m,1H),1.97–1.91(m,2H),1.80–1.69(m,2H)。

Example 245.1- (3- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -6- [ (2-methyl-1H-1, 3-benzooxadiazol-6-yl) oxy ] quinoxalin-5-yl) pyrrolidin-2-one

m/z ES+[M+H] ⁺ 530.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.13(s,1H),8.52(s,1H),8.27(s,1H),7.99(d,J＝9.2Hz,1H),7.52(d,J＝8.4Hz,1H),7.37(d,J＝9.2Hz,1H),7.25(d,J＝2.0Hz,1H),7.04(dd,J＝2.4,8.8Hz,1H),4.38(d,J＝6.8Hz,2H),4.14(q,J＝7.2Hz,1H),3.82(m,1H),2.73-2.68(m,4H),2.58(s,3H),2.52–2.51(m,4H),2.17–2.14(m,1H)。

EXAMPLE 246 (2S) -1- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propan-2-ol

m/z ES+[M+H] ⁺ 452.9； ¹ H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.65(s,1H),8.37(s,1H),7.94(d,J＝9.2Hz,1H),7.35(d,J＝8.8Hz,1H),7.23(d,J＝9.2Hz,1H),7.11(m,1H),5.20–4-98(br,1H),4.19-4.05(m,3H),2.54(s,3H),1.11(d,J＝6.0Hz,1H)。

EXAMPLE 247 (2S) -1- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propan-2-ol

m/z ES+[M+H] ⁺ 434.9； ¹ H NMR(400MHz,DMSO-d6)δ12.34–12.22(br,1H),9.32(s,1H),8.64(s,1H),8.36(s,1H),7.95(d,J＝9.2Hz,1H),7.50(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.21(br,1H),6.95(dd,J＝2.4,8.4Hz,1H),5.01(br,1H),4.19-4.05(m,3H),2.48(s,3H),1.10(d,J＝5.2Hz,1H)。

Example 248.4-chloro-N- (3- {1- [ (3, 3-difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -6- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-5-yl) butanamide

m/z ES+[M+H] ⁺ 566.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.11(s,1H),8.53(s,1H),8.32(s,1H),7.91(d,J＝9.2Hz,1H),7.49(d,J＝8.4Hz,1H),7.36(d,J＝9.2Hz,1H),7.20(br,1H),7.01(dd,J＝2.0,8.4Hz,1H),4.38(d,J＝7.2Hz,2H),3.68(t,J＝7.2Hz,2H),2.74-2.66(m,4H),2.56(s,3H),2.46(m,2H),2.17(m,2H)。

Example 249.8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -2- {1- [4- (2, 2-trifluoroethyl) -4-azaspiro [2.5] oct-7-yl ] -1H-pyrazol-4-yl } quinoxaline

m/z ES+[M+H] ⁺ 586.3； ¹ H NMR(400MHz,DMSO-d6)δ13.08-12.26(br,1H),9.32(s,1H),8.80(s,1H),8.39(s,1H),7.94(d,J＝9.6Hz,1H),7.34(d,J＝8.0Hz,1H),7.23(d,J＝9.6Hz,1H),7.10(m,1H),7.10(t,J＝8.4Hz,1H),4.57(m,1H),3.59(m,1H),3.40(m,1H),3.01(m,2H),2.53(s,3H),2.35(m,1H),2.25(m,1H),1.88(m,1H),1.36(m,1H),0.67(m,3H),0.51(m,1H)。

EXAMPLE 250.3- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -1, 1-trifluoro-2-methylpropan-2-ol

m/z ES+[M+H] ⁺ 521.0； ¹ H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.70(s,1H),8.43(s,1H),7.95(d,J＝9.2Hz,1H),7.35(d,J＝8.8Hz,1H),7.24(d,J＝9.2Hz,1H),7.30(d,J＝2.0Hz,1H),7.10(t,J＝8.4Hz,1H),6.55(s,1H),4.86(q,J＝14.0Hz,1H),2.53(s,3H),1.26(s,3H)。

EXAMPLE 251 (4 r) -6- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) spiro [3.3] hept-2-ol

m/z ES+[M+H] ⁺ 486.9； ¹ H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.75(s,1H),8.35(s,1H),7.98(d,J＝9.2Hz,1H),7.61(d,J＝8.8Hz,1H),7.37(d,J＝9.2Hz,1H),7.30(d,J＝2.0Hz,1H),7.06(dd,J＝2.0,8.4Hz,1H),5.01(br,1H),4.88(quint,J＝8.4Hz,1H),4.02(m,1H),2.58-2.54(m,5H),2.46–2.41(m,3H),2.29(m,1H),1.92(m,2H)。

EXAMPLE 252 (4 s) -6- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) spiro [3.3] hept-2-ol

m/z ES+[M+H] ⁺ 486.9； ¹ H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.74(s,1H),8.35(s,1H),7.97(d,J＝9.2Hz,1H),7.58(d,J＝8.4Hz,1H),7.35(d,J＝9.2Hz,1H),7.27(d,J＝1.6Hz,1H),7.03(dd,J＝2.0,8.4Hz,1H),5.0(br,1H),4.88(quint,J＝8.4Hz,1H),2.55-2.47(m,5H),2.43(m,3H),1.92(m,2H)。

EXAMPLE 253 (2S) -2- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propan-1-ol

m/z ES+[M+H] ⁺ 434.9； ¹ H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.70(s,1H),8.36(s,1H),8.0(d,J＝9.2Hz,1H),7.69(d,J＝8.4Hz,1H),7.40(d,J＝9.2Hz,1H),7.38(m,1H),7.16(dd,J＝2.0,8.8Hz,1H),4.50(m,1H),3.71(m,2H),3.09(m,1H),2.66(s,3H),1.46(d,J＝6.8Hz,1H)。

EXAMPLE 254 (2R) -2- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propan-1-ol

m/z ES+[M+H] ⁺ 434.9； ¹ H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.69(s,1H),8.35(s,1H),7.95(d,J＝9.2Hz,1H),7.52(d,J＝8.4Hz,1H),7.31(d,J＝9.2Hz,1H),7.23(d,J＝2.4Hz,1H),6.96(dd,J＝2.4,8.4Hz,1H),5.04(br,1H),4.50(m,1H),3.70(m,2H),2.51(s,3H),1.46(d,J＝7.2Hz,1H),

EXAMPLE 255 (4 r) -6- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) spiro [3.3] hept-2-ol

m/z ES+[M+H] ⁺ 504.9； ¹ H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.74(s,1H),8.34(s,1H),7.93(d,J＝9.2Hz,1H),7.36(d,J＝8.4Hz,1H),7.23(d,J＝9.2Hz,1H),7.11(t,J＝7.6Hz,1H),4.88(quint,J＝8.4Hz,1H),4.03(quint,J＝7.2Hz,1H),2.54(m,5H),2.44(m,3H),2.28(m,1H),1.91(m,2H)。

EXAMPLE 256 (4 s) -6- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) spiro [3.3] hept-2-ol

m/z ES+[M+H] ⁺ 504.9； ¹ H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.74(s,1H),8.35(s,1H),7.93(d,J＝8.8Hz,1H),7.33(d,J＝8.8Hz,1H),7.21(d,J＝9.2Hz,1H),7.08(m,1H),5.01(d,J＝5.2Hz,1H),4.90(quint,J＝8.0Hz,1H),4.03(m,1H),2.17(m,2H),2.52(s,3H),2.45(m,3H),2.28(m,1H),1.92(m,2H)。

Example 257.1- [ (4- { 8-iodo-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclopropan-1-ol

m/z ES+[M+H] ⁺ 538.8； ¹ H NMR(400MHz,CD ₃ OD)δ9.14(s,1H),8.66(s,1H),8.39(s,1H),7.99(d,J＝8.8Hz,1H),7.68(d,J＝8.8Hz,1H),7.34(d,J＝9.2Hz,1H),7.26(s,1H),7.21(m,1H),4.38(s,2H),2.27(s,3H),0.29(m,4H)。

EXAMPLE 258 (2R) -1- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propan-2-ol

m/z ES+[M+H] ⁺ 452.9； ¹ H NMR(400MHz,CD ₃ OD)δ9.13(s,1H),8.56(s,1H),8.36(s,1H),7.86(d,J＝9.2Hz,1H),7.33(d,J＝7.6Hz,1H),7.23(d,J＝9.3Hz,1H),7.09(t,J＝7.6Hz,1H),4.22(m,3H),2.60(s,3H),1.24(d,J＝6.0Hz,3H)。

EXAMPLE 259.1- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -2-methylpropan-2-ol

m/z ES+[M+H] ⁺ 467.3； ¹ H NMR(400MHz,CD ₃ OD)δ9.08(s,1H),8.52(s,1H),8.31(s,1H),7.81(d,J＝9.3Hz,1H),7.30(d,J＝8.6Hz,1H),7.20(d,J＝9.3Hz,1H),7.07(app t,J＝7.9Hz,1H),4.21(s,2H),2.59(s,3H),1.24(s,6H)。

EXAMPLE 260 (2R) -1- (4- { 8-chloro-7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propan-2-ol

m/z ES+[M+H] ⁺ 434.9； ¹ H NMR(400MHz,CD ₃ OD)δ9.19(s,1H),8.56(s,1H),8.35(s,1H),7.95(d,J＝3.6Hz,1H),7.66(d,J＝8.8Hz,1H),7.43(d,J＝9.2Hz,1H),7.25(d,J＝2.0Hz,1H),7.20(dd,J＝2.4,8.8Hz,1H),4.21(m,1H),2.73(s,3H),4.39(d,J＝6.8Hz,1H),4.32(m,1H),4.24(m,1H),2.73(s,3H),1.24(d,J＝6.0Hz,3H)。

Example 261.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -8- (2, 5-dimethyl-1H-pyrrol-1-yl) -7- [ (2-methyl-1H-1, 3-benzooxadiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 540.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.12(s,1H),8.56(s,1H),8.37(s,1H),8.12(s,1H),8.06(d,J＝9.6Hz,1H),7.46(d,J＝9.2Hz,2H),7.11(br,1H)6.91(dd,J＝2.4,8.8Hz,1H),5.89(s,2H),4.32(d,J＝6.8Hz,1H),2.69(m,3H),2.55(s,1H),2.44(m,1H),6.41(s,6H)。

Example 262.2- {1- [ (3, 3-Difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } -7- [ (2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8- (oxolan-3-yl) quinoxaline

m/z ES+[M+H] ⁺ 517.0； ¹ H NMR(400MHz,CD ₃ OD)δ9.09(s,1H),8.56(s,1H),8.32(s,1H),7.85(d,J＝9.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.29(d,J＝8.8Hz,1H),7.11(s,1H)6.97(dd,J＝2.4,8.8Hz,1H),4.93(m,1H),4.39(d,J＝6.8Hz,1H),4.32(m,1H),4.24(m,1H),4.15(m,1H),4.04(m,1H),2.2(m,4H),2.51(s,3H),2.47(m,2H),2.31(m,1H)。

EXAMPLE 263.8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -2- (1- { 4-methyl-4-azaspiro [2.5] oct-7-yl } -1H-pyrazol-4-yl) quinoxaline

m/z ES+[M+H] ⁺ 518.4； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.7–12.58(br,1H),9.31(s,1H),8.81(s,1H),8.37(s,1H),8.15(s,1H),7.94(d,J＝9.2Hz,1H),7.34(d,J＝8.8Hz,1H),7.23(d,J＝9.2Hz,1H),7.10(d,J＝8.0Hz,1H),4.53(m,1H),2.95(m,2H),2.56(m,1H),2.53(s,3H),2.43(s,3H),2.30(m,1H),1.86(m,1H),1.29(m,1H),0.66–0.54(m,3H),0.46(m,1H)。

EXAMPLE 264.8-chloro-7- [ (7-chloro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -2- {1- [ (3, 3-difluorocyclobutyl) methyl ] -1H-pyrazol-4-yl } quinoxaline

m/z ES+[M+H] ⁺ 514.8； ¹ H NMR(400MHz,DMSO-d ₆ )δ13.11–12.51(br,1H),9.30(s,1H),8.76(s,1H),8.38(s,1H),7.92(d,J＝8.8Hz,1H),7.49(d,J＝8.4Hz,1H),7.12–7.08(m,2H),4.39(d,J＝5.6Hz,1H),2.69(m,3H),2.54(s,3H)。

Example 265.1- [ (4- {7- [ (7-chloro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -8-fluoroquinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclopropan-1-ol

m/z ES+[M+H] ⁺ 464.9； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.34(s,1H),8.69(s,1H),8.35(s,1H),7.81(d,J＝9.2Hz,1H),7.47(d,J＝8.8Hz,1H),7.21(t,J＝8.8Hz,1H),7.10(t,J＝8.4Hz,1H),4.28(s,2H),2.54(s,3H),0.76(m,2H),0.72(m,2H)。

Example 266.3- [ (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] oxetan-3-ol

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m/z ES+[M+H] ⁺ 480.9； ¹ H NMR(400MHz,CD ₃ OD)δ9.28(s,1H),9.25(s,1H),8.51(br,1H),7.98(d,J＝9.6Hz,1H),7.37(m,2H)7.12(m,1H),4.83(s,2H),4.66(d,J＝12.4Hz,1H),3.86(s,2H),2.61(s,3H)。

Example 267.2- (1- { 4-azaspiro [2.5] oct-7-yl } -1H-pyrazol-4-yl) -8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxaline

m/z ES+[M+H] ⁺ 504.3； ¹ H NMR(400MHz,CD ₃ OD)δ9.17(s,1H),8.66(s,1H),8.41(s,1H),7.90(d,J＝9.2Hz,1H),7.36(d,J＝8.8Hz,1H),7.27(d,J＝9.2Hz,1H),7.11(dd,J＝8.8,9.2Hz,1H),4.76(m,1H),3.50(m,1H),3.25(m,1H),2.68(m,1H),2.62(s,3H),2.43(m,1H),2.32(m,1H),1.83(m,1H),1.03–0.98(m,2H),0.92–0.87(m,2H)。

Example 268.1- [ (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) methyl ] cyclobutan-1-ol

m/z ES+[M+H] ⁺ 478.9； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.61(s,1H),8.36(s,1H),7.93(d,J＝9.2Hz,1H),7.34(d,J＝8.4Hz,1H),7.22(d,J＝9.2Hz,1H),7.09(t,J＝8.0Hz,1H),5.50(br,1H),4.31(s,2H),2.53(s,3H),2.17-2.13(m,2H),2.02-1.94(m,2H),1.67(m,1H),1.55(m,1H)。

Example 269.4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazole-1-carboxylic acid propan-2-yl ester

m/z ES+[M+H] ⁺ 480.9； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.7(br,1H),9.52(s,1H),9.35(s,1H),8.63(d,J＝0.4Hz,1H),7.99(d,J＝9.2Hz,1H),7.37–7.30(m,2H),7.11(dd,J＝7.6,8.4Hz,1H),5.24(septet,J＝6.4Hz,2H),2.52(s,3H),1.44(d,J＝6.4Hz,2H)。

Example 270.2- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -2-methylpropan-1-ol

m/z ES+[M+H] ⁺ 467.3； ¹ H NMR(400MHz,CD ₃ OD)δ9.19(s,1H),8.68(s,1H),8.39(s,1H),7.88(d,J＝9.2Hz,1H),7.34(d,J＝8.7Hz,1H),7.24(d,J＝9.2Hz,1H),7.09(dd,J＝8.6,7.3Hz,1H),3.83(s,2H),2.61(s,3H),1.67(s,6H)。

EXAMPLE 271 (1R, 3 r) -3- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) cyclobutan-1-ol

m/z ES+[M+H] ⁺ 465.0； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.31(s,1H),8.79(s,1H),8.38(s,1H),7.93(d,J＝9.2Hz,1H),7.34(d,J＝8.4Hz,1H),7.22(d,J＝9.2Hz,1H),7.09(t,J＝7.4Hz,1H),5.12–5.07(m,1H),4.55–4.49(m,1H),2.75–2.72(m,2H),(s,3H),3.06(s,3H),2.44–2.40(m,2H)。

Example 272.3- (4- { 8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -1, 1-trifluoropropan-2-ol

m/z ES+[M+H] ⁺ 506.9； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.76(br,1H)9.32(s,1H),8.77(s,1H),8.44(s,1H),7.95(d,J＝9.6Hz,1H),7.34(d,J＝8.8Hz,1H),7.24(d,J＝9.6Hz,1H),7.09(t,J＝8.4Hz,1H),6.88–6.84(m,1H),4.55(m,2H),4.40(m,2H),2.52(s,3H)。

Example 273.8-chloro-7- [ (7-fluoro-2-methyl-1H-1, 3-benzodiazol-6-yl) oxy ] -2- [1- ({ 5H,6H, 8H-imidazo [4,3-c ] [1,4] oxazin-3-yl } methyl) -1H-pyrazol-4-yl ] quinoxaline

m/z ES+[M+H] ⁺ 530.9； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.33(s,1H),8.76(s,1H),8.39(s,1H),7.94(d,J＝9.2Hz,1H),7.74(d,J＝8.4Hz,1H),7.23(d,J＝9.2Hz,1H),7.09(t,J＝7.8Hz,1H),6.77(s,1H),5.58(s,2H),4.77(s,2H),4.09(m,2H),3.97(m,2H)。

Example 274 biological Activity of exemplary Compounds

The following are non-limiting examples describing cell proliferation assays for determining the biological activity of the compounds of the present disclosure. More specifically, the assay is used to assess the ability of a compound to inhibit cell proliferation.

Briefly, SNU-16 (FGFR 2-expanded) cells were resuspended in RPMI containing 10% heat-inactivated FBS, 1% L-glutamine at 18,520c/mL and dispensed in duplicate (463 c/well) into 384-well plates. UM-UC-14 (FGFR 3-S249C) cells were resuspended in RPMI containing 10% heat-inactivated FBS, 1% L-glutamine at 40,000C/mL and dispensed in duplicate (1000C/well) into 384 well plates. DMS-114 (FGFR 1 over-expression) cells were resuspended in RPMI containing 10% heat-inactivated FBS, 1% l-glutamine at 40,000c/mL and dispensed in duplicate (1000 c/well) into 384-well plates. RT-112 (FGFR 3-Tacc3 fusion) cells were resuspended in RPMI containing 10% heat-inactivated FBS, 1% L-glutamine at 40,000c/mL and dispensed in 384-well plates in duplicate (1000 c/well). To determine the effect of compounds of the present disclosure on cell proliferation, SNU-16, UM-UC-14, DMS-114 and RT112 cells were incubated at different concentrations for 72 hours in the presence of vehicle control (DMSO) or compounds of the present disclosure. Inhibition of cell growth was then determined by luminescence quantification (Envision by Perkin Elmer) of intracellular ATP content using CellTiterGlo (Promega) according to the protocol provided by the manufacturer. To determine IC50 values, vehicle-treated cells were normalized to living cells and analyzed using CDD Vault software (Collaborative Drug Discovery, burlingame, CA).

Tables A1 and A2 specify various compound potency codes: A. b, C or D. According to the code, A represents IC ₅₀ Value of<20nM; b represents IC ₅₀ The value is equal to or more than 20nM<100nM; c represents IC ₅₀ The value is equal to or more than 100nM<400nM; and D represents IC ₅₀ The value is equal to or more than 400nM.

Table A1

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Table A2

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Equivalent forms

The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and claims. In the description and the appended claims, the singular forms also include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

The foregoing description is presented for purposes of illustration only and is not intended to limit the disclosure to the exact forms disclosed, but is limited by the appended claims.

Claims

1. A compound of formula (I'):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

W ⁴ is C (R) ^W4 ) Or N;

R ^WW4 is H, halogen, cyano, C ₁ -C ₆ Alkyl or-S (=o) ₂ -(C ₁ -C ₆ An alkyl group);

W ⁵ is C (R) ^W5 ) Or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

each R ^3a Independently halogen, cyano, oxo, -OH, NH ₂ 、-NH(C ₁ -C ₆ Alkyl), -NHC (=o) O (C) ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ One S (=O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein NHC (=o) O (C ₁ -C ₆ Alkyl) optionally substituted with one or more halogens;

R ⁵ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁶ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

z is absent, H, C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more RZ;

each RZ is independently oxo, halo, cyano, -OH, =nr ^Za 、NH ₂ 、NHR ^Za 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) (3-to 12-membered heterocycloalkyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, or 5-to 10-membered heteroaryl optionally substituted with one or more RZa;

each RZa is independently H, oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocycloalkyl optionally substituted with one or more R ^Zb Substitution; and is also provided with

2. A compound according to claim 1, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0;

R ^W1 is H;

R ^W2 is H;

W ³ is N;

W ⁴ is C (R) ^W4 )；

R ^W4 Is H or halogen;

W ⁵ is C (R) ^W5 )；

R ^W5 Is H or halogen;

R ^W6 is H or C ₁ -C ₆ An alkyl group;

X ¹ is N;

X ² is C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ is C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

each R ^3a Independently halogen, oxo, NHC (=o) O (C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl), -C (=O) O (C) ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl, wherein-NHC (=o) O (C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) (C ₁ -C ₆ Alkyl group),-C(＝O)O(C ₁ -C ₆ Alkyl group, C ₁ -C ₆ Alkyl or C ₂ -C ₆ Alkenyl groups are optionally substituted with one or more halogens;

R ⁵ is H or C ₁ -C ₆ An alkyl group;

R ⁶ is H or halogen;

z is absent and is C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more RZ;

each R ^Z Independently oxo, halogen, -OH, =nr ^Za 、NH ₂ 、NHR ^Za 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl group,C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(C ₁ -C ₆ Alkyl), -S (=o) (=nr ^Za )-(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₁ -C ₆ Alkyl), -S (=o) ₂ -(C ₂ -C ₆ Alkenyl), -C (=o) NH (C) ₁ -C ₆ Alkyl), -C (=O) NR ^Za 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl), -C (=o) - (C ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₁₂ Cycloalkyl, 3-to 12-membered heterocycloalkyl or 5-to 10-membered heteroaryl optionally substituted with one or more R ^Za Substitution;

Each R ^Zb Independently oxo, halogen, -OH.

3. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen or cyanoRadicals or C ₁ -C ₆ An alkyl group;

each R ^Za Independently oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more R ^Zb Substitution; and is also provided with

4. A compound according to claim 3, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ Is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

5. A compound according to claim 3, wherein:

each of which isIndependently represents a single bond or a double bond;

n is 0 or 1;

W ³ is C or N;

X ¹ is C or N;

X ² n, O or C (R) ^X2 )；

R ^X2 Is H or C ₁ -C ₆ An alkyl group;

X ³ n, O or C (R) ^X3 )；

R ^X3 Is H or C ₁ -C ₆ An alkyl group;

R ¹ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ² is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ³ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

R ⁴ is H, halogen, cyano or C ₁ -C ₆ An alkyl group;

z is C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally Geodesic one or more R ^Z Substitution;

each R ^Z Independently oxo, halogen, cyano, -OH, NH ₂ 、NH(C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl, wherein NH (C ₁ -C ₆ Alkyl), N (C) ₁ -C ₆ Alkyl group ₂ 、-S(＝O) ₂ -(C ₁ -C ₆ Alkyl), -C (=o) - (C ₁ -C ₆ Alkyl), -C (=o) - (C ₂ -C ₆ Alkenyl group, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocycloalkyl optionally substituted with one or more RZa;

6. A compound according to any one of the preceding claims whereinIs that

7. A compound according to any one of the preceding claims whereinIs that

8. The compound of any one of the preceding claims, wherein R ¹ H.

9. The compound of any one of the preceding claims, wherein R ¹ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

10. A compound according to any one of the preceding claims, R ² H.

11. The compound of any one of the preceding claims, wherein R ² Is halogen, cyano or C ₁ -C ₆ An alkyl group.

12. The compound of any one of the preceding claims, wherein R ³ H.

13. The compound of any one of the preceding claims, wherein R ³ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

14. The compound of any one of the preceding claims, wherein R ⁴ H.

15. The compound of any one of the preceding claims, wherein R ⁴ Is halogen, cyano or C ₁ -C ₆ An alkyl group.

16. The compound of any one of the preceding claims, wherein Y is absent.

17. A compound according to any one of the preceding claims wherein Y is C optionally substituted with one or more oxo or-OH ₁ -C ₆ An alkyl group.

18. The compound of any one of the preceding claims, wherein Z is absent.

19. A method according to any preceding claimThe compound, wherein Z is C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein C ₃ -C ₁₂ Cycloalkyl, C ₃ -C ₁₂ Cycloalkenyl, 3-to 12-membered heterocycloalkyl, 3-to 12-membered heterocycloalkenyl, C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R ^Z And (3) substitution.

20. The compound of any one of the preceding claims, having formula (I-a), (I-b), (I-c), (I-d), (II-a), (II-b), (II-c), or (II-d):

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or a pharmaceutically acceptable salt or stereoisomer thereof.

21. A compound according to any one of the preceding claims selected from the compounds described in table I and table II or a pharmaceutically acceptable salt or stereoisomer thereof.

22. A pharmaceutical composition comprising a compound according to any one of the preceding claims and one or more pharmaceutically acceptable carriers or excipients.

23. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound according to any one of the preceding claims.

24. A compound according to any one of the preceding claims for use in the treatment or prevention of cancer in a subject.

25. Use of a compound according to any one of the preceding claims in the manufacture of a medicament for treating or preventing cancer in a subject.

26. Use of a compound according to any one of the preceding claims for treating or preventing cancer in a subject.

27. The method, compound or use of any one of claims 23 to 26, wherein the subject has previously undergone at least one round of anti-cancer therapy.

28. The method, compound or use of any one of claims 23-27, wherein the cancer is characterized by at least one oncogenic mutation in the FGFR2 gene or the FGFR3 gene.

29. The method, compound or use of any one of claims 23-27, wherein the cancer is characterized by overexpression of the FGFR2 gene or the FGFR3 gene.

30. The method, compound or use of any one of claims 23-27, wherein the cancer is characterized by at least one oncogenic variant of FGFR2 or FGFR 3.

31. The method, compound or use of any one of claims 23 to 30, wherein the cancer is a carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, kidney cancer, stomach cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulval cancer, joint cancer, oral cancer, pharyngeal cancer or colorectal cancer.