CN117203202A - Quinoxaline derivative and use thereof - Google Patents

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 derivatives and uses thereof

Cross-reference to related applications

This application claims priority to and the benefit of U.S. Provisional Application No. 63/146,312 filed on February 5, 2021, U.S. Provisional Application No. 63/223,255 filed on July 19, 2021, and U.S. Provisional Application No. 63/242,260 filed on September 9, 2021, the contents of each of which are incorporated herein by reference in their entirety.

Background Art

Specific mutations in the human genes FGFR2 and FGFR3 encoding proteins FGFR2 and FGFR3, respectively, have been associated with several different types of cancers. Various FGFR2 and/or FGFR3 inhibitors for the treatment of cancer have been developed, including FDA-approved drugs such as erdafitinib and pemigatinib. However, existing inhibitors show various defects, limiting their effectiveness clinically. First, some existing inhibitors only target FGFR2, and fail to inhibit FGFR3, which limits the ability of its treatment of certain types of cancer. In addition, several existing inhibitors also target FGFR1, resulting in dose-limited toxicity, such as hyperphosphatemia. Finally, after applying some existing inhibitors, many patients produce other mutations in FGFR2 and/or FGFR3, called gatekeeper mutations, which result in resistance to existing inhibitors. Therefore, this area has long needed novel therapies specifically for FGFR2 and FGFR3. The present disclosure provides compositions and methods for preventing or treating cancer in patients with overexpression and/or oncogenic mutations in FGFR2 and/or FGFR3.

Summary of the invention

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

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C( ^RW1 ) when attached to one double bond and one single bond, N( ^RW1 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) or O when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^W4 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 alkyl);

^W5 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 alkyl);

^W6 is C ( ^RW6 ) when attached to one double bond and one single bond, N ( ^RW6 ) when attached to two single bonds, or N when attached to one double bond and one 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 alkyl);

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

^R3 is H, halogen, cyano, _NH2 , -NH( _C1 - _C6 alkyl), -NHC(=O)( _C1 - _C6 haloalkyl), -NHC(=O)O( _C1 - _C6 alkyl), N(C1- _C6 alkyl) ₂ , -S(=O) _2- (C1-C6 alkyl), -C(=O)H, -C(=O)( _C1 - _C6 alkyl), -C(=O)O( _C1 - _C6 alkyl), _C1 -C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1- _{C6 alkoxy, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein -NH(C1-C6 alkyl ) is C3 - C12 cycloalkyl} , _C3 - _C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, _C6 - _C10 aryl, or 5- to 10-membered heteroaryl. _{R 3a substituted by one or more R 3a ; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​} ^​

each R ^3a is 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) ₂ , -S(═O) _2- (C ₁ -C ₆ alkyl), -C(═O)( _{C 1} -C ₆ alkyl), -C(═O)O(C ₁ -C ₆ alkyl), 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) is optionally substituted with one or more halogen;

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

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

Y is absent and is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy is optionally substituted by 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 optionally substituted by -(C ₁ -C ₆ alkyl)(C ₆ -C ₁₀ aryl), or C ₃ -C ₁₂ cycloalkyl;

Z is absent and is 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 is optionally substituted with one or more R ^Z ;

each R ^Z is independently oxo, halogen, cyano, -OH, =NR ^Za , NH ₂ , NHR ^Za , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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), C ₁ -C ₆ alkyl, C ₂ -C 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} alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) _2- (C _{1 -C} alkyl), -C(═O)-(C ₁ -C alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently H, oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C 1 -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C 6 alkoxy, C 3 -C ₁₂ cycloalkyl, or 3 to 12 membered heterocycloalkyl ₁ - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, _C3 - _C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more ^RZb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

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

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C(R ^W1 ) when attached to one double bond and one single bond, N(R ^W1 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

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

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

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

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

Y is absent or is C ₁ -C ₆ alkyl optionally substituted with one or more oxo or -OH;

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 is optionally substituted by one or more R ^Z ;

Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

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

In some aspects, the 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 methods comprising administering to the subject a therapeutically effective amount of a compound described herein.

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

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

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. In this specification, unless the context clearly specifies otherwise, the singular also includes the plural. Although methods and materials similar to or equivalent to the methods and materials described herein can be used to practice or test the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. It is not recognized that the references cited herein are prior art for the claimed invention. In the event of a conflict, the present specification including the definition shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to be restrictive. In the event of a conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure shall prevail.

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

DETAILED DESCRIPTION

Compounds of the Disclosure

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

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C( ^RW1 ) when attached to one double bond and one single bond, N( ^RW1 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) or O when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^W4 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 alkyl);

^W5 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 alkyl);

^W6 is C ( ^RW6 ) when attached to one double bond and one single bond, N ( ^RW6 ) when attached to two single bonds, or N when attached to one double bond and one 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 alkyl);

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

^R3 is H, halogen, cyano, _NH2 , -NH( _C1 - _C6 alkyl), -NHC(=O)( _C1 - _C6 haloalkyl), -NHC(=O)O( _C1 - _C6 alkyl), N(C1- _C6 alkyl) ₂ , -S(=O) _2- (C1-C6 alkyl), -C(=O)H, -C(=O)( _C1 - _C6 alkyl), -C(=O)O( _C1 - _C6 alkyl), _C1 -C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1- _{C6 alkoxy, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein -NH(C1-C6 alkyl ) is C3 - C12 cycloalkyl} , _C3 - _C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, _C6 - _C10 aryl, or 5- to 10-membered heteroaryl. _R 3a substituted with one or more R 3a ; -NHC(═O)(C ₁ -C ₆ haloalkyl), -NHC(═O)O(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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), 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 is optionally substituted with one or more R ^3a ;

each R ^3a is 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) ₂ , -S(═O) _2- (C ₁ -C ₆ alkyl), -C(═O)( _{C 1} -C ₆ alkyl), -C(═O)O(C ₁ -C ₆ alkyl), 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) is optionally substituted with one or more halogen;

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

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

Y is absent and is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy is optionally substituted by 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 optionally substituted by -(C ₁ -C ₆ alkyl)(C ₆ -C ₁₀ aryl), or C ₃ -C ₁₂ cycloalkyl;

Z is absent and is 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 is optionally substituted with one or more R ^Z ;

each R ^Z is independently oxo, halogen, cyano, -OH, =NR ^Za , NH ₂ , NHR ^Za , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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), C ₁ -C ₆ alkyl, C ₂ -C 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} alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) _2- (C _{1 -C} alkyl), -C(═O)-(C ₁ -C alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently H, oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C 1 -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C 6 alkoxy, C 3 -C ₁₂ cycloalkyl, or 3 to 12 membered heterocycloalkyl ₁ - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, _C3 - _C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more ^RZb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

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

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C( ^RW1 ) when attached to one double bond and one single bond, N( ^RW1 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

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

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

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

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

Y is absent or is C ₁ -C ₆ alkyl optionally substituted with one or more oxo or -OH;

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 is optionally substituted by one or more R ^Z ;

Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

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

Each independently represents a single bond or a double bond;

n is 0;

^W1 is C(R ^W1 ) when attached to one double bond and one single bond, N(R ^W1 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W1 is H;

^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) or O when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W2 is H;

W ³ is N;

W ⁴ is C(R ^W4 );

R ^W4 is H or halogen;

^W5 is C(R ^W5 );

R ^W5 is H or halogen;

^W6 is C ( ^RW6 ) when attached to one double bond and one single bond, N ( ^RW6 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W6 is H or C ₁ -C ₆ alkyl;

X ¹ is N;

^X2 is C(R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is C(R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

^R3 is H, halogen, cyano, _NH2 , NHC(=O)O( _C1 - _C6 alkyl), -S ₍ =O) _2- (C1- _C6 alkyl), -C(=O)( _C1 - _C6 alkyl), -C(=O)O( _C1 - _C6 alkyl), _C1 -C6 alkyl, _C2 - _C6 alkenyl, _C3 - _C12 cycloalkyl, 3- to ₁₂ -membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, or 5- to 10-membered heteroaryl, wherein NHC(=O)O( _C1 - _C6 alkyl), -S(=O) _2- ( _C1 - _C6 alkyl), -C(=O)( _C1 - _C6 alkyl), -C(=O)O( _C1 - _C6 alkyl), _C1 -C _6- membered alkyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^3a ;

each R ^3a is 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), 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), C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl is optionally substituted with one or more halogen;

R ⁵ is H or C ₁ -C ₆ alkyl;

^R6 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, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy is optionally substituted by one or more halogen, oxo, cyano, -OH, NH ₂ , C ₁ -C ₆ alkyl, C ₂ -C 6 alkenyl, C ₁ -C ₆ alkoxy optionally substituted by –(C ₁ -C ₆ alkyl)( _{C 6} -C ₁₀ aryl), or C ₃ -C ₁₂ cycloalkyl;

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 is optionally substituted with one or more R ^Z ;

each R ^Z is independently oxo, halogen, -OH, =NR ^Za , NH ₂ , NHR ^Za , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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 ₁ -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), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, C ₃ -C 6 the _alkyl ), -S(═O)(═NR Za )-(C ₁ -C ₆ alkyl), -S(═O) ₂ -(C ₁ -C ₆ alkyl), -S(═O) ₂ -(C ₁ -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), _{C 1} -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, C _{3 -C 6 12} -membered cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^Za ;

each R ^Za is independently H, oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C 6 alkyl), 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 ₁₂ -membered cycloalkyl or 3 to 12-membered heterocycloalkyl is optionally substituted with one or more R ^Zb ; and

Each R ^Zb is 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 independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C ( ^RW1 ) or N ( ^RW1 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C ( ^RW2 ) or N ( ^RW2 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

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

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

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

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

Y is absent or is C ₁ -C ₆ alkyl optionally substituted with one or more oxo or -OH;

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 optionally substituted by one or more R ^Z ;

Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

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

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C ( ^RW1 ) or N ( ^RW1 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C ( ^RW2 ) or N ( ^RW2 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

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

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

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

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

Y is C ₁ -C ₆ alkyl optionally substituted by one or more oxo or -OH;

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 optionally substituted by one or more R ^Z ;

Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

Variables n, ^W1 , ^RW1 , ^W2 , ^RW2 , ^W3 , ^W4 , ^RW4 , ^W5 , ^RW5 , ^W6 , and ^RW6

In some embodiments, each independently represents a single bond or a double bond.

In some embodiments, each In some embodiments, each independently represents a double bond.

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

In some embodiments, ^W1 is C( ^RW1 ) when attached to one double bond and one single bond, N( ^RW1 ) when attached to two single bonds, or N when attached to one double bond and one single bond.

In some embodiments, ^W1 when attached to one double bond and one single bond is C( ^RW1 ).

In some embodiments, ^W1 when attached to two single bonds is N( ^RW1 ).

In some embodiments, W ¹ is N when attached to one double bond and one single bond.

In some embodiments, ^W1 is C( ^RW1 ) or N( ^RW1 ).

In some embodiments, W ¹ is C(R ^{W 1} ). In some embodiments, W ¹ is CH.

In some embodiments, W ¹ is N(R ^{W 1} ). 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 is 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 alkyl.

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, ^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) when attached to two single bonds, or N when attached to one double bond and one single bond.

In some embodiments, ^W2 when attached to one double bond and one single bond is C( ^RW2 ).

In some embodiments, ^W2 when attached to two single bonds is N( ^RW2 ).

In some embodiments, ^W2 is N when attached to one double bond and one single bond.

In some embodiments, ^W2 is C( ^RW2 ) or N( ^RW2 ).

In some embodiments, ^W2 is C( ^RW2 ). In some embodiments, ^W2 is CH.

In some embodiments, ^W2 is N( ^RW2 ). In some embodiments, ^W2 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, ^W2 is N.

In some embodiments, R ^W2 is 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 alkyl.

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, ^W3 is C. In some embodiments, ^W3 is N.

In some embodiments, W ⁴ is C(R ^{W 4} ). In some embodiments, W ⁴ is CH. In some embodiments, W ⁴ is C(halogen).

In some embodiments, ^W4 is N.

In some embodiments, R ^W4 is 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 is 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 alkyl.

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, ^W5 is C( ^RW5 ). In some embodiments, ^W5 is CH. In some embodiments, ^W5 is C(halogen).

In some embodiments, ^W5 is N.

In some embodiments, R ^W5 is 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 halo. In some embodiments, R ^W5 is F, Cl, Br, or I. In some embodiments, R ^W5 is 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 alkyl.

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, ^W6 is C( ^RW6 ) when attached to one double bond and one single bond, N( ^RW6 ) when attached to two single bonds, or N when attached to one double bond and one single bond.

In some embodiments, ^W6 when attached to one double bond and one single bond is C( ^RW6 ).

In some embodiments, ^W6 when attached to two single bonds is N( ^RW6 ).

In some embodiments, W ⁶ is N when attached to one double bond and one single bond.

In some embodiments, ^W6 is C( ^RW6 ) or N( ^RW6 ).

In some embodiments, ^W6 is C( ^RW6 ). In some embodiments, ^W6 is CH.

In some embodiments, ^W6 is N( ^RW6 ). In some embodiments, ^W6 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, ^W6 is N.

In some embodiments, R ^W6 is 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 halo. In some embodiments, R ^W6 is F, Cl, Br, or I. In some embodiments, R ^W6 is 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 alkyl.

In some embodiments, R ^W6 is C ₁ -C ₆ alkoxy.

In some embodiments, R ^W6 is C ₁ -C ₆ haloalkyl.

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, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for

The variables ^X1 , ^X2 , ^RX2 , ^X3 , and ^RX3

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

In some embodiments, ^X2 is N. In some embodiments, ^X2 is O.

In some embodiments, X ² is C( ^RX2 ). In some embodiments, X ² is 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, ^RX2 is H.

In some embodiments, R ^X2 is C ₁ -C ₆ alkyl. In some embodiments, R ^X2 is CH ₃ .

In some embodiments, ^X3 is N. In some embodiments, ^X3 is O.

In some embodiments, X ³ is C( ^RX3 ). In some embodiments, X ³ is 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, ^RX3 is H.

In some embodiments, ^RX3 is C ₁ -C ₆ alkyl. In some embodiments, ^RX3 is CH ₃ . In some embodiments, X ¹ is N, X ² is C( ^RX2 ), and X ³ is C( ^RX3 ).

In some embodiments, ^X1 is C, ^X2 is C( ^RX2 ), and ^X3 is O.

In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for In some embodiments, for Variables R ¹ , R ² , R ³ , R ^3a , R ⁴ , R ⁵ and R ⁶

In some embodiments, R ¹ is H.

In some embodiments, R ¹ is halogen, cyano, or C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is halo. In some embodiments, R ¹ is F or Cl.

In some embodiments, R ¹ is 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 alkyl. In some embodiments, R ¹ is CH ₃ .

In some embodiments, ^R2 is H.

In some embodiments, R ² is halogen, cyano, or C ₁ -C ₆ alkyl.

In some embodiments, R ² is halo. In some embodiments, R ² is F or Cl.

In some embodiments, R ² is 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 alkyl. 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) 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), 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 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) 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), 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 is optionally substituted _by one or more R ^3a replaced.

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) 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), 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, ^R3 is H.

In some embodiments, R ³ is 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) 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), 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 _-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) 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), 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 _by one or more R ^3a replaced.

In some embodiments, R ³ is 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) 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), 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, 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) 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), 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) 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). ₆ alkyl) or -C(═O)O(C ₁ -C ₆ alkyl) is optionally substituted with one or more R ^3a .

In some embodiments, R ³ is 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) 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), N(C ₁ -C ₆ alkyl) 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), 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) 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). ₆ alkyl) or -C(═O)O(C ₁ -C ₆ alkyl) is optionally substituted with one or more R ^3a .

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) 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) 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) ₂ is optionally substituted with one or more R ^3a .

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) ₂ .

In some embodiments, R ³ is NH ₂ .

In some embodiments, R ³ is -NH(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^3a .

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

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

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

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

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

In some embodiments, R ³ is N(C ₁ -C ₆ alkyl) ₂ optionally substituted with one or more R ^3a .

In some embodiments, R ³ is N(C ₁ -C ₆ alkyl) 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) is optionally substituted with one or more R ^3a .

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 is -S(=O) ₂ -(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^3a .

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 is -C(=O)(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^3a .

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

In some embodiments, R ³ is -C(=O)O(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^3a .

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 is optionally substituted with one or more R ^3a .

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.

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, 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 .

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.

In some embodiments, R ³ is C ₁ -C ₆ alkyl optionally substituted with one or more R ^3a .

In some embodiments, R ³ is C ₂ -C ₆ alkenyl optionally substituted with one or more R ^3a .

In some embodiments, R ³ is C ₂ -C ₆ alkenyl.

In some embodiments, R ³ is C ₂ -C ₆ alkynyl optionally substituted with one or more R ^3a .

In some embodiments, R ³ is C ₂ -C ₆ alkynyl.

In some embodiments, R ³ is C ₁ -C ₆ alkoxy optionally substituted with one or more R ^3a .

In some embodiments, R ³ is C ₁ -C ₆ alkoxy.

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 is optionally substituted with one or more R ^3a .

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 is C ₃ -C ₁₂ cycloalkyl optionally substituted with one or more R ^3a .

In some embodiments, R ³ is C ₃ -C ₁₂ cycloalkyl.

In some embodiments, R ³ is C ₃ -C ₁₂ cycloalkenyl optionally substituted with one or more R ^3a .

In some embodiments, R ³ is C ₃ -C ₁₂ cycloalkenyl.

In some embodiments, R ³ is 3 to 12 membered heterocycloalkyl optionally substituted with one or more R ^3a .

In some embodiments, R ³ is 3 to 12 membered heterocycloalkyl.

In some embodiments, R ³ is 3 to 12 membered heterocycloalkenyl optionally substituted with one or more R ^3a .

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

In some embodiments, R ³ is C ₆ -C ₁₀ aryl optionally substituted with one or more R ^3a .

In some embodiments, R ³ is C ₆ -C ₁₀ aryl.

In some embodiments, R ³ is 5- to 10-membered heteroaryl optionally substituted with one or more R ^3a .

In some embodiments, R ³ is 5- to 10-membered heteroaryl.

In some embodiments, R ³ is halogen, cyano, or C ₁ -C ₆ alkyl.

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

In some embodiments, R ³ is 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 alkyl. In some embodiments, R ³ is CH ₃ .

In some embodiments, each R ^3a is 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)(C ₁ -C ₆ alkyl), -C(═O)O(C ₁ -C ₆ alkyl), 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) ₂ , -S(＝O) ₂ -(C ₁ -C ₆ alkyl), -C(＝O)(C ₁ -C ₆ alkyl), -C(＝O)O(C ₁ -C ₆ alkyl), 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 halogen.

In some embodiments, each R ^3a is 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) ₂ , -S(═O) _2- (C ₁ -C ₆ alkyl), -C(═O)(C ₁ -C ₆ alkyl), -C(═O)O(C ₁ -C ₆ alkyl), 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) is optionally substituted with one or more halogens.

In some embodiments, each R ^3a is 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) 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) is optionally substituted with one or more halogen.

In some embodiments, each R ^3a is independently halo, cyano, oxo, or -OH.

In some embodiments, each R ^3a is independently halo. In some embodiments, each R ^3a is independently cyano. In some embodiments, each R ^3a is independently oxo. In some embodiments, each R ^3a is independently -OH.

In some embodiments, each R ^3a is independently NH ₂ , -NH(C ₁ -C ₆ alkyl), -NHC(═O)O(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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) is optionally substituted with one or more halogens.

In some embodiments, each R ^3a is independently NH ₂ .

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

In some embodiments, each R ^3a is independently -NHC(═O)O(C ₁ -C ₆ alkyl) optionally substituted with one or more halogens.

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

In some embodiments, each R ^3a is independently N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, each R ^3a is independently -S(=O) ₂ -(C ₁ -C ₆ alkyl).

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

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

In some embodiments, each R ^3a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ alkoxy.

In some embodiments, each R ^3a is independently C ₁ -C ₆ alkyl.

In some embodiments, each R ^3a is independently C ₂ -C ₆ alkenyl.

In some embodiments, each R ^3a is independently C ₂ -C ₆ alkynyl.

In some embodiments, each R ^3a is independently C ₁ -C ₆ alkoxy.

In some embodiments, each R ^3a is 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 is independently C ₃ -C ₁₂ cycloalkyl.

In some embodiments, each R ^3a is independently 3-12 membered heterocycloalkyl.

In some embodiments, each R ^3a is independently C ₆ -C ₁₀ aryl.

In some embodiments, each R ^3a is independently 5- to 10-membered heteroaryl.

In some embodiments, ^R4 is H.

In some embodiments, R ⁴ is halogen, cyano, or C ₁ -C ₆ alkyl.

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

In some embodiments, R ⁴ is 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 alkyl. In some embodiments, R ⁴ is CH ₃ .

In some embodiments, ^R5 is H.

In some embodiments, R ⁵ is halogen, cyano, or C ₁ -C ₆ alkyl.

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

In some embodiments, R ⁵ is 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 alkyl. In some embodiments, R ⁵ is CH ₃ .

In some embodiments, ^R6 is H.

In some embodiments, R ⁶ is halogen, cyano, or C ₁ -C ₆ alkyl.

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

In some embodiments, R ⁶ is 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 alkyl. In some embodiments, R ⁶ is CH ₃ .

Variables Y, Z, R ^Z , R ^Za and R ^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, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₁ -C ₆ alkoxy is 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 optionally substituted with -(C ₁ -C ₆ alkyl)(C ₆ -C ₁₀ aryl), or C ₃ -C ₁₂ cycloalkyl.

In some embodiments, Y is absent.

In some embodiments, Y is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₁ -C ₆ alkoxy, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₁ -C ₆ alkoxy is 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 optionally substituted with –(C ₁ -C ₆ alkyl)(C ₆ -C ₁₀ aryl), or C _{3 -C 12} cycloalkyl.

In some embodiments, Y is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₁ -C ₆ alkoxy.

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.

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

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

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

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

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

In some embodiments, Y is methyl substituted with oxo, ie, Y is -C(=O)-.

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

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

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

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

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

In some embodiments, Z is H.

In some embodiments, Z is C3 _{- C12} cycloalkyl, _C3 - _C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, _C6 - _C10 aryl, or 5- to 10-membered heteroaryl, wherein C3 _{- C12} cycloalkyl, _C3 - _C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, _C6 - _C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more ^RZ .

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 C ₃ -C ₁₂ cycloalkyl optionally substituted with one or more R ^Z .

In some embodiments, Z is C ₃ -C ₁₂ cycloalkyl.

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

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

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

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

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

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

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

In some embodiments, Z is C ₆ -C ₁₀ aryl.

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

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 is optionally substituted with one or more R ^Z .

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 the C ₃ -C ₈ cycloalkyl or 3 to 8 membered heterocycloalkyl is substituted with one or more R ^Z .

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

In some embodiments, Z is C ₃ -C ₈ cycloalkyl.

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

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

In some embodiments, Z is cyclobutyl optionally substituted with one or more ^RZ .

In some embodiments, Z is cyclohexyl optionally substituted with one or more ^RZ .

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

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

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

In some embodiments, Z is azetidinyl or oxetanyl, wherein the azetidinyl or oxetanyl is optionally substituted with one or more ^RZ .

In some embodiments, Z is azetidinyl or oxetanyl.

In some embodiments, Z is azetidinyl or oxetanyl, wherein the azetidinyl or oxetanyl is substituted with one or more ^RZ .

In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl, wherein said pyrrolidinyl or tetrahydrofuranyl is optionally substituted with one or more ^RZ .

In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl.

In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl, wherein the pyrrolidinyl or tetrahydrofuranyl is substituted with one or more ^RZ .

In some embodiments, Z is piperidinyl or tetrahydropyranyl, wherein said piperidinyl or tetrahydropyranyl is optionally substituted with one or more ^RZ .

In some embodiments, Z is piperidinyl or tetrahydropyranyl.

In some embodiments, Z is piperidinyl or tetrahydropyranyl, wherein said piperidinyl or tetrahydropyranyl is substituted with one or more ^RZ .

In some embodiments, each R ^Z is independently oxo, halogen, cyano, -OH, =NR ^Za , NH ₂ , NHR ^Za , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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 ₁ -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), C ₁ -C ₆ alkyl, C ₂ -C 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} alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) _2- (C _{1 -C} alkyl), -C(═O)-(C ₁ -C alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 are optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently oxo, halogen, cyano, -OH, =NR ^Za , NH ₂ , NHR ^Za , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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 ₁ -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), C ₁ -C ₆ alkyl, C ₂ -C The invention may be a C ₂ -C ₆ alkenyl group, a C ₂ -C 6 alkynyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₁₂ cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group.

In some embodiments, each R ^Z is independently oxo, halo, cyano, -OH.

In some embodiments, each ^RZ is independently ^RZ is oxo.

In some embodiments, each ^RZ is independently ^RZ is halo. In some embodiments, each ^RZ is independently F or Cl.

In some embodiments, each ^RZ is independently F. In some embodiments, each ^RZ is independently Cl.

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

In some embodiments, each R ^Z is independently =NR ^Za . In some embodiments, each R ^Z is independently NHR ^Za .

In some embodiments, each R ^Z is independently NH ₂ , NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ , wherein NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ is optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently NH ₂ .

In some embodiments, each R ^Z is independently NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ , wherein NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ is optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, each R ^Z is independently NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ , wherein NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ is substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently -S(═O) ₂ -(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently -S(=O) ₂ -(C ₁ -C ₆ alkyl).

In some embodiments, each R ^Z is independently -S(=O) ₂ -CH ₃ .

In some embodiments, each R ^Z is independently -S(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^Za .

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

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

In some embodiments, each R ^Z is independently -S(═NR ^Za )-(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently -S(═NR ^Za )-(C ₁ -C ₆ alkyl) substituted with one or more R ^Za .

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

In some embodiments, each R ^Z is independently -S(C ₂ -C ₆ alkenyl) optionally substituted with one or more R ^Za .

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

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) is optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently -C(=O)-(C ₁ -C ₆ alkyl) or -C(=O)-(C ₂ -C ₆ alkenyl).

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

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

In some embodiments, each R ^Z is independently -C(=O)-CH=CH ₂ .

In some embodiments, each R ^Z is independently -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 .

In some embodiments, each R ^Z is independently -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) is optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently -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).

In some embodiments, each R ^Z is independently -S(═O) ₂ -(C ₂ -C ₆ alkenyl) optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently -S(=O) ₂ -(C ₂ -C ₆ alkenyl).

In some embodiments, each R ^Z is independently -C(═O)(3- to 12-membered heterocycloalkyl) optionally substituted with one or more R ^Za .

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

In some embodiments, each R ^Z is independently -C(═O)NH(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^Za .

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

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

In some embodiments, each R ^Z is independently -C(═O)-(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C(═O)-(C ₁ -C ₆ alkyl).

In some embodiments, each R ^Z is independently -C(═O)-(C ₂ -C ₆ alkenyl) optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently -C(=O)-(C ₂ -C ₆ alkenyl).

In some embodiments, each R ^Z is independently -C(═O)-(C ₁ -C ₆ alkoxy) optionally substituted with one or more R ^Za .

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

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

In some embodiments, each R ^Z is independently a 5- to 10-membered heteroaryl.

In some embodiments, each R ^Z is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ alkoxy, 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 .

In some embodiments, each R ^Z is independently C ₁ -C ₆ alkyl optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₁ -C ₆ alkyl.

In some embodiments, each R ^Z is independently C ₁ -C ₆ alkyl substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₂ -C ₆ alkenyl optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₂ -C ₆ alkenyl.

In some embodiments, each R ^Z is independently C ₂ -C ₆ alkenyl substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₂ -C ₆ alkynyl optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₂ -C ₆ alkynyl.

In some embodiments, each R ^Z is independently C ₂ -C ₆ alkynyl substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₁ -C ₆ alkoxy optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₁ -C ₆ alkoxy.

In some embodiments, each R ^Z is independently C ₁ -C ₆ alkoxy substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₃ -C ₁₂ cycloalkyl or 3 to 12 membered heterocycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl or 3 to 12 membered heterocycloalkyl is optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₃ -C ₈ cycloalkyl or 3 to 8 membered heterocycloalkyl, wherein C ₃ -C ₈ cycloalkyl or 3 to 8 membered heterocycloalkyl is optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₃ -C ₁₂ cycloalkyl optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₃ -C ₁₂ cycloalkyl.

In some embodiments, each R ^Z is independently C ₃ -C ₁₂ cycloalkyl substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₃ -C ₈ cycloalkyl optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently C ₃ -C ₈ cycloalkyl.

In some embodiments, each R ^Z is independently C ₃ -C ₈ cycloalkyl substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently 3-12 membered heterocycloalkyl optionally substituted with one or more R ^Za .

In some embodiments, each R ^Z is independently 3-12 membered heterocycloalkyl.

In some embodiments, each R ^Z is independently 3-12 membered heterocycloalkyl substituted with one or more R ^Za .

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

In some embodiments, each R ^Z is independently 3-8 membered heterocycloalkyl.

In some embodiments, each R ^Z is independently 3-8 membered heterocycloalkyl substituted with one or more R ^Za .

In some embodiments, each R ^Za is independently H, oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C 6 alkenyl), _{R Zb is optionally substituted with one} ^or _{more R Zb .}

In some embodiments, each R ^Za is independently H, oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(＝O) _2- (C ₁ -C ₆ alkyl), -C(＝O)-(C ₁ -C ₆ alkyl), -C(＝O)-(C ₂ -C ₆ alkenyl), 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 ^RZa is independently H.

In some embodiments, each R ^Za is independently oxo, halo, cyano, -OH.

In some embodiments, each R ^Za is independently oxo.

In some embodiments, each R ^Za is independently halo. In some embodiments, each R ^Za is independently F or Cl.

In some embodiments, each R ^Za is independently F. In some embodiments, each R ^Za is independently Cl.

In some embodiments, each R ^Za is independently cyano.

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

In some embodiments, each R ^Za is independently NH ₂ , NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ , wherein NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ is optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently NH ₂ .

In some embodiments, each R ^Za is independently NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ , wherein NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ is optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, each R ^Za is independently NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ , wherein NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ is substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently -S(═O) ₂ -(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently -S(=O) ₂ -(C ₁ -C ₆ alkyl).

In some embodiments, each R ^Za is independently -S(=O) ₂ -CH ₃ .

In some embodiments, each R ^Za is independently -S(═O) ₂ -(C ₁ -C ₆ alkyl) substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently -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 optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently -C(=O)-(C ₁ -C ₆ alkyl) or -C(=O)-(C ₂ -C ₆ alkenyl).

In some embodiments, each R ^Za is independently -C(=O)-(C ₁ -C ₆ alkyl).

In some embodiments, each R ^Za is independently -C(=O)-(C ₁ -C ₆ alkyl).

In some embodiments, each R ^Za is independently -C(=O)-CH=CH ₂ .

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

In some embodiments, each R ^Za is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ alkoxy, 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 .

In some embodiments, each R ^{Za is} independently C ₁ -C ₆ alkyl optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₁ -C ₆ alkyl.

In some embodiments, each R ^Za is independently C ₁ -C ₆ alkyl substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₂ -C ₆ alkenyl optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₂ -C ₆ alkenyl.

In some embodiments, each R ^Za is independently C ₂ -C ₆ alkenyl substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₂ -C ₆ alkynyl optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₂ -C ₆ alkynyl.

In some embodiments, each R ^Za is independently C ₂ -C ₆ alkynyl substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₁ -C ₆ alkoxy optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₁ -C ₆ alkoxy.

In some embodiments, each R ^Za is independently C ₁ -C ₆ alkoxy substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₃ -C ₁₂ cycloalkyl or 3 to 12 membered heterocycloalkyl, wherein the C ₃ -C ₁₂ cycloalkyl or 3 to 12 membered heterocycloalkyl is optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₃ -C ₁₂ cycloalkyl optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₃ -C ₁₂ cycloalkyl.

In some embodiments, each R ^Za is independently C ₃ -C ₁₂ cycloalkyl substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently 3-12 membered heterocycloalkyl optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently 3-12 membered heterocycloalkyl.

In some embodiments, each R ^Za is independently 3-12 membered heterocycloalkyl substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₃ -C ₈ cycloalkyl or 3 to 8 membered heterocycloalkyl, wherein C ₃ -C ₈ cycloalkyl or 3 to 8 membered heterocycloalkyl is optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₃ -C ₈ cycloalkyl optionally substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently C ₃ -C ₈ cycloalkyl.

In some embodiments, each R ^Za is independently C ₃ -C ₈ cycloalkyl substituted with one or more R ^Zb .

In some embodiments, each R ^Za is independently 3-8 membered heterocycloalkyl optionally substituted with one or more R ^{Z b} .

In some embodiments, each R ^Za is independently 3-8 membered heterocycloalkyl.

In some embodiments, each R ^Za is independently 3-8 membered heterocycloalkyl substituted with one or more R ^Zb .

In some embodiments, each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ alkoxy.

In some embodiments, each R ^Zb is independently oxo, halo, cyano, or -OH.

In some embodiments, each R ^Zb is independently oxo.

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

In some embodiments, each R ^Zb is independently F. In some embodiments, each R ^Zb is independently Cl.

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

In some embodiments, each R ^Zb is independently NH ₂ , NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, each R ^Zb is independently NH ₂ .

In some embodiments, each R ^Zb is independently NH(C ₁ -C ₆ alkyl).

In some embodiments, each R ^Zb is independently N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, each R ^Zb is independently -S(=O) ₂ -(C ₁ -C ₆ alkyl).

In some embodiments, each R ^Zb is independently -C(=O)-(C ₁ -C ₆ alkyl) or -C(=O)-(C ₂ -C ₆ alkenyl).

In some embodiments, each R ^Zb is independently -C(=O)-(C ₁ -C ₆ alkyl).

In some embodiments, each R ^Zb is independently -C(=O)-(C ₂ -C ₆ alkenyl).

In some embodiments, each R ^Zb is independently -C(=O)-CH=CH ₂ .

In some embodiments, each R ^Zb is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ alkoxy.

In some embodiments, each R ^Zb is independently C ₁ -C ₆ alkyl.

In some embodiments, each R ^Zb is independently C ₂ -C ₆ alkenyl.

In some embodiments, each R ^Zb is independently C ₂ -C ₆ alkynyl.

In some embodiments, each R ^Zb is independently C ₁ -C ₆ alkoxy.

Exemplary embodiments of 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 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 compound is a compound 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 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is a compound described in Table 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound described in Table 1

Table I

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

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 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

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 should be understood that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotopic derivatives can generally be prepared by replacing a non-isotopically labeled reagent with an isotopically labeled reagent and implementing the procedures disclosed in the schemes and/or examples described herein.

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

In some embodiments, the isotopic derivative is a deuterium-labeled compound of any of the compounds of the formulae 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 1, 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 1

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 will be appreciated that a deuterium-labeled compound includes deuterium atoms having an abundance of deuterium substantially greater than the natural abundance of deuterium, which is 0.015%.

In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor 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) for each deuterium atom. As used herein, the term "deuterium enrichment factor" means the ratio between the abundance of deuterium and the natural abundance of deuterium.

It should be understood that any of a variety of techniques recognized in the art can be used to prepare deuterium-labeled compounds. For example, deuterium-labeled compounds can generally be prepared by replacing non-deuterium-labeled reagents with deuterium-labeled reagents and implementing the procedures disclosed in the schemes and/or examples described herein.

Compounds of the present disclosure containing such deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure.Further, substitution with deuterium (ie, ² H) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

For the avoidance of doubt, it should be understood that where in this specification, when a group is defined by "described herein", that group encompasses the first occurring and broadest definition as well as each and all specific definitions for that group.

Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of the compounds of the present disclosure having sufficient basicity, for example, acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present disclosure having sufficient acidity 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 pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

It should 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 compounds that have the same molecular formula but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers", and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture".

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 a mixture of diastereomers (referred to as a "diastereomeric mixture"). When one chiral center is present, the stereoisomers may be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. The substituents contemplated for attachment to the chiral center are ordered according to the Sequence Rule of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; Erratum 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

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

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

It should be understood that the structures and other compounds discussed in this disclosure include all atropicisomers thereof. It should also be understood that not all atropicisomers 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 arranged differently in space. Atropisomers exist due to restricted rotation caused by hindered rotation of large groups around a central bond. Such atropisomers usually exist as a mixture, however, due to recent advances in chromatographic techniques, a mixture of two atropisomers can be separated in selected cases.

As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in the migration of the form of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist in the form of a mixture of tautomer groups in solution. In a solution where tautomerization may occur, the chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are mutually converted by tautomerization is called tautomerism. Among the various types of tautomerism that may be possible, two are usually observed. In keto-enol tautomerism, electrons and hydrogen atoms move simultaneously. 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 cyclic (ring-shaped) form, as presented by glucose.

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

Compounds that have the same molecular formula but differ in the nature or order of bonding of the atoms or the arrangement of the atoms in space are called "isomers". Isomers whose atoms are arranged differently in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by Cahn and Prelog's rules of R and S order, or by the way the molecule rotates the plane of polarized light, and are designated as right-handed or left-handed (i.e., designated as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

Compounds of the present disclosure may have one or more asymmetric centers; therefore, such compounds may be produced as separate (R) or (S) stereoisomers or mixtures thereof. Unless otherwise indicated, descriptions or naming of specific compounds in the specification and claims are intended to include single enantiomers thereof and mixtures thereof, racemic or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J.March, John Wiley & Sons, New York City, 2001), for example, by synthesizing from optically active starting materials or by splitting racemic forms. Some compounds of the present disclosure may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that the present disclosure encompasses all optical diastereomers and geometric isomers and mixtures thereof with inflammasome inhibitory activity.

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

It should be understood that compounds of any formula 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, mesylate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthylidenesulfonate, and acetate (e.g., trifluoroacetate).

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

It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

As used herein, the term "solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance, wherein the water retains its molecular state as _H2O .

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

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

As used herein, the term "bioisostere" refers to a compound produced by exchanging one atom or group of atoms with another roughly similar atom or group of atoms. The purpose of bioisosteric substitution is to produce new compounds with similar biological properties as the parent compound. Bioisosteric substitution can be physicochemical or topological. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

It should also be understood that certain compounds of the present disclosure may exist in solvated forms as well as in non-solvated forms (such as, for example, hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates or trihydrates. It should be understood that the present disclosure includes all such solvated forms having inflammasome inhibitory activity.

It should also be understood that some compounds of the present disclosure may show polymorphism, and the present disclosure includes all such forms or mixtures thereof, which have inflammasome inhibitory activity. It is well known that conventional techniques can be used to analyze crystalline materials, such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectrum, near infrared (NIR) spectrum, solution and/or solid-state nuclear magnetic resonance spectrum. The water content of such crystalline materials can be determined by Karl Fischer analysis.

Compound of the present disclosure can exist with many different tautomeric forms, and mention that compound of the present disclosure includes all such forms.In order to avoid doubt, compound can exist with one in several tautomeric forms, and only one is specifically described or shown, and all other compounds are still included in formula (I).The example of tautomeric form includes keto form, enol form and enolate form, such as following tautomer pair: keto/enol (as shown below), imines/enamine, amide/imino alcohol, amidine/amidine, nitroso group/oxime, thioketone/enethiol and nitro/acid-nitro.

Compounds of the present disclosure containing amine functional groups can also form N-oxides. It is mentioned herein that compounds containing amine functional groups disclosed herein also include N-oxides. In the case where the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March's "Advanced Organic Chemistry", 4th edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of L.W.Deady ("Syn. Comm.", 1977, 7, 509-514), wherein an amine compound is reacted with meta-chloroperbenzoic acid (mCPBA) in, for example, an inert solvent such as dichloromethane.

The compounds of the present disclosure can 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 change the physical properties and/or pharmacokinetic properties of the compounds of the present disclosure. When the compounds of the present disclosure contain suitable groups or substituents, prodrugs can be formed, and the groups that change the properties can be connected to the suitable groups or substituents. Examples of prodrugs include derivatives containing alkyl or acyl substituents that can be cleaved in vivo on the sulfonylurea group of the compounds of any one of the formulas disclosed herein.

Therefore, the present disclosure includes those compounds of the present disclosure as defined above when obtainable by organic synthesis, and when obtainable in the human or animal body by cleavage of its prodrug. Therefore, the present disclosure includes those compounds of the present disclosure produced by organic synthesis means, and such compounds produced in the human or animal body by metabolism of 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 that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs have been described in, for example, the following documents: a) Methods in Enzymology, vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press 1985); b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, Design and Application of Prodrugs, edited by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, vol. Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Vol. 14; and h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

Suitable pharmaceutically acceptable prodrugs of compounds of the present disclosure having hydroxyl groups are, for example, esters or ethers thereof that can be cleaved in vivo. Ester or ether that can be cleaved in vivo of compounds of the present disclosure containing hydroxyl groups are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester forming groups of hydroxyl groups include inorganic esters, such as phosphates (including aminophosphoric acid cyclic esters). Other suitable pharmaceutically acceptable ester forming groups for hydroxyl groups include C ₁ -C ₁₀ alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, C ₁ -C ₁₀ alkoxycarbonyl (such as ethoxycarbonyl), N,N-(C ₁ -C ₆ alkyl) _2carbamoyl , 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C ₁ -C ₄ alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy 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 amides formed with amines, such as ammonia, C _1-4 alkylamines such as methylamine, (C ₁ -C ₄ alkyl) ₂ amines such as 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 alkylamines such as benzylamine, and amino acids such as glycine or their esters.

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, amides formed with C ₁ -C ₁₀ alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,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 after 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 the metabolism of 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 that is obtainable by a method for preparing a compound described herein, or obtained by said method, or directly obtained by said method.

In some aspects, the disclosure provides an intermediate useful in a method of preparing a compound described herein.

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

In the descriptions of synthetic methods described herein and any referenced synthetic methods for preparing starting materials, it is understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, experimental duration and workup procedures, can be selected by one skilled in the art.

Those skilled in the art of organic synthesis will understand that the functionality present on the various parts of the molecule must be compatible with the reagents and reaction conditions used.

It should be understood that during the synthesis of the disclosed compound in the method defined herein or during the synthesis of some starting materials, it may be necessary to protect certain substituents to prevent undesirable reactants. A skilled chemist will know when such protection is needed, and how such protecting groups can be placed in the appropriate position and removed subsequently. For examples of protecting groups, see one of many general teaching materials on the subject, such as "Protective Groups in Organic Synthesis", Theodora GreeN (Publisher: John Wiley & Sons). Protecting groups can be removed as needed by any convenient method described in the literature or known to a skilled chemist for removing the protecting groups in question, and such methods are selected to achieve the removal of protecting groups in the case of minimal interference caused to groups elsewhere in the molecule. Therefore, if reactants include groups such as amino, carboxyl or hydroxyl, it may be necessary to protect the groups in some reactions mentioned herein.

As an example, the suitable protecting group of amino or alkylamino is for example acyl group, for example alkanoyl group such as acetyl, alkoxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, arylmethoxycarbonyl group, for example benzyloxycarbonyl or aroyl group, for example benzoyl.The deprotection condition of the above-mentioned protecting group must change with the selection of protecting group.Therefore, for example, acyl group such as alkanoyl or alkoxycarbonyl group or aroyl group can be removed by for example hydrolysis with suitable alkali such as alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.Alternately, acyl group such as tert-butoxycarbonyl group can be removed for example by processing with suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl group such as benzyloxycarbonyl can be for example by hydrogenation on catalyst such as carbon-supported palladium, or by removing by processing with Lewis acid such as tris (trifluoroacetic acid boron). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

Suitable blocking groups for hydroxyl 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 of the above-mentioned blocking groups will inevitably change along with the selection of blocking groups. Therefore, for example, acyl groups such as alkanoyl or aroyl groups can be for example removed by using suitable alkali such as alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or ammonia hydrolysis. Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by being removed by hydrogenation on catalyst (such as palladium on carbon).

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

Once a compound of the present disclosure has been 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 the compound of the present disclosure into 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 disclosure can 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 relevant reaction conditions. 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, cyclopentyl methyl 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 mixtures with water.

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

The reaction times is usually in the range of a fraction of a minute to several days, depending on the reactivity of the corresponding compound and corresponding reaction conditions. Suitable reaction times can be easily determined by methods known in the art (e.g. reaction monitoring). Based on the temperature of reaction provided above, suitable reaction times is usually in the range of 10min and 48 hours.

In addition, by utilizing the procedures described herein, in combination with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily appreciate that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure can be easily obtained by various synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily identify what type of reagents and reaction conditions should be used and how to apply and adapt in any specific example, when necessary or applicable, to obtain the compounds of the present disclosure. In addition, some compounds of the present disclosure can be easily synthesized by reacting other compounds of the present disclosure under suitable conditions, such as by converting a specific functional group present in the compounds of the present disclosure or its suitable precursor molecule into another functional group by applying standard synthetic methods (such as reduction, oxidation, addition or substitution reactions); these methods are well known to those skilled in the art. Similarly, one skilled in the art will apply synthetic protecting (or protective) groups as necessary 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, 4th Edition (2006) (John Wiley & Sons).

General routes for preparing compounds of the present application are described in Schemes 1 and 2.

Solution 1

Bioassay

Once produced, the compounds designed, selected and/or optimized by the methods described above can be characterized using various assays known to those skilled in the art for determining whether a compound has biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether these molecules have the predicted activity, binding activity and/or binding specificity.

In addition, high throughput screening can be used to accelerate the analysis using such assays. Therefore, the activity of the molecules described herein can be quickly screened using techniques known in the art. For example, general methods for performing high throughput screening are described in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High throughput assays can 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, biological assays assess the ability of a compound to inhibit cell proliferation.

In some embodiments, cells (e.g., SNU-16 (FGFR2-amplified) cells) can be suspended and distributed in a plate. In some embodiments, cells (e.g., UM-UC-14 (FGFR3-S249C) cells) can be suspended and distributed in a plate. In some embodiments, cells (e.g., DMS-114 (FGFR1 overexpressing) cells) can be suspended and distributed in a plate. In some embodiments, cells (e.g., RT-112 (FGFR3-Tacc3 fusion) cells) can be suspended and distributed in a plate. In some embodiments, to determine the effect of the compounds 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 compounds of the present disclosure, and inhibition of cell growth can be determined by luminescence quantification (e.g., quantification of intracellular ATP content using CellTiterGlo) according to the manufacturer's protocol. In some embodiments, to determine _IC50 values, vehicle-treated cells are normalized to viable cells and growth is analyzed using software (e.g., CDD Vault software (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 as 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 encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The compounds of the present disclosure may be formulated into forms for oral administration, 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, buffers and pH regulators and mixtures thereof.

Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-cyclodextrin and trimethyl-γ-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 ethylenediaminetetraacetic acid and its metal salts, 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, ethylparaben, polyaminopropyl biguanide, and butylparaben, as well as sorbic acid and mixtures thereof.

The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, 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 glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (carbopols - 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 (usually a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly 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 adjusting agent. The pH adjusting agent is typically an inorganic acid or a metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or alkaline pH adjusting agents are added to adjust the formulation to a target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base, and depending on the formulation, adding one of the acid or base may be sufficient to bring the mixture to a 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 (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate) and ε-aminocaproic acid and mixtures thereof.

The formulation may further comprise a wetting agent. Suitable wetting agent types include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), oxyethylated octylphenol polymers (tyloxapol), polyoxyethylene 40 stearate, 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 can be encapsulated in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of a tablet, lozenge or capsule. Liquid carriers can also be used to prepare oral compositions for use as mouthwashes, wherein the compound in the liquid carrier is orally administered, and the mouth is rinsed and spit out or swallowed. Pharmaceutically compatible binders and/or auxiliary materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, 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 flavorings such as mint, methyl salicylate or orange flavoring.

According to another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, 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 tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders), or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, 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 treatment is an amount sufficient to treat or prevent, slow the progression of, and/or alleviate the symptoms associated with an inflammasome-associated condition mentioned herein.

According to well-known medical principles, the size of the dose of the compounds of the present disclosure for therapeutic or preventive purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

How to use

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

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

In some aspects, the present disclosure provides for 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 use of 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 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 for use of 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 a method 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 a method 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 a method 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 preparation of a medicament for treating or preventing cancer in a subject.

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

In some aspects, the present disclosure provides for 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 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 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 for 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 methods 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 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 or preventing 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 methods of treating cancer in a subject, the methods 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 preparation of a medicament for treating or preventing cancer in a subject.

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

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

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

FGFR2 is a human gene located on chromosome 10, which encodes a protein called FGFR2. FGFR3 is a human gene located on chromosome 4, which encodes a protein called FGFR3. Both FGFR2 and FGFR3 are produced with a variety of different isoforms by alternative splicing." b isoforms" are mainly expressed in epithelial tissues, while " c isoforms" are mainly expressed in interstitial tissues.

FGFR2 and FGFR3 are members of the fibroblast growth factor receptor family.The member of the fibroblast growth factor receptor family is the protein that is located at the cell surface and is attached to the various members of the fibroblast growth factor (FGF) protein family.FGFR2 and FGFR3 have an extracellular ligand domain, which is composed of three immunoglobulin-like domains, a single transmembrane helical domain and an intracellular tyrosine kinase domain.When the FGF ligand is combined with the extracellular ligand domain, receptor dimerization, and the intracellular tyrosine kinase domain in the dimer crosses phosphorylation each other, thereby activating the kinase domain, allowing them to be attached to the adapter protein subsequently and by other intracellular signal transduction molecules phosphorylation.Known members of the fibroblast growth factor receptor family regulate various cellular processes, including but not limited to proliferation and differentiation, particularly under the background of development and tissue repair.

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

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

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

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

Fusions of the FGFR2 gene that produce FGFR2 protein have been associated with a variety of different cancers including, but not limited to, bladder cancer and intrahepatic bile duct cancer.

Fusions of the FGFR3 gene that produce FGFR3 protein have been associated with 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 anticancer therapy. In some embodiments, the subject has previously undergone at least one round of anticancer therapy and has acquired resistance to treatment with the anticancer therapy. In some embodiments, the anticancer therapy may include administration of at least one of fobactinib, pemitinib, erdafitinib, infigratinib, 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 understood that a cancer characterized by at least one oncogenic mutation in the FGFR2 gene and/or the FGFR3 gene is a cancer that is generally associated with at least one oncogenic mutation in the FGFR2 gene and/or the FGFR3 gene, including but not limited to a cancer whose primary oncogenic activity is believed to be driven by at least one oncogenic mutation in the FGFR2 gene and/or the FGFR3 gene.

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

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

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

In some embodiments, the cancer is characterized by at least one oncogenic variant of FGFR3.

It is understood that a cancer characterized by at least one oncogenic variant of FGFR2 and/or FGFR3 is a cancer that is generally 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 FGFR3.

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

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

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

It is to be understood that an oncogenic variant of FGFR2 is a FGFR2 protein that comprises at least one oncogenic mutation and is produced as a result of the expression of a FGFR2 gene comprising at least one oncogenic mutation.

It is understood that an oncogenic variant of FGFR3 is a FGFR3 protein that comprises at least one oncogenic mutation and is produced as a result of the expression of a FGFR3 gene comprising 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 at least one tumor and/or cancer cell that expresses an oncogenic variant of FGFR2.

In some embodiments, the subject has at least one tumor and/or cancer cell that expresses an oncogenic variant of FGFR3.

In some embodiments, the subject has at least one tumor and/or cancer cell that overexpresses FGFR2.

In some embodiments, the subject has at least one tumor and/or cancer cell that overexpresses FGFR3.

As will be understood by those skilled in the art, in the case of a gene (e.g., FGFR2 and/or FGFR3), oncogenic mutations may include, but are not limited to, mutations that cause one amino acid to replace another amino acid at a specific position in FGFR2 and/or FGFR3, mutations that cause one or more amino acids to replace one or more amino acids between two specific positions in FGFR2 and/or FGFR3, mutations that cause one or more amino acids to be inserted between two positions in FGFR2 and/or FGFR3, mutations that cause one or more amino acids to be deleted between two positions in FGFR2 and/or FGFR3, and mutations that cause FGFR2 and/or FGFR3 or a portion thereof to fuse with another protein or a portion thereof, or any combination thereof. As will be understood by those skilled in the art, 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 of one or more nucleotides, inversions and deletions. As will be understood by those skilled in the art, in the case of a gene (e.g., FGRF2 and/or FGFR3), a gene may have one or more of the aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations.

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

In some embodiments, the oncogenic mutation of FGFR2 may be any of the FGFR2 mutations presented in Table 1a. In some embodiments, the oncogenic mutation of FGFR2 may be a gatekeeper mutation that leads to resistance to existing inhibitors, wherein the gatekeeper mutation is V565I or V565F.

Table 1a. FGFR2 mutations

S252W V565F V565I V565I N550K

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

Table 1b. FGFR3 mutations

S249C Tacc3 fusion V555L V555F V555M

In some embodiments, the oncogenic variant of FGFR2 can be any FGFR2 variant 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 FGFR3 variant 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 may comprise a gatekeeper mutation that confers resistance to existing inhibitors, wherein the gatekeeper mutation is V565I or V565F.

In some embodiments, the oncogenic variant of FGFR3 may comprise a gatekeeper mutation that confers resistance to existing inhibitors, 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: a) increased ligand binding of FGFR2 and/or FGFR3; b) ligand-independent dimerization and activation of FGFR2 and/or FGFR3; and c) increased kinase activity of FGFR2 and/or FGFR3.

In some embodiments, the cancer is 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, renal 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, vulvar 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, bile duct carcinoma, colon adenocarcinoma, lymphoid neoplasms diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, brain low-grade glioma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic cancer, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, uterine carcinosarcoma, 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 cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, bile duct cancer, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumors, breast cancer, cancer of unknown primary (CUP), cancer that has spread to the bone, cancer that has spread to the brain, cancer that has spread to the liver, cancer that has spread to the lungs, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chromomyeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, stomach cancer, Gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, plastic gastritis, liver cancer, lung cancer, lymphoma, malignant schwannoma, mediastinal germ cell tumor, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral and oropharyngeal cancer, myeloma, nose and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancer, signet ring cell carcinoma cell cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, T-cell childhood non-Hodgkin lymphoma (NHL), testicular cancer, thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal gland tumors, uterine cancer, vaginal cancer, vulvar cancer, Wilms' tumor, womb cancer, and gynecological cancers. Examples of cancer also include, but are not limited to, hematological malignancies, lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, chromolymphocytic leukemia, chronic myeloid leukemia, acute myeloid 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, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

In some embodiments, the cancer is gastric cancer, triple negative breast cancer, melanoma, hepatobiliary carcinoma, cancer of unknown primary, 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 carcinoma, or glioblastoma.

definition

Unless otherwise stated, the following terms used in the specification and claims have the following meanings set forth below.

Without wishing to be limited by such statements, it should be understood that although various options of variables are described herein, the present disclosure is intended to cover operable embodiments with combinations of options. The present disclosure may be interpreted to exclude inoperable embodiments resulting from certain combinations of options.

It should be understood that the compounds of the present disclosure can 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 should be understood that such description also refers to various neutral forms, cationic forms, and anionic forms of the compound. For another example, when a compound of the present disclosure is described in anionic form, it should be understood that such description also refers to various salts (e.g., sodium salts) of the anionic form of the compound.

"Therapeutically effective amount" means the 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, and 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 straight chain (linear) saturated aliphatic hydrocarbon groups 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 alkyl groups. 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, a straight chain or branched chain alkyl group has six or fewer carbon atoms (eg, C ₁ -C ₆ for straight chain, C ₃ -C ₆ for branched chain), and in another embodiment, a straight chain or branched chain alkyl group has four or fewer carbon atoms.

As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having a specified substituent 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, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino) groups. The invention also includes but is not limited to alkylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonic acid group (sulphonato), sulfamoyl (sulphamoyl), sulfonamido (sulphonamido), nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or aromatic or heteroaromatic moiety.

As used herein, the term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the above-mentioned alkyl but containing at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, straight or branched alkenyl groups have six or less carbon atoms in their backbone (e.g., C ₂ -C ₆ for straight chain, C ₃ -C ₆ for branched chain). The term "C ₂ -C ₆ " includes alkenyl groups containing two to six carbon atoms. The term "C ₃ -C ₆ " includes alkenyl groups containing three to six carbon atoms.

As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl 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, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, 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 above-mentioned alkyl groups 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, a straight chain or branched chain alkynyl group has six or less carbon atoms in its backbone (e.g., _C2 - _C6 for a straight chain and _C3 - _C6 for a branched chain). The term " _C2 - _C6 " includes alkynyl groups containing two to six carbon atoms. The term " _C3 - _C6 " includes alkynyl groups containing three to six carbon atoms. As used herein, " _C2 - _C6 alkenylene linker" or " _C2 - _C6 alkynylene linker" is intended to include _C2 , _C3 , _C4 , C5 or _C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, _C2 - _C6 alkenylene linkers are intended to include _C2 , _{C3 , C4} , _C5 and _C6 alkenylene linker groups.

As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl groups or alkynyl groups 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, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfonic acid, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (such as 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 includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged or spiro) system having 3 to 30 carbon atoms (e.g., _C3 - _C12 , _C3 - _C10 or _C3 - _C8 ). Examples of cycloalkyl 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, only one ring in the cycloalkyl 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 (such as 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 specified. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxirane, azetidinyl, oxetanyl, thienyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepinyl, 1,4-oxa-5-azepinyl, 2-oxa-5-azepinyl, Bicyclo[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'-isobenzofuran]-yl, 7'H-spiro[ Cyclohexane-1,5'-furano[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]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-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octanyl-6-yl, etc. In the case of polycyclic heterocycloalkyl, only one ring of the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

As used herein, the term "aryl" includes groups having aromaticity, including "conjugated" or polycyclic systems having one or more aromatic rings, and does not contain any heteroatoms in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl include but are not limited to phenyl, biphenyl, naphthyl, etc. Conveniently, aryl 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, which consist 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 be optionally oxidized (i.e., N→O and S(O) _p , wherein p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle is not greater than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

In addition, the terms "aryl" and "heteroaryl" include polycyclic aromatic and heteroaryl groups, for example, tricyclic, bicyclic, for example, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

The 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, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, amino The aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic to form a polycyclic system (e.g., tetralin, 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 the designated atom are replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom is not exceeded, and the substitution forms a stable compound. When the substituent is an oxo or keto group (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 (e.g., C=C, C=N or N=N) formed between two adjacent ring atoms. "Stable compound" and "stable structure" mean a compound that is robust enough to be isolated from a reaction mixture to a useful degree of purity and formulated into an effective therapeutic agent.

When a bond on a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via 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 any constituent or compound formula, 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 0-2 R moieties, then the group may be optionally substituted with up to two R moieties, and at each occurrence, R is selected independently of 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 groups having -OH or ^-O- .

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 a 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, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino) groups. The invention also includes but is not limited to alkylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonic acid group (sulphonato), sulfamoyl (sulphamoyl), sulfonamido (sulphonamido), nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or aromatic or heteroaromatic moiety.

As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals 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, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, 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 A, B or C", "one or more of A, B and C", "one or more A, B and C", "selected from the group consisting of A, B and C", "selected from A, B and C", etc. are used interchangeably and all refer to selected from the group consisting of A, B and/or C, that is, one or more A, one or more B, one or more C or any combination thereof, unless otherwise specified.

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

It should be understood that throughout the description, when a composition is described as having, including or comprising a particular component, it is contemplated that the composition is also substantially composed of or consists of said component. Similarly, when a method or process is described as having, including or comprising a particular process step, the process is also substantially composed of or consists of said processing step. Further, it should be understood that as long as the disclosure remains operable, the order of steps or the order in which certain actions are performed is insignificant. In addition, two or more steps or actions may be performed simultaneously.

It should be understood that the synthetic methods disclosed herein can tolerate a wide variety of functional groups and thus can use a variety of substituted starting materials. The methods provide substantially the desired final compound at or near the end of the entire process, but in some cases may require further conversion of the compound into a pharmaceutically acceptable salt thereof.

It should be understood that the compounds of the present disclosure can 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 the skilled artisan in view of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the art. Although not limited to any one or several sources, classic texts such as Smith, M.B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Press, Inc., (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; Synthesis, John Wiley & Sons, Inc. (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Inc. (1995) are useful and recognized reference textbooks on organic synthesis known to those skilled in the art.

Those of ordinary skill in the art will note that during the reaction sequence and synthesis scheme described herein, the order of some steps can be changed, such as the introduction and removal of blocking groups. Those of ordinary skill in the art will recognize that some groups may need to be protected from the influence of reaction conditions via the use of blocking groups. Blocking groups can also be used to distinguish similar functional groups in molecules. The list of blocking groups and how to introduce and remove these groups can be found in T.W., Wuts, P.G.M. " Protective Groups in Organic Synthesis ", the 3rd edition, John Wiley & Sons: New York, 1999.

It should be understood that, unless otherwise indicated, any description of a method 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 a medicament for treating or preventing such conditions. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

As used herein, the term "subject" includes 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 can 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 can also be a bird or poultry. In some embodiments, the subject is a human.

As used herein, the term "subject in need" refers to a subject with a disease or an increased risk of developing the disease. A subject in need may be a subject previously diagnosed or identified as having a disease or condition disclosed herein. A subject in need may also be a subject suffering from a disease or condition disclosed herein. Alternatively, a subject in need may be a subject with an increased risk of developing a class disease or condition relative to the general population (i.e., a subject who is prone to developing such a condition relative to the general population). A subject in need may suffer from a refractory or drug-resistant disease or condition disclosed herein (i.e., a disease or condition disclosed herein that is unresponsive or not yet responsive to treatment). The subject may be resistant at the beginning of treatment or may become resistant during treatment. In some embodiments, a subject in need has received all known effective therapies for a disease or condition disclosed herein but the treatment has failed. In some embodiments, a subject in need has received at least one previous therapy.

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

It will be appreciated that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, may or may also be used to prevent related diseases, conditions or disorders, or to identify suitable candidates for such purposes.

As used herein, the terms "preventing or preventing" or "protecting against" describe the reduction or elimination of the onset of symptoms or complications of such disease, condition or disorder.

Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methods useful in practicing the present disclosure. The examples do not limit the disclosure claimed. Based on the present disclosure, the technician can identify and adopt other components and methods that can be used to practice the present disclosure.

In the synthetic schemes described herein, compounds may be drawn in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or more isomers, tautomers, positional isomers, or stereoisomers, nor excluding mixtures of isomers, tautomers, positional isomers, or stereoisomers; however, it should be 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 understood that those skilled in the art can refer to general reference texts to describe in detail the known techniques or equivalent techniques discussed herein. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York City (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, Inc., New York City; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, Inc., New York City; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 18th edition (1990). Of course, these texts may also be referenced when making or using aspects of the present disclosure.

It will 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 preparation containing a compound of the present disclosure, which is in a form suitable for application to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any one of a variety of forms, including, for example, a single pump or vial on a capsule, an intravenous bag, a tablet, an aerosol inhaler. The amount of active ingredient (e.g., a preparation of a disclosed compound or its salt, hydrate, solvate or isomer) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. It will be appreciated by those skilled in the art that it is sometimes necessary to make routine changes to the dosage according to the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, oral, sublingual, intrapleural, intrathecal, intranasal, etc. The 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 mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that are 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 problems or complications commensurate with a reasonable benefit/risk ratio.

As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically or otherwise desirable, and includes excipients that are acceptable for veterinary use and human pharmaceutical use. "Pharmaceutically acceptable excipient" as used in the specification and claims includes 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 routes of administration. Examples of routes of administration include parenteral, for example, intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous applications may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates, and agents for adjusting tension, such as sodium chloride or dextrose. pH can be adjusted with an acid or base (such as hydrochloric acid or sodium hydroxide). Parenteral preparations may be packaged in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to subjects in many well-known methods currently used for chemotherapy. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity, or taken orally, or applied through the skin with a patch. The selected dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. Preferably, the patient's disease condition (e.g., a disease or condition disclosed herein) and health status should be closely monitored during and after treatment within a reasonable time period.

As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that is used to treat, ameliorate or prevent an established disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the combination of treatments or therapies selected 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 should be understood that for any compound, the therapeutically effective amount can be initially estimated in a cell culture assay such as a tumor cell, or in an animal model (usually a rat, mouse, rabbit, dog or pig). Animal models can also be used to determine suitable concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/preventive efficacy and toxicity can be determined by standard pharmaceutical procedures such as _ED50 (dose effective for 50% of the population) and _LD50 (dose lethal to 50% of the population) in cell culture or experimental animals. The dose ratio between toxic effects and therapeutic effects is the therapeutic index and can be expressed as a ratio _LD50 / _ED50 . Pharmaceutical compositions that exhibit a large therapeutic index are preferred. The dosage can vary within this range, depending on the dosage form employed, the sensitivity of the patient and the route of administration.

Dosage and administration are adjusted to provide sufficient levels 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, the time and frequency of administration, drug combination, reaction sensitivity and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered once every 3 to 4 days, weekly or biweekly, depending on the half-life and clearance rate of the particular formulation.

The pharmaceutical composition comprising the active compound of the present disclosure can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing processes. Pharmaceutical compositions can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, which include excipients and/or adjuvants that contribute to processing the active compound into pharmaceutically usable preparations. Of course, suitable preparations depend on the selected route of administration.

Pharmaceutical compositions suitable for injection include sterile aqueous solutions (water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injection solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL ^TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid that is easily injectable to some extent. It must be stable under the conditions of production and storage, and must prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be achieved by, for example, using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant to maintain. By various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc., it is possible to achieve the effect of preventing microorganisms. 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 an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the required amount of the active compound into an appropriate solvent containing one or a combination of the above-listed ingredients, followed by filtration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile carrier containing a basic dispersion medium and other ingredients required from the above-listed ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional desired ingredients from its previously sterile filtered solution.

Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of a tablet, lozenge or capsule. Liquid carriers can also be used to prepare oral compositions for use as mouthwashes, wherein the compound in the liquid carrier is orally administered, and the mouth is rinsed and spit out or swallowed. Pharmaceutically compatible binders and/or auxiliary materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, 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 flavorings such as mint, methyl salicylate or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gel or cream, as generally known in the art.

The active compound can be prepared with a pharmaceutically acceptable carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. The methods for preparing such preparations will be obvious to those skilled in the art, and these materials can also be commercially available from Alza Corporation and Nova Pharmaceuticals. Liposomal suspensions (including liposomes targeting 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. Patent No. 4,522,811.

It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

In therapeutic applications, the dosage of the pharmaceutical composition used according to the disclosure varies according to the experience and judgment of the clinician or practitioner of the medicament, the age, body weight and clinical condition of the patient, and the administration of the therapy, as well as other factors affecting the selected dosage. In general, the dosage should be enough to cause the symptoms of the disease or illness disclosed herein to slow down and preferably disappear, and also preferably cause the complete disappearance of the disease or illness. The dosage can be in the range of about 0.01mg/kg to about 5000mg/kg per day. In preferred aspects, the dosage can be in the range of about 1mg/kg to about 1000mg/kg per day. In one aspect, the dosage will be in the range of about 0.1mg/day to about 50g/day, about 0.1mg/day to about 25g/day, about 0.1mg/day to about 10g/day, about 0.1mg to about 3g/day or about 0.1mg to about 1g/day, and it is in single dose, divided dose or continuous dose (the dosage can be adjusted according to the patient's body weight in kg, in ^m2 of body surface area and in years of age). An effective amount of a pharmaceutical agent is an amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improvements in survival and growth indicate regression. As used herein, the term "dosage effective manner" refers to the amount of active compound that produces a desired biological effect in a subject or cell.

It will be understood that the pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

It should be understood that for compounds of the present disclosure that are capable of further forming salts, all such forms are also contemplated to be within the scope of the claimed disclosure.

As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, wherein the parent compound is modified by preparing an acid or alkaline salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acid salts or organic acid salts of basic residues such as amines, alkali salts 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 by 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, glycolamidophenylarsonic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydrochloric acid Iodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, para-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and common amino acids, for example, glycine, alanine, phenylalanine, arginine, etc.

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

Other examples of pharmaceutically acceptable salts include hexanoic 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, tert-butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or coordinated 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 can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

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

The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, pulmonary, inhaled, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain administration routes.

The dosage regimen using the compound is selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or liver function; and the specific compound or salt thereof employed. A generally skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progression of the patient.

Techniques for formulating and administering the disclosed compounds of the present disclosure can be found in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing Co., Easton, PA (1995). In an embodiment, 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 compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methods useful in practicing the present disclosure. The examples do not limit the disclosure claimed. Based on the present disclosure, the technician can identify and adopt other components and methods that can be used to practice the present disclosure.

In the synthetic schemes described herein, compounds may be drawn in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or more isomers, tautomers, positional isomers, or stereoisomers, nor excluding mixtures of isomers, tautomers, positional isomers, or stereoisomers; however, it should be 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.

As will be appreciated by the skilled artisan, the FGFR2 gene is often 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. Therefore, these terms are used interchangeably herein to refer to the FGFR2 gene.

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

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

As will be appreciated by the skilled artisan, the FGFR3 gene is often referred to as one of FGFR3, fibroblast growth factor receptor 3, ACH, CD333, cluster of differentiation 333, CEK2, HSFGFR3EX, and JTK4. Therefore, these terms are used interchangeably herein to refer to the BRAF gene.

As will be appreciated by the skilled artisan, the FGFR3 protein encoded by the FGFR3 gene is often referred to as one of FGFR3, fibroblast growth factor receptor 3, ACH, CD333, cluster of differentiation 333, CEK2, HSFGFR3EX, and JTK4. Therefore, these terms are used interchangeably herein to refer to the FGFR3 protein.

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

All publications and patent documents cited herein are incorporated herein by reference, as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended as an admission that any content is relevant prior art, nor does it constitute any admission about its content or date. Now that the present disclosure has been described by written specification, those skilled in the art will recognize that the present disclosure can be practiced in various embodiments, and the foregoing description and the following examples are for the purpose of illustrating rather than limiting the following claims.

Exemplary embodiments

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

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C(R ^W1 ) when attached to one double bond and one single bond, N(R ^W1 ) when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) or O when attached to two single bonds, or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^W4 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 alkyl);

^W5 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 alkyl);

^W6 is C ( ^RW6 ) when attached to one double bond and one single bond, N ( ^RW6 ) when attached to two single bonds, or N when attached to one double bond and one 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 alkyl);

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

^R3 is H, halogen, cyano, _NH2 , -NH( _C1 - _C6 alkyl), -NHC(=O)( _C1 - _C6 haloalkyl), -NHC(=O)O( _C1 - _C6 alkyl), N(C1- _C6 alkyl) ₂ , -S(=O) _2- (C1-C6 alkyl), -C(=O)H, -C(=O)( _C1 - _C6 alkyl), -C(=O)O( _C1 - _C6 alkyl), _C1 -C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1- _{C6 alkoxy, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein -NH(C1-C6 alkyl ) is C3 - C12 cycloalkyl} , _C3 - _C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, _C6 - _C10 aryl, or 5- to 10-membered heteroaryl. _R 3a substituted with one or more R 3a ; -NHC(═O)(C ₁ -C ₆ haloalkyl), -NHC(═O)O(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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), 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 is optionally substituted with one or more R ^3a ;

each R ^3a is 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) ₂ , -S(═O) _2- (C ₁ -C ₆ alkyl), -C(═O)( _{C 1} -C ₆ alkyl), -C(═O)O(C ₁ -C ₆ alkyl), 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) is optionally substituted with one or more halogens;

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

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

Y is absent and is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy is optionally substituted by 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 optionally substituted by -(C ₁ -C ₆ alkyl)(C ₆ -C ₁₀ aryl), or C ₃ -C ₁₂ cycloalkyl;

Z is absent and is 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 is optionally substituted with one or more R ^Z ;

each R ^Z is independently oxo, halogen, cyano, -OH, =NR ^Za , NH ₂ , NHR ^Za , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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), C ₁ -C ₆ alkyl, C ₂ -C 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} alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) _2- (C _{1 -C} alkyl), -C(═O)-(C ₁ -C alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently H, oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C 1 -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C 6 alkoxy, C 3 -C ₁₂ cycloalkyl, or 3 to 12 membered heterocycloalkyl ₁ - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, _C3 - _C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more ^RZb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

Embodiment 2. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C ( ^RW1 ) or N ( ^RW1 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C ( ^RW2 ) or N ( ^RW2 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

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

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

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

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

Y is absent or is C ₁ -C ₆ alkyl optionally substituted with one or more oxo or -OH;

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 is optionally substituted by one or more R ^Z ;

Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

Embodiment 3. A compound according to any one of the preceding embodiments, wherein:

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C ( ^RW1 ) or N ( ^RW1 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C ( ^RW2 ) or N ( ^RW2 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

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

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

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

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

Y is absent or is C ₁ -C ₆ alkyl optionally substituted with one or more oxo or -OH;

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 optionally substituted by one or more R ^Z ;

Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

Embodiment 4. A compound according to any one of the preceding embodiments, wherein:

Each independently represents a single bond or a double bond;

n is 0 or 1;

^W1 is C ( ^RW1 ) or N ( ^RW1 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

^W2 is C ( ^RW2 ) or N ( ^RW2 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond;

R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl);

W ³ is C or N;

^X1 is C or N;

^X2 is N, O or C (R ^X2 );

^RX2 is H or _C1 - _C6 alkyl;

^X3 is N, O or C (R ^X3 );

^RX3 is H or _C1 - _C6 alkyl;

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

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

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

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

Y is C ₁ -C ₆ alkyl optionally substituted by one or more oxo or -OH;

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 optionally substituted by one or more R ^Z ;

Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ;

each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and

Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy.

Embodiment 5. A compound according to any one of the preceding embodiments, wherein for

Embodiment 6. A compound according to any one of the preceding embodiments, wherein for

Embodiment 7. A compound according to any one of the preceding embodiments, wherein for

Embodiment 8. A compound according to any one of the preceding embodiments, wherein for

Embodiment 9. A compound according to any one of the preceding embodiments, wherein for

Embodiment 10. A compound according to any one of the preceding embodiments, wherein for

Embodiment 11. A compound according to any one of the preceding embodiments, wherein R ¹ is H.

Embodiment 12. A compound according to any one of the preceding embodiments, wherein R ¹ is halogen, cyano or C ₁ -C ₆ alkyl.

Embodiment 13. A compound according to any one of the preceding embodiments, wherein R ¹ is C ₁ -C ₆ alkyl.

Embodiment 14. A compound according to any one of the preceding embodiments, wherein ^R1 is _CH3 .

Embodiment 15. A compound according to any one of the preceding embodiments, wherein ^R2 is H.

Embodiment 16. A compound according to any one of the preceding embodiments, wherein R ² is halogen, cyano or C ₁ -C ₆ alkyl.

Embodiment 17. A compound according to any one of the preceding embodiments, wherein ^R3 is H.

Embodiment 18. A compound according to any one of the preceding embodiments, wherein R ³ is halogen, cyano or C ₁ -C ₆ alkyl.

Embodiment 19. A compound according to any one of the preceding embodiments, wherein R ³ is halogen.

Embodiment 20. A compound according to any one of the preceding embodiments, wherein R ³ is Cl.

Embodiment 21. A compound according to any one of the preceding embodiments, wherein R ³ is C ₁ -C ₆ alkyl.

Embodiment 22. A compound according to any one of the preceding embodiments, wherein R ³ is CH ₃ .

Embodiment 23. A compound according to any one of the preceding embodiments, wherein ^R4 is H.

Embodiment 24. A compound according to any one of the preceding embodiments, wherein R ⁴ is halogen, cyano or C ₁ -C ₆ alkyl.

Embodiment 25. A compound according to any one of the preceding embodiments, wherein R ⁴ is halogen.

Embodiment 26. A compound according to any one of the preceding embodiments, wherein R ⁴ is Cl.

Embodiment 27. A compound according to any one of the preceding embodiments, wherein R ⁴ is C ₁ -C ₆ alkyl.

Embodiment 28. A compound according to any one of the preceding embodiments, wherein R ⁴ is CH ₃ .

Embodiment 29. A compound according to any one of the preceding embodiments, wherein Y is absent.

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

Embodiment 31. A compound according to any one of the preceding embodiments, wherein Y is C ₁ -C ₆ alkyl.

Embodiment 32. A compound according to any one of the preceding embodiments, wherein Y is _-CH2- .

Embodiment 33. A compound according to any one of the preceding embodiments, wherein Y is C ₁ -C ₆ alkyl substituted with one or more -OH.

Embodiment 34. A compound according to any one of the preceding embodiments, wherein Z is H.

Embodiment 35. A compound according to 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 is optionally substituted with one or more R ^Z .

Embodiment 36. A compound according to any one of the preceding embodiments, wherein Z is azetidinyl or oxetanyl, wherein the azetidinyl or oxetanyl is optionally substituted with one or more ^RZ .

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

Embodiment 38. A compound according to any one of the preceding embodiments, wherein Z is pyrrolidinyl or tetrahydrofuranyl, wherein the pyrrolidinyl or tetrahydrofuranyl is optionally substituted with one or more ^RZ .

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

Embodiment 40. A compound according to any one of the preceding embodiments, wherein Z is piperidinyl or tetrahydropyranyl, wherein piperidinyl or tetrahydropyranyl is optionally substituted with one or more ^RZ .

Embodiment 41. A compound according to any one of the preceding Embodiments, wherein Z is piperidinyl or tetrahydropyranyl.

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

Embodiment 43. A compound according to 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) ₂ , wherein NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ is optionally substituted with one or more R ^Za .

Embodiment 44. A compound according to any one of the preceding embodiments, wherein at least one R ^Z is -S(=O) ₂ -(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^Za .

Embodiment 45. A compound according to any one 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) is optionally substituted with one or more R ^Za .

Embodiment 46. A compound according to any one of the preceding embodiments, wherein at least one R ^Z is -C(=O)-CH=CH ₂ .

Embodiment 47. A 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, 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 .

Embodiment 48. A compound according to any one of the preceding embodiments, wherein at least one R ^Z is C ₁ -C ₆ alkyl optionally substituted with one or more R ^Za .

Embodiment 49. A compound according to 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 the C ₃ -C ₈ cycloalkyl or 3 to 8 membered heterocycloalkyl is optionally substituted with one or more R ^Za .

Embodiment 50. A compound according to any one of the preceding embodiments, wherein at least one R ^Za is oxo, halogen, cyano or -OH.

Embodiment 51. A compound according to any one 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) ₂ , wherein NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ is optionally substituted with one or more R ^Zb .

Embodiment 52. A compound according to any one of the preceding embodiments, wherein at least one R ^Za is -S(=O) ₂ -(C ₁ -C ₆ alkyl) optionally substituted with one or more R ^Zb .

Embodiment 53. A compound according to 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), wherein -C(=O)-(C ₁ -C ₆ alkyl) or -C(=O)-(C ₂ -C ₆ alkenyl) is optionally substituted with one or more R ^Zb .

Embodiment 54. A compound according to any one of the preceding embodiments, wherein at least one R ^Za is -C(=O)-CH=CH ₂ .

Embodiment 55. A compound according to 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, 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 .

Embodiment 56. A compound according to any one of the preceding embodiments, wherein at least one R ^Za is C ₃ -C ₈ cycloalkyl or 3 to 8 membered heterocycloalkyl, wherein the C ₃ -C ₈ cycloalkyl or 3 to 8 membered heterocycloalkyl is optionally substituted with one or more R ^Zb .

Embodiment 57. A compound according to any one of the preceding embodiments, wherein at least one R ^Zb is oxo, halogen, cyano or -OH.

Embodiment 58. A compound according to any one 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) ₂ .

Embodiment 59. A compound according to any one of the preceding embodiments, wherein at least one R ^Zb is -S(=O) ₂ -(C ₁ -C ₆ alkyl).

Embodiment 60. A compound according to 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).

Embodiment 61. A compound according to any one of the preceding embodiments, wherein at least one R ^Zb is -C(=O)-CH=CH ₂ .

Embodiment 62. The compound of any one of the previous 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 alkoxy.

Embodiment 63. A compound according to any of the preceding embodiments, said compound having formula (I-a), (I-b), (I-c) or (I-d):

or a pharmaceutically acceptable salt or stereoisomer thereof.

Embodiment 64. A compound according to any one of the preceding embodiments, wherein the compound has formula (II):

or a pharmaceutically acceptable salt or stereoisomer thereof.

Embodiment 65. A compound according to any one of the preceding embodiments, said compound 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, which is selected from the compounds described in Table I and Table II, or pharmaceutically acceptable salts or stereoisomers thereof.

Embodiment 67. An isotopic derivative of a compound according to any one of the preceding embodiments.

Embodiment 68. A process for preparing a compound according to any one of the preceding embodiments.

Embodiment 69. A pharmaceutical composition comprising a compound according to any one 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. A compound according to any one of the preceding embodiments for use in treating or preventing cancer in a subject.

Embodiment 72. Use of a compound according to any of the preceding embodiments for the preparation of a medicament for treating or preventing cancer in a subject.

Embodiment 73. Use of a compound according to any of the preceding embodiments for treating or preventing cancer in a subject.

Embodiment 74. The method, compound or use according to any one 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 according to any one of Embodiments 70-75, wherein the cancer is characterized by at least one oncogenic mutation in the FGFR2 gene.

Embodiment 77. The method, compound or use according to any one of Embodiments 70-75, wherein the 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 the FGFR2 gene.

Embodiment 79. The method, compound or use according to any one of Embodiments 70-75, wherein the cancer is characterized by overexpression of the 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 FGFR2.

Embodiment 81. 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 FGFR3.

Embodiment 82. The method, compound or use according to any one of Embodiments 70-75, wherein the cancer is characterized by overexpression of FGFR2.

Embodiment 83. The method, compound or use according to any one of Embodiments 70-75, wherein the cancer is characterized by overexpression of FGFR3.

Embodiment 84. The method, compound or use of any one 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, renal 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, vulvar cancer, joint cancer, oral cancer, pharyngeal cancer or colorectal cancer.

Embodiment 85. The method, compound or use of any one of Embodiments 70-83, wherein the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, invasive breast cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, bile duct cancer, colon adenocarcinoma, lymphoid neoplasms diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, brain low-grade glioma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic cancer, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid cancer, thymoma, uterine carcinosarcoma, 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 cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, bile duct cancer, esophageal cancer, anal cancer, salivary gland cancer, vulvar cancer, cervical cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumors, breast cancer, cancer of unknown primary (CUP), cancer spread to bone, cancer spread to brain, cancer spread to liver, cancer spread to lung, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chromomyeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell sarcoma, gallbladder cancer, gastric cancer, Gastroesophageal junction cancer, germ cell tumor, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, plastic gastritis, liver cancer, lung cancer, lymphoma, malignant schwannoma, mediastinal germ cell tumor, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral and oropharyngeal cancer, myeloma, nose and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer, retinoblastoma, salivary gland cancer, secondary cancer, signet ring cell carcinoma Examples of cancer include, but are not limited to, hematological malignancies, lymphomas, cutaneous T-cell lymphomas, peripheral T-cell lymphomas, Hodgkin's lymphomas, non-Hodgkin's lymphomas, multiple myeloma, chromolymphocytic leukemia, chronic myeloid leukemia, acute myeloid 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, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

Embodiment 86. The method, compound or use of any one of Embodiments 70-83, wherein the cancer is gastric cancer, triple-negative breast cancer, melanoma, hepatobiliary carcinoma, cancer of unknown primary, 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 carcinoma or glioblastoma.

Example

For exemplary purposes, salts of compounds of formula (I') and (I) are synthesized and tested in the Examples. It should be understood that the neutral compounds of formula (I') and (I) can be similarly synthesized and tested using the exemplary procedures described in the Examples. In addition, it should be understood that the salts (e.g., sodium salts) of compounds of formula (I') and (I) can be converted into corresponding neutral compounds using conventional techniques in the art (e.g., pH adjustment and optionally, extraction (e.g., into an aqueous phase)).

Compounds of formula (I') and (I) can be prepared using the methods described in detail herein. Those skilled in the art can use a variety of starting materials and reagents to prepare the disclosed compounds of formula (I') and (I) and make further modifications to be able to envision alternative synthetic routes. For exemplary purposes, salts of some compounds of formula (I') and (I) are synthesized and tested in the Examples. It should be understood that the neutral compounds of formula (I') and (I) can be similarly synthesized and tested using the exemplary procedures described in the Examples. In addition, it should be understood that the salts (e.g., hydrochlorides) of the compounds of formula (I') and (I) can be converted to the corresponding neutral compounds using conventional techniques in the art (e.g., pH adjustment and optionally, extraction (e.g., into an aqueous phase)).

abbreviation:

aq. Water-based

ACN: Acetonitrile

¹ H NMR Proton nuclear magnetic resonance spectroscopy

CDCl _3- deuterated chloroform

DCM Dichloromethane

DMF: N,N-dimethylformamide

DMSO-d ₆ hexadeuterated dimethyl sulfoxide

EtOAc Ethyl acetate

eq. equivalent

h hour

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 tert-butyl 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-carboxylate

Step 1. tert-Butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate

To the solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl esters (500mg, 2.48mmol) in dichloromethane (10mL), triethylamine (754mg, 7.45mmol) and p-toluenesulfonyl chloride (947mg, 4.97mmol) are added. The mixture is stirred at 25 ° C for 16 hours. After completion, the mixture is poured into water (50mL) and extracted with ethyl acetate (30mL x 3). The organic layer is washed with 1M hydrochloric acid (10mL), and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 3/1) to obtain 4- (p-toluenesulfonyloxy) piperidine-1-carboxylic acid tert-butyl esters (600mg, 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (1 g, 1.97 mmol) in N,N-dimethylformamide (10 mL) 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 ° C 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 tert-butyl 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (2 g, crude) as a yellow oil. ¹ H NMR (400 MHz, 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 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 (2 g, 2.90 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at 25 ° C 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]; (B%: 50% - 55%, 10 min) to give 2-[[6-[5-chloro-3-[1-(4-piperidinyl) pyrazol-4-yl] quinoxalin-6-yl] oxy-2-methyl-benzoimidazol-1-yl] methoxy] ethyl-trimethyl-silane (700 mg, 1.19 mmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, 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),5.8 2-5.59(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. 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)azetidine-1-carboxylate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (2g, 3.94mmol), 3-iodoazetidine-1-carboxylic acid tert-butyl ester (1.67g, 5.92mmol) in N,N-dimethylformamide (20mL), potassium carbonate (1.09g, 7.89mmol) was added. The mixture was stirred at 60°C for 32h. At 20°C, the reaction mixture was quenched by adding water (200mL), then diluted with ethyl acetate (200mL) and extracted with ethyl acetate (200mL×3). The combined organic layer was washed with water (100mL×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 tert-butyl 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-carboxylate (2.70 g, 3.67 mmol, 93%) as a yellow solid. m/z ES+[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

A solution of 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 (2.5 g, 3.77 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (20 mL) was stirred at 25° C. for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate (50 mL) at 25° C., then diluted with dichloromethane (50 mL), and extracted with dichloromethane (50 mL×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]imidazol-6-yl)oxy)quinoxaline (2.0 g, 2.49 mmol, 66%) as a yellow solid. 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-thiazinane 1,1-dioxide

Step 1. Methyl 2-(cyanomethyl)acrylate

To a solution of methyl 2-(bromomethyl)acrylate (23.0 g, 128 mmol) and trimethylsilylcarbonitrile (12.7 g, 128 mmol) in acetonitrile (500 mL) was added tetrabutylammonium fluoride (1 M in THF, 128.48 mL) dropwise at 25° C., and the mixture was stirred at 25° C. 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, 103 mmol, 80%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.40 (d, J=0.8 Hz, 1H), 6.01 (s, 1H), 3.75 (d, J=0.8 Hz, 3H), 3.35 (s, 2H).

Step 2. Methyl 3-(benzylthio)-2-(cyanomethyl)propanoate

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 benzylthiol (7.74 g, 62.3 mmol), the mixture was stirred at 20 ° C for 1 hour. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layer was 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 obtain methyl 3-(benzylthio)-2-(cyanomethyl)propanoate (22.0 g, 88.2 mmol, 85%) as a colorless oil.

Step 3. 4-Amino-2-((benzylthio)methyl)butan-1-ol

At 0 ° C, lithium aluminum hydride (4.57 g, 120 mmol) was carefully added in batches to a solution of methyl 3-(benzylthio)-2-(cyanomethyl)propanoate (10.0 g, 40.1 mmol) in tetrahydrofuran (200 mL). The mixture was stirred at 25 ° C 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 product) 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), imidazole (3.17 g, 46.5 mmol) in dichloromethane (50 mL) was stirred at 25 ° C for 16 hours. 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, 14.2 mmol, 45%) as a yellow oil. m/z ES+[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 °C 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. Methyl 3-(benzylthio)-2-(cyanomethyl)propanoate

A solution of 4-amino-2-[[tert-butyl(diphenyl)silyl]oxymethyl]butane-1-sulfonyl chloride (2.8 g, 6.36 mmol) and triethylamine (1.93 g, 19.0 mmol) in dichloromethane (30 mL) was stirred at 25 ° C 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-thiazinane 1,1-dioxide (1 g, 2.48 mmol, 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]octan-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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (830 mg, 1.65 mmol) and 2-bromo-5,8-dioxaspiro[3.4]octane (350 mg, 1.80 mmol) in N,N-dimethylformamide (9 mL), potassium carbonate (680 mg, 4.90 mmol) and potassium iodide (27.0 mg, 165 umol) were added. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layer was 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]octan-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, 1.05 mmol, 64%) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[5-chloro-3-[1-(5,8-dioxaspiro[3.4]octan-2-yl)pyrazol-4-yl]quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (680 mg, 1.10 mmol) in dichloromethane (6.8 mL) and water (0.5 mL) was added formic acid (8.30 g, 180 mmol). The mixture was stirred at 40 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water (20 mL). The mixture was adjusted to pH = 8-9 with saturated sodium bicarbonate (30 mL) and then extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (25 mL x 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (550 mg, crude) as a white solid. m/z ES+[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

A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (350 mg, 0.61 mmol) in trifluoroacetic acid (3.5 mL) was stirred at 25 ° C for 0.5 hours. The reaction mixture was concentrated under reduced pressure and 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]quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (300 mg, crude) as a white solid. 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, 1 H), 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (1 g, 1.97 mmol) in N,N-dimethylformamide (15 mL), cesium carbonate (1.29 g, 3.94 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (614 mg, 2.17 mmol) were added. The mixture was stirred at 50 ° C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*40mm*15um; mobile phase: [water (0.1% TFA)-acetonitrile]; (B%: 35%-65%, 11mm) to give tert-butyl 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-carboxylate (800mg, 1.21mmol, 61%) as a white solid. m/z ES+[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

A mixture of 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 (790 mg, 1.19 mmol) in trifluoroacetic acid (3 mL) was stirred at 25° C. for 6 hours. The reaction mixture was concentrated under reduced pressure to give 2-[1-(azetidin-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (500 mg, crude, TFA salt) as a yellow solid. 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-Butyloxycarbonyl-N-(3,5-difluoro-2-nitro-phenyl)carboxylate

Step 1. N-tert-Butyloxycarbonyl-N-(3,5-difluoro-2-nitro-phenyl)carboxylate

4-dimethylaminopyridine (35.1 mg, 287 umol), di-tert-butyl dicarbonate (1.25 g, 5.74 mmol) and triethylamine (872 mg, 8.62 mmol) were added to a solution of 3,5-difluoro-2-nitro-aniline (500 mg, 2.87 mmol) in dichloromethane (8 mL), and the mixture was stirred at 25 ° C 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 obtain tert-butyl N- tert-butoxycarbonyl-N- (3,5-difluoro-2-nitro-phenyl) carboxylate (800 mg, 1.34 mmol, 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

Step 1. (3,3-Difluorocyclobutyl)methyl methanesulfonate

At 0 ° C, to a solution of (3,3-difluorocyclobutyl)methanol (5 g, 41.0 mmol) and triethylamine (10.4 g, 102 mmol) in dichloromethane (60 mL), methanesulfonyl chloride (7.04 g, 61.4 mmol, 4.75 mL) was added, and the mixture was stirred at 20 ° C for 1 hour. The reaction mixture was quenched with water (15 mL) and then extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (3,3-difluorocyclobutyl)methyl methanesulfonate (9 g, crude product) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ4.25 (d, J = 6.4 Hz, 2H), 3.03 (d, J = 1.2 Hz, 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-(4,4,5,5-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 cyclopenta-2,4-diene-1-yl(diphenyl)phosphine; dichloropalladium; iron (II) (902 mg, 1.23 umol). The mixture was stirred at 60 ° C for 12 hours under nitrogen. After completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (125 mL x 3). The combined organic phase was 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 °C 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 x 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/z ES+[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-pyrazole-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), the mixture was stirred at 80 ° C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layer was 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 obtain a residue. The residue was triturated with petroleum ether/ethyl acetate (20:1, 40 mL) at 20 °C for 30 min to give 7-bromo-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxaline (800 mg, 2.11 mmol, 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

A mixture of 7-bromo-2-[1-[(3,3-difluorocyclobutyl)methyl]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]phosphane (67.2 mg, 158 umol) and potassium hydroxide (888 mg, 15.8 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. under a nitrogen atmosphere 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, 1.26 mmol, 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 a solution of 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-ol (400 mg, 1.26 mmol) in chloroform (5 mL), N-chlorosuccinimide (338 mg, 2.53 mmol), nickel chloride (164 mg, 1.26 mmol) and triethylamine (128 mg, 1.26 mmol) were added. The mixture was stirred at 60 ° C 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 obtain 5-chloro-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxaline-6-ol (500 mg, 1.43 mmol, 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-Butyloxycarbonyl-N-(5-fluoro-2-nitro-phenyl)carbamate

Step 1. N-tert-Butyloxycarbonyl-N-(5-fluoro-2-nitro-phenyl)carbamate

To the solution of 5-fluoro-2-nitro-aniline (10g, 64.1umol) in dichloromethane (100mL), di-tert-butyl dicarbonate (28.0g, 128umol), triethylamine (19.5g, 192umol) and N, N-dimethylpyridine-4-amine (783mg, 6.41umol) are added. The mixture is stirred at 20 ° C for 1 hour. After completion, the reaction mixture is concentrated under reduced pressure. The residue is purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 8/1) to obtain tert-butyl N-tert-butoxycarbonyl-N-(5-fluoro-2-nitro-phenyl)carbamate (20g, 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)ethyl methanesulfonate

Step 1. 2-[4-[8-Chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethanol

To a mixture of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (2 g, 3.94 mmol) and 2-bromoethanol (1.48 g, 11.83 mmol, 840 μL) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.64 g, 11.83 mmol). The mixture was heated to 80 ° C and stirred for 16 hours. After completion, at 20 ° C, the reaction mixture was quenched with water (150 mL) 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethanol (2.5 g, 3.86 mmol, 98%) as a yellow oil. m/z ES+[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]ethyl methanesulfonate

To a mixture of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethanol (2.5 g, 4.54 mmol) in dichloromethane (30 mL) at 0° C., triethylamine (1.38 g, 13.61 mmol) and methanesulfonyl chloride (1.04 g, 9.07 mmol) were added. The mixture was stirred at 0° C. for 2 hours. Upon completion, the reaction mixture was quenched with water (30 mL) at 0° C. 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate (2.6 g, 3.64 mmol, 80%) as a yellow oil. m/z ES+[M+H] ⁺ 629.4.

Intermediates 14, 23 and 15: tert-butyl (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-carboxylate, tert-butyl 8-chloro-2-(1-((3S,4S)-3-fluoropiperidine-4 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. tert-Butyl (3S,4R)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Methanesulfonyl chloride (392 mg, 3.42 mmol) and triethylamine (692 mg, 6.84 mmol) were added to a solution of (3S, 4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.28 mmol) in dichloromethane (5 mL), and the mixture was stirred at 0 ° C for 0.5 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layer was washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (3S, 4R)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (720 mg, crude product) as an orange solid. ¹ HNMR (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).

Step 2. (3S,4S)-tert-butyl 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-carboxylate

To 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 (600 mg, 1.18 mmol) in N,N-dimethylformamide (4 mL) were added potassium carbonate (491 mg, 3.55 mmol) and tert-butyl (3S,4R)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (704 mg, 2.37 mmol) and the mixture was stirred at 100 °C for 12 h. 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 condition, 85-90% acetonitrile, 5 min) to give (3S,4S)-tert-butyl 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-carboxylate (600 mg, 849 umol, 72%) as ^{an off} -white solid. NMR (400MHz, DMSO-d6) δ9.33 (d, J = 3.6 Hz, 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),4.7 8-4.70(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

A solution of (3S,4S)-tert-butyl 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-carboxylate (300 mg, 424 umol) in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) was stirred at 25 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure to give 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 (250 mg, crude) as a ^yellow oil. 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 a solution of 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 (250 mg, 411 umol) in tetrahydrofuran (2 mL) was added pyridine hydrofluoric acid (407 mg, 4.11 mmol) and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions, 30%-40% acetonitrile, 5 min) to give 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 (120 mg, 251 umol, 55%) as an off-white solid. m/z ES+[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

At 0°C, NaH (7.58 g, 189 mmol, 60% in mineral oil) was added portionwise to a solution of 5-bromo-2-methyl-1H-benzimidazole (20 g, 94.8 mmol) in THF (400 mL). The reaction was stirred at 0°C for 0.5 hours. (2-(chloromethoxy)ethyl)trimethylsilane (23.7 g, 142 mmol, 25 mL) was then added dropwise at 0°C. The mixture was stirred at 25°C for 1.5 h. Upon 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 x 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]imidazole (39 g, crude, mixture of regioisomers) as a white solid. 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

To a solution of 2-[(5-bromo-2-methyl-benzoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (39.29 g, 115 mmol, mixture of regioisomers) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (87.69 g, 345 mmol) in dioxane (600 mL) was added potassium acetate (33.89 g, 345 mmol) and cyclopenta-2,4-dien-1-yl(diphenyl)phosphine; dichloropalladium; iron(II) (8.42 g, 11.51 mmol). The mixture was stirred at 60° C. under nitrogen for 12 hours. After completion, the reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 0/1) to afford 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (44.2 g, 114 mmol, 99%, mixture of regioisomers) as a yellow solid. m/z ES+[M+H] ⁺ 389.3.

Step 3. (2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)boronic acid

To a solution of trimethyl-[2-[[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]methoxy]ethyl]silane (25 g, 64.37 mmol) in tetrahydrofuran (250 mL) and water (250 mL), sodium periodate (41.30 g, 193 mmol) and ammonium acetate (14.89 g, 193 mmol) were added. The mixture was stirred at 30 ° C 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: ID 100 mm*H 400 mm, mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; (B%: 20-75%, 40 min; 75%, 35 min) to give ( ² -methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)boronic acid (8.2 g, 26.78 mmol, 42%) as a white solid. 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)quinoxalin-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 with nitrogen 3 times, and then stirred at 100° C. for 3 hours under nitrogen. 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, 5.39 mmol, 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),2.2 2-2.10(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 ° C for 2 hours. The reaction mixture was cooled to 25 ° C 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 HNMR (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 a solution of 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]boronic acid (1.22 g, 3.99 mmol) in 1,2-dimethoxyethane (30 mL) were added cesium carbonate (2.67 g, 8.21 mmol), MS (1.50g) and copper (II) acetate (813mg, 4.48mmol). Under an oxygen atmosphere, the mixture was stirred at 60 ° C for 6 hours. 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]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (670mg, 980umol, 26%) as a yellow solid. 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 a solution of 2-[[6-[5-bromo-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (670 mg, 1.05 mmol) in methanol (7 mL) was added hydrochloric acid (1 M, 7 mL) and the mixture was stirred at 25 ° C 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]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (360 mg, 587 umol, 55%) as a yellow oil. m/z ES+[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 a solution of 2-[[6-[5-bromo-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (290 mg, 526 umol) and (3,3-difluorocyclobutyl)methyl methanesulfonate (158 mg, 789 umol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (218 mg, 1.58 mmol). The mixture was stirred at 80° C. 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 x 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]imidazol-6-yl)oxy)quinoxaline (430 mg, crude) as a yellow solid. m/z ES+[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

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) were added to a solution of 3- (1-tetrahydropyran-2-ylpyrazol-4-yl) quinoxaline-6-ol (4.50 g, 15.2 mmol) in chloroform (90 mL). The mixture was stirred at 60 ° C 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 obtain 2-chloro-3- (2-fluoro-5-methoxyphenoxy) -6-nitroaniline (7 g, 21.2 mmol, 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-ylpyrazole-4-yl)quinoxaline-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), potassium carbonate (4.93 g, 35.7 mmol) was added. The mixture was stirred at 130 ° C 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 layer was 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-diamine (6.59 g, 12.2 mmol, 69%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.44 (s, 1H), 8.90 (s, 1H), 8.38 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.86 (dd, J = 1.6, 9.6 Hz, 1H), 7.69 (d, J = 9.2 Hz, 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 a solution of 3-[5-chloro-3-(1-tetrahydropyran-2-ylpyrazole-4-yl)quinoxaline-6-yl]oxy-2-fluoro-6-nitro-aniline (6.59 g, 13.6 mmol) in ethanol (80 mL) and water (40 mL), ammonium chloride (7.27 g, 136 mmol) and iron powder (3.80 g, 68.0 mmol) were added. The mixture was stirred at 60 ° C 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 layer was 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, 9.38 mmol, 69%) as a yellow solid. ¹ HNMR (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 a solution of 4-[5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline-6-yl]oxy-3-fluoro-benzene-1,2-diamine (4.40 g, 9.67 mmol) and 1,1,1-trimethoxyethane (5.81 g, 48.4 mmol) in methanol (100 mL) was added sulfamic acid (1.88 g, 19.4 mmol). The mixture was stirred at 25 ° C for 1 hour. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (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]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (4.80 g, crude) as a yellow solid. m/z ES+[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 a solution of 8-chloro-7-[(4-fluoro-2-methyl-3H-benzimidazol-5-yl)oxy]-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline (2.60 g, 5.43 mmol) in tetrahydrofuran (60 mL) was added sodium hydride (543 mg, 13.6 mmol, 60% in mineral oil) portionwise at 0° C. The mixture was then stirred at 0° C. for 0.5 h. Then, a solution of ((2-(chloromethoxy)ethyl)trimethylsilane (1.36 g, 8.14 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise at 0°C. The mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (30 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 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 (2.90 g, 4.76 mmol, 88%) as a yellow solid. 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 a solution of 2-[[6-[5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (2.90 g, 4.76 mmol) in methanol (29 mL) was added aqueous hydrochloric acid solution (1 N, 29 mL). The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was basified with saturated aqueous sodium bicarbonate solution 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]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (2.60 g, crude) as a white solid. 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]octan-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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 952 μmol) and 2-bromo-5,8-dioxaspiro[3.4]octane (276 mg, 1.43 mmol) in N,N-dimethylformamide (8 mL), potassium carbonate (395 mg, 2.86 mmol) and potassium iodide (15.8 mg, 95.2 μmol) were added. The mixture was stirred at 100 ° C for 24 h. After completion, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was 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]octan-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 μmol, 72%) as a ^yellow solid. 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＝10.4 Hz,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/zES+[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 a solution of 2-[[6-[5-chloro-3-[1-(5,8-dioxaspiro[3.4]octan-2-yl)pyrazol-4-yl]quinoxaline-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (360 mg, 565 μmol) in dichloromethane (1.8 mL) and water (0.5 mL), formic acid (4.39 g, 95.4 mmol, 3.6 mL) was added. The mixture was stirred at 40 ° C 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 sodium bicarbonate aqueous solution. The mixture was then extracted with ethyl acetate (20 mL×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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutanone (280 mg, 467 μmol, 83%) as a yellow oil. 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

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-aniline (1.94 g, 10.1 mmol). The mixture was stirred at 110 ° C 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. 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 ° C 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/z ES+[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 1,1,1-trimethoxyethane (6.85 g, 57.0 mmol) and aminosulfonic acid (2.21 g, 22.8 mmol). The mixture was stirred at 20 °C for 2 hours. Upon 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]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (3.9 g, 6.75 mmol, 59%) as a yellow solid. 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 a solution of 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 (2.0 g, 4.32 mmol) in anhydrous tetrahydrofuran (60 mL) was added sodium hydride (1.04 g, 26.0 mmol, 60% in mineral oil) at 0°C. The mixture was stirred at 0°C for 2 hours. (2-(chloromethoxy)ethyl)trimethylsilane (865 mg, 5.19 mmol) was then added. The mixture was stirred at 20°C for 14 hours. Upon 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]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (600 mg, 810 μmol, 19%) as a yellow solid. m/z ES+[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 a solution of 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 (450 mg, 759 μmol) in methanol (5 mL) was added hydrochloric acid (1 M, 4.5 mL). The mixture was stirred at 20 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to afford 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (600 mg, crude) as a yellow solid. 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 methanesulfonate

Step 1. 4,4-Difluorocyclohexyl methanesulfonate

Methanesulfonyl chloride (631 mg, 5.51 mmol) was added to a solution of 4,4-difluorocyclohexanol (500 mg, 3.67 mmol) and triethylamine (743 mg, 7.35 mmol) in dichloromethane (1 mL). The mixture was stirred at 0 ° C 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 obtain 4,4-difluorocyclohexyl methanesulfonate (750 mg, 3.50 mmol, 95%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.95-4.92 (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)cyclohexan-1-one

Step 1. 1,4-Dioxaspiro[4.5]decan-8-ylmethyl methanesulfonate

To a solution of 1,4-dioxaspiro [4.5] decane-8-ylmethanol (500 mg, 2.90 mmol) and triethylamine (582 mg, 5.75 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (444 mg, 3.88 mmol). The mixture was stirred at 0 ° C for 1 hour. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (12 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1,4-dioxaspiro [4.5] decane-8-ylmethyl methanesulfonate (850 mg, crude product) as a yellow oil. 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]decan-8-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 1,4-dioxaspiro[4.5]decane-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]ethyl-trimethyl-silane (500 mg, 986 umol) in N,N-dimethylformamide (8 mL) was added potassium carbonate (300 mg, 2.17 mmol). The mixture was stirred at 80 ° C 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]decan-8-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (900 mg, crude) as a yellow oil. m/z ES+[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 a solution of 2-[[6-[5-chloro-3-[1-(1,4-dioxaspiro[4.5]decane-8-ylmethyl)pyrazol-4-yl]quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (900 mg, 1.36 mmol) in dichloromethane (4 mL) was added formic acid (4 mL). The mixture was stirred at 25 ° C 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×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]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclohexanone (780 mg, crude) as a yellow oil. m/z ES+[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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 296 umol) and (3,3-dimethoxycyclobutyl)methyl methanesulfonate (79.6 mg, 355 umol) in N,N-dimethylformamide (1.5 mL) were added potassium carbonate (123 mg, 887 umol) and potassium iodide (49.1 mg, 296 umol) and the mixture was heated at 80 °C. Stir for 16 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 2-[[6-[5-chloro-3-[1-[(3,3-dimethoxycyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (180 mg, crude) as a yellow oil. 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 a solution of 2-[[6-[5-chloro-3-[1-[(3,3-dimethoxycyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (180 mg, 283 umol) in dichloromethane (1 mL) was added formic acid (13.6 mg, 283 umol) and the mixture was stirred at 25 ° C 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 (3×5 mL). The combined organic layers were washed with brine (3 x 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclobutanone (110 mg, crude) as a yellow gum. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.31 (d, J = 4.4 Hz, 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: tert-Butyl 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-carboxylate

Step 1. tert-Butyl 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-carboxylate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (1 g, 1.97 mmol) in acetonitrile (10 mL) was added tert-butyl 4-(2-ethoxy-2-oxo-ethylidene)piperidine-1-carboxylate (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 ° C 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 tert-butyl 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-carboxylate (900 mg, 1.04 mmol, 53%) as a yellow solid. m/z ES+[M+H] ⁺ 776.5.

Step 2. tert-Butyl 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-carboxylate

At 0 ° C, diisobutylaluminum hydride (1M in toluene, 2.7 mL) was added to a solution of 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]-4-(2-ethoxy-2-oxo-ethyl)piperidine-1-carboxylic acid tert-butyl ester (700 mg, 902 μmol) in tetrahydrofuran (14 mL). The mixture was stirred at 0 ° C for 1.5 h. 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 tert-butyl 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-carboxylate (350 mg, 451 μmol, 50%) as a yellow solid. m/z ES+[M+H] ⁺ 734.1.

Intermediate 26: 2-(1-((2-azabicyclo[2.2.1]heptane-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. tert-Butyl 5-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

At 0 ° C, 2- (tert-butoxycarbonyl) -2- azabicyclo [2.2.1] heptane -5- carboxylic acid (500mg, 2.07mmol) in tetrahydrofuran (6mL) was added dropwise to a solution of borane tetrahydrofuran complex (1M, 12.4mL). The mixture was stirred at 25 ° C for 12 hours. After completion, the reaction mixture was carefully quenched with methanol (60mL) at 25 ° C, and then stirred at 60 ° C 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 obtain 5- (hydroxymethyl) -2- azabicyclo [2.2.1] heptane -2- carboxylic acid tert-butyl esters (460mg, 2.03mmol, 78%) as a yellow oil. 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. tert-Butyl 5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To the solution of 5-(hydroxymethyl)-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl esters (460mg, 2.02mmol) in dichloromethane (6mL), triethylamine (614mg, 6.07mmol, 0.845mL) and methanesulfonyl chloride (348mg, 3.04mmol, 0.235mL) are added. The mixture is stirred at 0°C for 1 hour. After completion, the reaction mixture is quenched with water (10mL), and extracted with dichloromethane (20mL x 3). The combined organic layer is washed with brine (10mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl esters (760mg, crude product) as orange solid. 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. 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)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To 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 (360 mg, 710 μmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (294 mg, 2.13 mmol) and tert-butyl 5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (434 mg, 1.42 mmol). The mixture was stirred at 80° C. 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 condition, 95%-100% acetonitrile, 8 min) to afford 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)-2-azabicyclo[2.2.1]heptane-2-carboxylate (430 mg, 0.60 mmol, 85%) as an ^{orange solid} . 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 . 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

A solution of 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)-2-azabicyclo[2.2.1]heptane-2-carboxylate (400 mg, 558 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1C) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to give 2-(1-(2-azabicyclo[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 (340 mg, crude) as a yellow oil. m/z ES+[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. 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)methyl)azetidine-1-carboxylate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 986 umol) and tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (290 mg, 976 umol) in N,N-dimethylformamide (10 mL), cesium carbonate (1 g, 3.07 mmol) was added. The mixture was stirred at 100 ° C 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 tert-butyl 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]azetidine-1-carboxylate (800 mg, crude) as a yellow oil. m/z ES+[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

A solution of tert-butyl 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]azetidine-1-carboxylate (400 mg, 591 umol) in trifluoroacetic acid (4 mL) was stirred at 25° C. for 1.5 hours. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (mobile phase: [water (0.1% formic acid) - acetonitrile]; (B%: 10% -40%, 8 min) to give 2- [1- (azetidin-3-ylmethyl) pyrazol-4-yl] -8-chloro-7- [(2-methyl-3H-benzoimidazol-5-yl) oxy] quinoxaline (240 mg, 538 umol, 91%, formate) as a yellow solid. ¹ H NMR (400 MHz, 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (18.0 g, 86.5 mmol) in toluene (200 mL), p-toluenesulfonic acid (1.49 g, 8.65 mmol) and 3,4-dihydro-2H-pyrans (8.73 g, 103 mmol) were added. The mixture was stirred at 60 ° C 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 layer was 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (20 g, 68.4 mmol, 64%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (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

A mixture of 7-bromo-2-chloro-quinoxaline (16.0 g, 65.7 mmol), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (20.0 g, 68.4 mmol), tetrakis(triphenylphosphine)palladium (3.95 g, 3.42 mmol), potassium phosphate (29.1 g, 136 mmol) in dioxane (200 mL) and water (40 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 80° C. under 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, 69.6 mmol, 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 then the mixture was stirred at 100° C. under a nitrogen atmosphere 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, 54.8 mmol, 60%) as a white solid. m/z ES+[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-pyrazole-4-yl)quinoxaline-6-ol (16.0 g, 51.5 mmol) in chloroform (300 mL) was 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 ° C for 2 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 obtain 5-chloro-3-(5-methyl-1-tetrahydropyran-2-yl-pyrazole-4-yl)quinoxaline-6-ol (7 g, 20 mmol, 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-pyrazole-4-yl)quinoxaline-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 ° C 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]oxy-2-nitro-aniline (500 mg, 1.04 mmol, 22%) as a yellow solid. m/z ES+[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 a solution of 5-[5-chloro-3-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-nitro-aniline (500 mg, 1.04 mmol) in ethanol (10 mL) and water (5 mL), iron powder (464 mg, 8.32 mmol) and ammonium chloride (444 mg, 8.32 mmol) were added. The mixture was stirred at 60 ° C 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 layer was 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)quinoxaline-6-yl]oxybenzene-1,2-diamine (350 mg, crude) as a yellow solid. m/zES+[M+H] ⁺ 451.1

Step 7. 8-Chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]-2-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)quinoxaline

To a solution of 4-[5-chloro-3-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)quinoxalin-6-yl]oxybenzene-1,2-diamine (800 mg, 1.77 mmol) in methanol (10 mL) was added sulfamic acid (344 mg, 3.55 mmol) and 1,1,1-trimethoxyethane (1.07 g, 8.87 mmol). The mixture was stirred at 25 ° C for 2 hours. After completion, the reaction pH was adjusted to pH about 8 with saturated ammonium hydroxide and 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-benzoimidazol-5-yl)oxy]-2-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)quinoxaline (1 g, 2.11 mmol, 89%) as a yellow solid. 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

At 0°C, sodium hydroxide (134 mg, 3.37 mmol, 60% in mineral oil) was added to a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)quinoxaline (800 mg, 1.68 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 0°C for 0.5 hours. (2-(Chloromethoxy)ethyl)trimethylsilane (421 mg, 2.53 mmol) was then added dropwise, and the mixture was stirred at 25°C for 1.5 hours. After completion, the reaction mixture was quenched with water (20 mL) at 25°C, 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]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (900 mg, 3.14 mmol, 85%) as a yellow solid. 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (0.90 g, 1.49 mmol) in methanol (9 mL) was added aqueous hydrochloride (1 M, 9 mL). The mixture was stirred at 25 ° C 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]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (1.1 g, crude) as a yellow solid. 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (500 mg, 986 umol) in tetrahydrofuran (7 mL) was added sodium hydride (118 mg, 2.96 mmol, 60% in mineral oil), and the mixture was stirred at 25° C. for 30 min. And, 2-bromoacetic acid (206 mg, 1.48 mmol) was then added, and the mixture was stirred at 60° C. 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetic acid (556 mg, 984 umol, 99%) as a yellow solid. 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, 1 H),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 methanesulfonate 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

Step 1. (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 then stirred at 25 ° C for 2 hours. After completion, the reaction mixture was poured into water (80 mL) and methanol (10 mL), and then extracted with ethyl acetate (30 mL×3). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give tetrahydrothiopyran-4-ylmethanol (0.20 g, crude) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.47 (d, J = 6.0 Hz, 2H), 2.75–2.60 (m, 4H), 2.08 (dd, J = 13.2, 2.8 Hz, 2H), 1.60–1.50 (m, 1H), 1.45–1.35 (m, 2H).

Step 2. (Tetrahydro-2H-thiopyran-4-yl)methyl methanesulfonate

At 0 ° C, to a solution of tetrahydrothiopyran-4-ylmethanol (180 mg, 1.36 mmol) in dichloromethane (2 mL), methanesulfonyl chloride (312 mg, 2.72 mmol) and triethylamine (413 mg, 4.08 mmol) were added, and the mixture was stirred at 25 ° C 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 layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tetrahydrothiopyran-4-ylmethyl methanesulfonate (344 mg, crude product) 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 a mixture of tetrahydrothiopyran-4-ylmethyl methanesulfonate (0.30 g, 1.43 mmol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (723 mg, 1.43 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (394 mg, 2.85 mL), and the mixture was stirred at 80° C. for 12 hours. After completion, the mixture was concentrated under reduced pressure. The crude product was triturated with water (30 mL) at 15 °C for 40 min to give 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 (0.20 g, 0.32 mmol, 23%) as a yellow solid. m/z ES+[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

Step 1. (3S,4S)-tert-butyl 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-carboxylate

To a solution of (3S,4S)-4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (220 mg, 311 umol) and methylboronic acid (186 mg, 3.11 mmol) in dioxane (5 mL) and water (0.5 mL) was added sodium carbonate (98.8 mg, 932 umol) and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (36.7 mg, 46.6 umol). The mixture was stirred at 110° C. under nitrogen for 12 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was 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 (3S, 4S)-3-fluoro-4-(4-(8-methyl-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester (140 mg, 203 umol, 66%) as a yellow solid; m/z ES+[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 a solution of (3S,4S)-3-fluoro-4-[4-[8-methyl-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (130 mg, 189 umol) in dichloromethane (3 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol). The mixture was stirred at 25 ° C 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-((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 (100 mg, crude) as a yellow solid. m/z ES+[M+H] ⁺ 588.2.

Intermediates 35 and 36: tert-butyl 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-carboxylate 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. tert-Butyl 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-carboxylate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 0.99 mmol) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (302 mg, 1.08 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (409 mg, 2.96 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was diluted with H ₂ O (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=100/1 to 10/1) to give tert-butyl 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-carboxylate (700 mg, 974 μmol, 99%) as a yellow oil. m/z ES+[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 a solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (700 mg, 0.99 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL). The mixture was stirred at 25 ° C 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (832 mg, 1.64 mmol) in N,N-dimethylformamide (10 mL) 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 ° C 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 tert-butyl 4-[2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate (1.20 g, crude) as a yellow oil. m/z ES+[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

A solution of tert-butyl 4-[2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate (500 mg, 696 μmol) in trifluoroacetic acid (6 mL) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline (500 mg, crude) as a yellow oil. m/z ES+[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-(methylthio)cyclohexyl)methyl)-1H-pyrazol-4-yl)quinoxaline

Step 1. Ethyl 4-(p-Toluenesulfonyloxy)cyclohexanecarboxylate

4-methylbenzenesulfonyl chloride (1.22g, 6.39mmol), triethylamine (646mg, 6.39mmol) and 4-dimethylaminopyridine (70.9mg, 581umol) are added to the solution of 4-hydroxycyclohexanecarboxylic acid ethyl ester (1g, 5.81mmol) in dichloromethane (20mL), and the mixture is stirred at 20 DEG C for 24 hours.After completion, the mixture is quenched with water (10mL), and extracted with dichloromethane (3x 20mL).The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated.The residue is purified by column chromatography (petroleum ether/ethyl acetate of 50/1 to 10/1), to obtain 4- (tosyloxy) cyclohexanecarboxylic acid ethyl ester (1.7g, 5.21mmol, 87%) as 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. Ethyl 4-methylsulfanylcyclohexanecarboxylate

To a solution of ethyl 4-(p-toluenesulfonyloxy)cyclohexanecarboxylate (1.2 g, 3.68 mmol) in ethanol (20 mL) was added sodium thiomethoxide (1.29 g, 18.38 mmol), and the mixture was stirred at 80 ° C for 2 hours. After completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate was 20/1 to 5/1) to obtain ethyl 4-methylsulfanylcyclohexanecarboxylate (550 mg, 2.72 mmol, 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).

Step 3. (4-Methylsulfanylcyclohexyl)methanol

At 0 ° C, lithium borohydride (48.5 mg, 2.22 mmol) was added to a solution of 4-methylsulfanylcyclohexanecarboxylic acid ethyl ester (150 mg, 741 umol) in tetrahydrofuran (10 mL), and the mixture was stirred at 20 ° 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 was 10/1 to 3/1) to obtain (4-methylsulfanylcyclohexyl)methanol (60 mg, 370 umol, 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).

Step 4. (4-Methylsulfanylcyclohexyl)methyl methanesulfonate

To a solution of (4-methylsulfanylcyclohexyl)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 ° C 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-methylsulfanylcyclohexyl)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-methylsulfanylcyclohexyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

A mixture of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 umol), (4-methylsulfanylcyclohexyl)methyl methanesulfonate (68.2 mg, 286 umol) and potassium carbonate (81.8 mg, 592 umol) in N,N-dimethylformamide (2 mL) was stirred at 80° C. for 1 hour. Upon 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-methylsulfanylcyclohexyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (35 mg, 54.0 umol, 22%) as a yellow solid. m/z ES+[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. Methyl 1-tetrahydropyran-2-yloxycyclopropanecarboxylate

Pyridinium p-toluenesulfonate (216 mg, 861 umol) and 3,4-dihydro-2H-pyrans (761 mg, 9.04 mmol) are added to a solution of 1-hydroxycyclopropanecarboxylic acid methyl esters (1 g, 8.61 mmol) in dichloromethane (15 mL). The mixture is stirred at 25 ° C for 3 hours. The reaction mixture is diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 6/1) to obtain 1-tetrahydropyran-2-yloxycyclopropanecarboxylic acid methyl esters (1.15 g, 5.74 mmol, 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).

Step 2. (1-Tetrahydropyran-2-yloxycyclopropyl)methanol

At 0°C, under a nitrogen atmosphere, lithium aluminum hydride (37.9 mg, 998 umol) was added portionwise to a mixture of 1-tetrahydropyran-2-yloxycyclopropanecarboxylic acid methyl ester (100 mg, 499 umol) in tetrahydrofuran (1 mL), and the reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was quenched with water (3 mL), sodium hydroxide solution (4N, 3 mL), and then filtered. The filtrate was concentrated under reduced pressure to give (1-tetrahydropyran-2-yloxycyclopropyl)methanol (80.0 mg, 464 umol, 93%) as a white oil without further purification. ¹ H NMR (400 MHz, 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of (1-tetrahydropyran-2-yloxycyclopropyl)methanol (100 mg, 580 umol), 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (245 mg, 483 umol) in toluene (2 mL), triphenylphosphine (190 mg, 725 umol) was added, the reaction was degassed and purged with nitrogen 3 times. Diisopropyl azodicarboxylate (146 mg, 725 umol) was then added dropwise, and the mixture was stirred at 60 ° C for 1.5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layer was 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-yloxycyclopropyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 32.0 umol, 62%) as a yellow oil. m/z ES+[M+H] ⁺ 661.1.

Intermediate 40: tert-Butyl 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

Step 1. tert-Butyl 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate

To a mixture of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (500mg, 1.80mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (366mg, 1.89mmol) in N,N-dimethylformamide (8mL), potassium carbonate (500mg, 3.62mmol) was added. The mixture was then stirred at 80°C for 12 hours. The mixture was quenched with water (20mL) and extracted with ethyl acetate (25mL 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 tert-butyl 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (450 mg, 1.15 mmol, 57%) as a colorless oil. 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,2 H),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° C. for 12 hours. Upon 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 to give 2,7-dibromoquinoxaline (5.8 g, crude) as a red solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.01-7.95 (m, 1H), 7.90-7.84 (m, 1H).

Step 2. A mixture of 2,7-dibromoquinoxaline (5.8 g, 20.1 mmol), 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (5.32 g, 19.1 mmol), _KOAC (5.93 g, 60.4 mmol), Pd(dppf)Cl ₂ (1.47 g, 2.01 mmol) in dioxane (100 mL) and H 2 O (10 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 60° C. under N ₂ atmosphere 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 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. A mixture of 7-bromo-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline ₍ 3.5 g, 9.74 mmol), _Pd (dba) (892 mg, 974 μmol), t- _BuXPhos (413 mg, 974 μmol) and KOH (5.47 g, 97.4 mmol) in dioxane (30 mL) and H2O (10 mL) was degassed and purged with _N2 for 3 times, then the mixture was stirred at 100°C under _N2 atmosphere for 2 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 afford 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)quinoxaline-6-ol (3.4 g, 11.4 mmol) in acetonitrile (50 mL) was added N-chlorosuccinimide (1.53 g, 11.4 mmol) portionwise. The mixture was stirred at 80 ° C 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 5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline-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° C. for 12 hours. Upon 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]oxy-2-nitro-aniline (800 mg, 36%) as a yellow solid. m/z ES+[M+H] ⁺ 467.1.

Step 6. To a solution of 5-[ ₅ -chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxy-2-nitro-aniline (800 mg, 1.71 mmol) in ethanol (10 mL) and H 2 O (2 mL) was added iron powder (765 mg, 13.7 mmol) and NH ₄ Cl (733 mg, 13.7 mmol). The mixture was stirred at 60° C. for 12 hours. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was then 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]oxybenzene-1,2-diamine (300 mg, 36%) as a yellow solid. m/z ES+[M+H] ⁺ 504.4.

Step 7. To a solution of 4-[5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxybenzene-1,2-diamine (250 mg, 572 μmol) in methanol (3 mL) was added sulfamic acid (111 mg, 1.14 mmol) and 1,1,1-trimethoxyethane (343 mg, 2.86 mmol). The mixture was stirred at 25 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to afford 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline (400 mg, crude) as a red solid. m/z ES+[M+H] ⁺ 461.4.

Step 8. To a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline (380 mg, 824 μmol) in THF (5 mL) was added NaH (65.9 mg, 1.65 mmol, 60% purity) at 0°C, and the mixture was stirred at 0°C for 0.5 hours. SEM-Cl (206 mg, 1.24 mmol) was then added, and the mixture was stirred at 25°C for 1.5 hours. Upon 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]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (220 mg, 35%) as a yellow solid. m/z ES+[M+H] ⁺ 591.3.

Step 9. To a solution of 2-[[6-[5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (170 mg, 287 μmol) in dichloromethane (3 mL) was added TFA (462 mg, 4.05 mmol, 0.3 mL). The mixture was stirred at 25 °C for 0.5 hours. Upon 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]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50 mg, crude) as a red oil. m/z ES+[M+H] ⁺ 507.2.

Step 10. To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (45 mg, 88.7 μmol) in DMF (1 mL) was added K ₂ CO ₃ (36.8 mg, 266 μmol) and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (25.9 mg, 88.7 μmol). The mixture was stirred at 80° C. for 2 h. Upon 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 _Na2SO4 , filtered and concentrated under reduced pressure to give tert-butyl 4-[2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate (50 mg, crude) as a yellow oil. m/z ES+[M+H] ⁺ 718.3.

Step 11. A solution of tert-butyl 4-[2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate (45 mg, 62.6 μmol) in TFA (1 mL) was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline (50 mg, crude) as a red oil. m/z ES+[M+H] ⁺ 488.0.

Step 12. To a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline ( ₃₅ mg, 71.7 μmol) in THF (0.5 mL) and H 2 O (0.5 mL) was added NaHCO ₃ (18.1 mg, 215 μmol) and prop-2-enoyl chloride (9.74 mg, 108 μmol). The mixture was stirred at 0° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 15%-45%, 7 min) to give 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 (18.4 mg, 46%) as a yellow solid. m/z ES+[M+H] ⁺ 542.5; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (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),1.5 9-1.46(m,1H),1.16-0.99(m,2H).

Example 2. Synthesis of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(1,2,2-trimethyl-4-piperidinyl)methyl]pyrazol-4-yl]quinoxaline

Step 1. At 0°C, tBuOK (1.48 g, 13.2 mmol) was added portionwise to a solution of (methoxymethyl)triphenylphosphonium chloride (4.52 g, 13.2 mmol) in THF (15 mL). The mixture was stirred at 0°C for 1 hour, and then 2,2-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2 g, 8.8 mmol) in THF (15 mL) was added. The mixture was stirred at 30°C 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 , 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 tert-butyl 4-(methoxymethylene)-2,2-dimethyl-piperidine-1-carboxylate (1.7 g, 76%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.93 (s, 1H), 5.84 (s, 1H), 3.58 (s, 4H), 2.36-2.33 (m, 2H), 2.22 (t, J=6.0 Hz, 3H), 2.11 (s, 2H), 1.39 (s, 9H), 1.37 (s, 6H).

Step 2. At 0 ° C, HCl (1M, 7.99 mL) was added to a solution of 4- (methoxymethylene) -2,2- dimethyl - piperidine -1- carboxylic acid tert-butyl ester (1.7 g, 6.66 mmol) in acetonitrile (170 mL). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was quenched by saturated NaHCO ₃ solution (20 mL) 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 layer was washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain 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. _NaBH4 (276 mg, 7.29 mmol) was added to a solution of 4-formyl-2,2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 6.63 mmol) in ethanol (15 mL). The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was quenched with water (30 mL) at 0 ° C and extracted with dichloromethane (20 mL × 3). The combined organic layer was washed with brine (30 mL x 3) _, dried over _Na2SO4 , filtered and concentrated in vacuo to obtain 4-(hydroxymethyl)-2,2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (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) were dissolved in dichloromethane (5 mL) and cooled to 0° C., then PPh ₃ (647 mg, 2.47 mmol) was added. The mixture was stirred at 25° C. 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×3), dried over Na ₂ SO ₄ , 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 4-(bromomethyl)-2,2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (80 mg, 158 μmol) in DMF (1 mL) was added K ₂ CO ₃ (65.4 mg, 473 μmol), 4-(bromomethyl)-2,2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (72.47 mg, 237 μmol). The mixture was stirred at 100° C. 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 _Na2SO4 , filtered and concentrated in vacuo to give 4-[[4-[8-chloro- _7- [2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-2,2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, crude) as a yellow solid. m/zES ⁺ [M+H] ⁺ 732.3.

Step 6. A solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-2,2-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, 164 μmol) in TFA (1 mL) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to give 8-chloro-2-[1-[(2,2-dimethyl-4-piperidinyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (100 mg, crude) as a yellow oil. m/z ES ⁺ [M+H] ⁺ 502.0.

Step 7. To a solution of 8-chloro-2-[1-[(2,2-dimethyl-4-piperidinyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (90 mg, 146 μmol, TFA) in DMF (1 mL) was added formic acid (140 mg, 2.92 mmol) and paraformaldehyde (87.7 mg, 2.92 mmol). The mixture was stirred at 60° C. for 12 h. 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]; B%: 5%-35%, 10 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(1,2,2-trimethyl-4-piperidinyl)methyl]pyrazol-4-yl]quinoxaline (40.7 mg, 54%) as an off-white solid. m/z ES+[M+H] ⁺ 516.3; ¹ HNMR (400 MHz, DMSO-d ₆ )δ12.29(brs,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(brs,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,3 H),1.15(s,3H).

Example 3. Synthesis of 4-((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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.9 g, 36 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was diluted with H ₂ O (150 mL) and extracted with ethyl acetate (80 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)ethanone (7.2 g, 51%) as a white solid. 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 solution of tert-butyl 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (20 g, 51 mmol) and _2,7 -dibromoquinoxaline (18 g, 61 mmol) in dioxane (200 mL) and H 2 O (40 mL) was added KOAC (15 g, 0.15 mol) and Pd(dppf)Cl ₂ (3.7 g, 5.1 mmol). The mixture was stirred at 70° C. under N ₂ for 36 h. The reaction mixture was diluted with water H ₂ O (500 mL) and extracted with dichloromethane (300 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , 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 tert-butyl 4-((4-(7-bromoquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (27 g, 54%) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δppm9.05 (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 solution of tert-butyl 4-[[4-(7-bromoquinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (27 g, 58 mmol) in _dioxane (280 mL) and H 2 O (140 mL) was added Pd 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 purged with N ₂ for 3 times, and then it was stirred at 100° C. under N ₂ for 3 hours. The reaction mixture was diluted with water H ₂ O (500 mL) and extracted with dichloromethane (300 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , 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 a solution of tert-butyl 4-[[4-(7-hydroxyquinoxaline-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (10 g, 12 mmol) in acetonitrile (100 mL) was added N-chlorosuccinimide (1.5 g, 11 mmol) portionwise. The mixture was stirred at 80 °C for 12 hours. The solid was 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-hydroxyquinoxaline-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 a solution of tert-butyl 4-[[4-(8-chloro-7-hydroxy-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (4.7 g, 11 mmol) and 5-fluoro-2-nitro-aniline (2 g, 13 mmol) in DMF (50 mL) was added K ₂ CO ₃ (4.4 g, 32 mmol) and KI (0.17 g, 1.1 mmol). The mixture was stirred at 120° C. for 12 h. The reaction mixture was diluted with H ₂ O (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , 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 tert-butyl 4-((4-(7-(3-amino-4-nitrophenoxy)-8-chloroquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (3 g, 39%) as a yellow solid. m/z ES+[M+H] ⁺ 580.2.

Step 6. To a solution of _tert -butyl 4-[[4-[7-(3-amino-4-nitro-phenoxy)-8-chloro-quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (3 g, 4.1 mmol, 80% purity) in ethanol (40 mL) and H 2 O (20 mL) was added iron powder (1.2 g, 21 mmol) and NH ₄ Cl (2.2 g, 41 mmol). The mixture was stirred at 60° C. 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 dried over Na ₂ SO ₄ , 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 a solution of tert-butyl 4-[[4-[8-chloro-7-(3,4-diaminophenoxy)quinoxaline-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.6 g, 2.9 mmol) and 1,1,1-trimethoxyethane (1.7 g, 14 mmol, 1.8 mL) in methanol (30 mL) was added sulfamic acid (0.56 g, 5.7 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give tert-butyl 4-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (2.5 g, crude) as a yellow solid. m/z ES+[M+H] ⁺ 574.2.

Step 8. To a solution of tert-butyl 4-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.1 g, 1.9 mmol) in THF (15 mL) at 0°C was added NaH (0.15 g, 3.8 mmol, 60% purity) and the mixture was stirred at 0°C for 30 min. Then, SEM-Cl (0.48 g, 2.9 mmol, 0.51 mL) was added at 0°C. The mixture was stirred at 25°C for 1.5 hours. The reaction mixture was diluted with _H2O (100 mL) and extracted with ethyl acetate (50 mL x 3). _The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=100/1 to 20/1) to give tert-butyl 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-carboxylate (1 g, 1.3 mmol, 67%) as a yellow solid. m/z ES+[M+H] ⁺ 704.3.

Step 9. To a solution of tert-butyl 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.2 g, 1.7 mmol) in dichloromethane (15 mL) was added TFA (2.30 g, 20 mmol, 1.5 mL). The mixture was stirred at 25 ° C for 5 hours. The reaction mixture was diluted with NaHCO ₃ solution (50 mL) and extracted with dichloromethane (20 mL×3). _The combined organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure to give 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 (1.30 g, crude) as a brown solid. m/z ES+[M+H] ⁺ 604.2.

Step 10. To a solution of 2-[[6-[5-chloro-3-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (0.1 mg, 0.17 mmol) in DMF (2 mL) was added paraformaldehyde (99 mg, 3.3 mmol) and formic acid (0.16 g, 3.3 mmol). The mixture was stirred at 60 ° C for 12 hours. The reaction mixture was diluted with NaHCO ₃ solution (20 mL) and extracted with dichloromethane (10 mL×3). The combined organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure to give 8-chloro- ₇ -((2-methyl-1-((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) as a yellow oil. m/z ES+[M+H] ⁺ 618.3.

Step 11. To a solution of 2-[[ _6- [5-chloro-3-[1-[(1-methyl-4-piperidinyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (80 mg, 0.13 mmol) in H 2 O (4 mL) was added Hg(OAc) ₂ (0.1 g, 0.32 mmol) and 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid (91 mg, 0.31 mmol). The mixture was stirred at 100° C. for 16 h. The reaction mixture was diluted with NaHCO ₃ solution (20 mL) and extracted with dichloromethane (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)-1-methylpiperidin-2-one (12 mg, 19 μmol, 14%) as a yellow oil. m/z ES+[M+H] ⁺ 632.3.

Step 12. A solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)-benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-1-methyl-piperidin-2-one (12 mg, 19 μmol) in TFA (0.3 mL) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral condition column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 8%-38%, 10 min) to give 4-((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 (6 mg, 12 μmol, 62%) as an off-white solid. 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),1.8 0(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. A mixture of 7-bromo-2-chloro-quinoxaline (750 mg, 3.08 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine- ₁ -carboxylate (1.1 g, 2.93 mmol), KOAC (907 mg, 9.24 mmol), Pd(dppf) _Cl (225 mg, 308 μmol) in dioxane (10 mL) and H 2 O (2 mL) was degassed and purged with N ₂ for 3 times, then the mixture was stirred at 60° C. under N ₂ atmosphere for 12 hours. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL×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 tert-butyl 4-[4-(7-bromoquinoxalin-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (630 mg, 45%) as a white solid. m/z ES+[M+H] ⁺ 458.1.

Step 2. To a solution of tert-butyl 4-[4-(7-bromoquinoxalin-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (600 mg, 1.31 mmol) in dioxane (6 mL) and H ₂ O (2 mL) was added KOH (734 mg, 13.1 mmol), Pd ₂ (dba) ₃ (119 mg, 131 μmol) and t-BuXPhos (55.6 mg, 131 μmol). The mixture was stirred at 100 °C under nitrogen 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 tert-butyl 4-[4-(7-hydroxyquinoxalin-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (400 mg, 77%) as a white solid. 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,1 H), 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 a solution of tert-butyl 4-[4-(7-hydroxyquinoxaline-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (350 mg, 885 μmol) in acetonitrile (35 mL) was added N-chlorosuccinimide (118 mg, 885 μmol). The mixture was stirred at 80 ° C 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 tert-butyl 4-[4-(8-chloro-7-hydroxy-quinoxaline-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (350 mg, 92%) as a yellow solid. m/z ES+[M+H] ⁺ 430.3.

Step 4. To a solution of tert-butyl 4-[4-(8-chloro-7-hydroxy-quinoxalin-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (100 mg, 233 μmol), 5-fluoro-2-nitro-aniline (72.6 mg, 465 μmol) in DMF (1 mL) was added K ₂ CO ₃ (96.5 mg, 697 μmol). The mixture was stirred at 120° C. 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]) to afford tert-butyl 4-[4-[7-(3-amino-4-nitro-phenoxy)-8-chloro-quinoxalin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (50 mg, 38%) as a yellow solid. m/z ES+[M+H] ⁺ 566.5.

Step 5. To a solution of _tert -butyl 4-[4-[7-(3-amino-4-nitro-phenoxy)-8-chloro-quinoxalin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (30 mg, 53 μmol) in ethanol (5 mL) and H 2 O (5 mL) was added iron powder (14.8 mg, 265 μmol) and NH ₄ Cl (14.2 mg, 265 μmol). The mixture was stirred at 60° C. 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]) to afford tert-butyl 4-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (25 mg, 84%) as a yellow solid. m/z ES+[M+H] ⁺ 560.3.

Step 6. A solution of tert-butyl 4-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (25 mg, 44.6 μmol) in HCl/ethyl acetate (4M, 1.25 mL) was stirred at 25° C. for 10 min. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 2%-32%, 7 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-(4-piperidinyl)pyrazol-4-yl]quinoxaline (7.95 mg, 39%) as an off-white solid. 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 . 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 a solution of 2-[[6-[5-chloro-3-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50 mg, 82.75 μmol) and 2-iodopropane (17 mg, 99 μmol) in acetonitrile (1 mL) was added K ₂ CO ₃ (23 mg, 0.17 mmol). The mixture was stirred at 80° C. for 3 h. 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]imidazol-6-yl)oxy)quinoxaline (53 mg, crude) as a yellow solid. m/z ES+[M+H] ⁺ 646.4.

Step 2. A solution of 2-[[6-[5-chloro-3-[1-[(1-isopropyl-4-piperidinyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (53 mg, 82 μmol) in TFA (1 mL) was stirred at 25° C. 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*25mm*5um; mobile phase: [water ( _{10mM NH4HCO3} )-acetonitrile]; B%: 22%-52%, 10min) to give 8-chloro-2-(1-((1-isopropylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (15 mg, 32%, as formate salt) as a yellow solid. m/z ES+[M+H] ⁺ 516.2; ^1H NMR (400MHz, DMSO- _d6 ) 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. Synthesis of 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 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-(4,4,5,5-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° C. for 12 hours. Upon 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 tert-butyl 4-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (5 g, 40%) as a colorless oil. m/z ES+[M+H] ⁺ 406.5.

Step 2. A mixture of tert-butyl 4-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate ( 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 (902 mg, 1.23 mmol) in dioxane (50 mL) and H 2 O (10 mL) was degassed and purged with N ₂ for 3 times, then the mixture was stirred at 60° C. under N ₂ atmosphere for 3 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 2/1) to give tert-butyl 4-[[4-(7-bromoquinoxalin-2-yl)-3-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylate (3.1 g, 50%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.03 (d, J=18.4 Hz, 1H), 8.24-8.18 (m, 1H), 7.93-7.95 (m, 1H), 7.34-7.70 (m, 1H).

-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. A mixture of tert-butyl 4-[[4-(7-bromoquinoxalin-2-yl)-3-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylate (2.8 g, 5.76 mmol), _KOH (3.23 g, 57.5 mmol), t-BuXPhos (244 mg, 575 μmol) and _Pd2 (dba) ₃ (527 mg, 575 μmol) in dioxane (30 mL) and H2O (10 mL) was degassed and purged with _N2 for 3 times and then the mixture was stirred under _N2 atmosphere at 100°C for 2 h. 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 tert-butyl 4-[[4-(7-hydroxyquinoxalin-2-yl)-3-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.9 g, 72.3%) as a yellow solid. m/z ES+[M+H] ⁺ 424.1.

Step 4. To a solution of tert-butyl 4-[[4-(7-hydroxyquinoxaline-2-yl)-3-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.7 g, 4.01 mmol) in acetonitrile (20 mL) was added N-chlorosuccinimide (536 mg, 4.01 mmol). The mixture was stirred at 80 ° C 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 tert-butyl 4-[[4-(8-chloro-7-hydroxy-quinoxaline-2-yl)-3-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.1 g, 56%) as a yellow solid. 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 purified by SFC (column: Daicel ChiralPak IG (250*30mm, 10um; mobile phase: [0.1% ammonium hydroxide aqueous solution in methanol]; B%: 60%-60%, 5.9min; 60min) to give 4-[[4-(8-chloro-7-hydroxy-quinoxaline-2-yl)-3-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (450mg, 38%) as a yellow solid and 4-[[4-(8-chloro-7-hydroxy-quinoxaline-2-yl)-5-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (350mg, 29%) as a yellow solid.

Step 6. A mixture of tert-butyl 4-[[4-(8-chloro-7-hydroxy-quinoxalin-2-yl)-3-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylate (200 mg, 436 μmol), [2-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]boronic acid (200 mg, 655 μmol), Cu(OAc) ₂ (39.6 mg, 218 μmol), triethylamine (132 mg, 1.31 mmol) in dichloroethane (5 mL) was degassed and purged with _O2 for 3 times and then the mixture was stirred under _O2 atmosphere at 60°C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure to get 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)-benzoimidazol-5-yl]oxy-quinoxalin-2-yl]-3-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (60 mg, 16%) as a yellow oil. m/z ES+[M+H] ⁺ 539.3.

Step 7. A solution of tert-butyl 4-[[4-[8-chloro-7-[2-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]-3-methyl-pyrazol-1-yl]-methyl]piperidine-1-carboxylate (50 mg, 69.6 μmol) in TFA (1 mL) was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[3-methyl-1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (50 mg, crude) as a red oil. m/z ES+[M+H] ⁺ 488.1.

Step 8. To a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[3-methyl-1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (50 mg, 102.46 μmol) in DMF (1 mL) was added paraformaldehyde (61.5 mg, 2.05 mmol) and formic acid (98.4 mg, 2.05 mmol). The mixture was stirred at 60° C. for 12 hours. Upon completion, the solids were removed by filtration and the filtrate was concentrated. The residue was purified twice by preparative HPLC (column: Phenomenex Gemini-NXC18 75*30mm*3um; 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-[(1-methyl-4-piperidinyl)methyl]pyrazol-4-yl]quinoxaline (7.86 mg, 15%) as a brown solid. m/z ES+[M+H] ⁺ 502.5; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.50 (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. A mixture of tert-butyl 4-[[4-(8-chloro-7-hydroxy-quinoxalin-2-yl)-5-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylate (200 mg, 436 μmol), [2-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]boronic acid (200 mg, 655 μmol), Cu(OAc) ₂ (39.6 mg, 218 μmol), triethylamine (132 mg, 1.31 mmol) in dichloroethane (5 mL) was degassed and purged with _O2 for 3 times and then the mixture was stirred under _O2 atmosphere at 60°C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified twice by preparative TLC (silica gel, dichloromethane/methanol=10/1) to give tert-butyl 4-[[4-[8-chloro-7-[2-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]-5-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylate (50 mg, 13%) as a yellow oil. m/z ES+[M+H] ⁺ 507.2.

Step 10. A solution of 4-[[4-[8-chloro-7-[2-methyl-1-(2-trimethylsilyl-ethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]-5-methyl-pyrazol-1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (50 mg, 69.6 μmol) in TFA (1 mL) was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[5-methyl-1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (50 mg, crude) as a red oil. m/z ES+[M+H] ⁺ 488.1.

Step 11. To a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[5-methyl-1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (50 mg, 102.46 μmol) in DMF (1 mL) was added paraformaldehyde (61.5 mg, 2.05 mmol) and formic acid (98.4 mg, 2.05 mmol). The mixture was stirred at 60° C. for 12 hours. Upon completion, the solids were removed by filtration and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NXC18 75*30mm*3um; 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-[5-methyl-1-[(1-methyl-4-piperidinyl)methyl]pyrazol-4-yl]quinoxaline (18.2 mg, 35%) as a brown solid. m/z ES+[M+H] ⁺ 502.4; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.29 (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 ° C for 16 hours. After cooling to room temperature, the solid formed was separated by filtration, and the filter cake was washed with petroleum ether (50 mL) to obtain 7-bromo-8-fluoro-quinoxaline-2-ol (5 g, 94%) as a dark brown solid.

Step 2. A solution of 7-bromo-8-fluoro-quinoxaline-2-ol (5 g, 20.6 mmol) in POCl ₃ (15 mL) was stirred at 100 ° C for 1 hour. After completion, the mixture was concentrated under reduced pressure to obtain a residue. Then NaHCO ₃ aqueous solution (50 mL) was added, 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 obtain 7-bromo-2-chloro-8-fluoro-quinoxaline (4 g, 74%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 (s, 1H), 7.95-7.76 (m, 2H).

Step 3. A mixture of 7-bromo-2-chloro-8-fluoro-quinoxaline (4 g, 15.3 mmol), tert-butyl 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol- ₁ -yl]methyl]piperidine-1-carboxylate (6.58 g, 16.8 mmol), Pd(dppf) _Cl (560 mg, 764 μmol), KOAC (4.5 g, 45.89 mmol) in dioxane (40 mL) and H 2 O (20 mL) was degassed and purged with N ₂ for 3 times, then the mixture was stirred at 60° C. under N ₂ atmosphere for 16 hours. After completion, the mixture was poured into water (10 mL) and extracted with ethyl acetate (50 mL×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 tert-butyl 4-[[4-(7-bromo-8-fluoro-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (5 g, 66%) as a dark brown solid. m/z ES+[M+H] ⁺ 436.3.

Step 4. To a solution of tert-butyl 4-[[4-(7-bromo-8-fluoro-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate ( ₃ g, 6.12 mmol) in dioxane (50 mL), H 2 O (25 mL) was added Pd ₂ (dba) ₃ (280 mg, 305 μmol), KOH (3.43 g, 61.18 mmol) and t-BuXPhos (130 mg, 305.89 μmol). The mixture was stirred at 100 °C under nitrogen 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 tert-butyl 4-[[4-(8-fluoro-7-hydroxy-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.5 g, 57%) as a yellow solid. Then tert-butyl 4-[[4-(8-fluoro-7-hydroxy-quinoxaline-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.4 g) was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 um); mobile phase: [0.1% aqueous ammonium hydroxide solution in methanol]; B%: 55%-55%, 5 min; 40 min) to give tert-butyl 4-[[4-(8-fluoro-7-hydroxy-quinoxaline-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.1 g, 78%) as a yellow solid and tert-butyl 4-[[4-(5-fluoro-6-hydroxy-quinoxaline-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (300 mg, 21%) as a yellow solid. 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. Tert-butyl 4-[[4-(8-fluoro-7-hydroxy-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (300 mg, 701 μmol), [2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]boronic acid (429 mg, 1.4 mmol), Cu(OAc) ₂ (63.7 mg, 351 μmol), A mixture of MS (10 mg) and Cs ₂ CO ₃ (457 mg, 1.4 mmol) was stirred at 60 ° C under an O ₂ (15 psi) atmosphere for 16 hours. After completion, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, dichloromethane / methanol = 50 / 1) to give 4- [ [4- [8-fluoro-7- [2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl] oxy-quinoxalin-2-yl] pyrazol-1-yl] methyl] piperidine-1-carboxylic acid tert-butyl ester (140 mg, 29%) as a yellow solid. m / z ES + [M + H] ⁺ 688.6.

Step 6. A solution of 4-[[4-[8-fluoro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-piperidine-1-carboxylic acid tert-butyl ester (70 mg, 102 μmol) in TFA (1 mL) was stirred at 25° C. for 1 hour. Upon completion, the mixture was concentrated under reduced pressure to give 8-fluoro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (45 mg, crude) as a yellow oil. m/z ES+[M+H] ⁺ 458.4.

Step 7. To a solution of 8-fluoro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (45 mg, 98.3 μmol) in DMF (1 mL) was added paraformaldehyde (29.5 mg, 983 μmol) and formic acid (47.2 mg, 983 μmol). The mixture was stirred at 60° C. for 16 hours. Upon completion, the solid was removed by filtration and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 2%-32%, 7 min) to give 8-fluoro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(1-methyl-4-piperidinyl)-methyl]pyrazol-4-yl]quinoxaline (22.1 mg, 47%) as a brown solid. m/z ES+[M+H] ⁺ 472.5; ¹ H NMR (400 MHz, 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. A solution of tert-butyl 4-[[4-(8-chloro-7-hydroxy-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (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 toluene (10 mL) was stirred at 80° C. under N ₂ 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 tert-butyl 4-[[4-(7-hydroxy-8-methyl-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (250 mg, 37%) as a yellow solid. m/z ES+[M+H] ⁺ 424.4; ¹ H NMR (400MHz, CDCl ₃ ) δppm8.89 (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 a solution of tert-butyl 4-[[4-(7-hydroxy-8-methyl-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (240 mg, 0.28 mmol), [2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]boronic acid (350 mg, 0.57 mmol) in dichloroethane (2 mL) was added Cu(OAc) ₂ (102 mg, 0.28 mmol), MS (400 mg) and Cs ₂ CO ₃ (370 mg, 0.57 mmol). The mixture was stirred at 60 ° C under O ₂ (15 psi) 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] oxy-quinoxaline-2-yl] pyrazol-1-yl] methyl] piperidine-1-carboxylic acid tert-butyl ester (44 mg, 11%) as a yellow solid. m / z ES + [M + H] ⁺ 684.3.

Step 3. A solution of 4-[[4-[8-methyl-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)-benzoimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (44 mg, 64 μmol) in TFA (0.5 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 8-methyl-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]-2-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (35 mg, crude) as a yellow oil. m/z ES+[M+H] ⁺ 454.3.

Step 4. To a solution of 8-methyl-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (35 mg, 77 μmol) in DMF (0.5 mL) was added paraformaldehyde (46 mg, 1.5 mmol) and formic acid (74 mg, 1.5 mmol). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (neutral conditions; Waters Xbridge 150×25 mm×5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 24%-54%, 10 min) to give 8-methyl-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(1-methyl-4-piperidinyl)methyl]pyrazol-4-yl]quinoxaline (8.54 mg, 19%) as a white solid. m/z ES+[M+H] ⁺ 468.5; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 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,1 H),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. To a solution of 4-bromopyridin-2-amine (7 g, 40 mmol) and 1-bromo-2,2-dimethoxy-propane (36 g, 198.25 mmol, 26.68 mL) in H ₂ O (0.14 L), p-toluenesulfonic acid (1.32 g, 7.69 mmol) was added. The mixture was stirred at 105 ° C for 18 hours. The reaction mixture was adjusted to pH = 9 with saturated NaHCO ₃ aqueous solution and extracted with ethyl acetate (100 mL × 2). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 to 2/1) to obtain 7-bromo-2-methylimidazo [1,2-a] pyridine (2.9 g, 13.7 mmol, 34%) as a yellow solid. m/z ES+[M+H] ⁺ 213.0.

Step 2. To a solution of 7-bromo-2-methyl-imidazo[1,2-a]pyridine (1 g, 4.74 mmol) in dioxane (40 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (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 was stirred at 110° C. under N ₂ for 5 hours. The reaction mixture was diluted with H ₂ O (150 mL) and extracted with dichloromethane (100 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , 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]) to give (2-methylimidazo[1,2-a]pyridin-7-yl)boronic acid (480 mg, 2.73 mmol, 58%) as a white solid. m/z ES+[M+H] ⁺ 177.0.

Step 3. To a solution of tert-butyl 4-[[4-(8-chloro-7-hydroxy-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (50 mg, 0.11 mmol) and (2-methylimidazo[1,2-a]pyridin-7-yl)boronic acid (39.64 mg, 0.23 mmol) in dichloroethane (1 mL) was added Cu(OAc) ₂ (24.6 mg, 0.14 mmol), MS (100 mg) and Cs ₂ CO ₃ (73.4 mg, 0.23 mmol). The mixture was stirred at 60 ° C under 15 psi for 2 hours under O _2. 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]pyridin-7-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (12 mg, 17.4 μmol, 15%) as a yellow oil. m/z ES+[M+H] ⁺ 574.2.

Step 4. To a solution of tert-butyl 4-[[4-[8-chloro-7-(2-methylimidazo[1,2-a]pyridin-7-yl)oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (10 mg, 14.5 μmol) in dichloromethane (0.3 mL) was added TFA (154 mg, 1.35 mmol, 0.1 mL). The mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give the desired 8-chloro-7-((2-methylimidazo[1,2-a]pyridin-7-yl)oxy)-2-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)quinoxaline (10 mg, crude, as TFA salt) as a yellow oil. m/z ES+[M+H] ⁺ 474.2.

Step 5. To a solution of 8-chloro-7-(2-methylimidazo[1,2-a]pyridin-7-yl)oxy-2-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (10 mg, 17 μmol, TFA salt) in DMF (0.5 mL) was added aqueous paraformaldehyde solution (13.8 mg, 170 μmol, 37% purity). The mixture was stirred at 25° C. for 0.5 h. NaBH(OAc) ₃ (18 mg, 85 μmol) was then added. The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-acetonitrile]; B%: 18%-48%, 10 min) to give 8-chloro-7-((2-methylimidazo[1,2-a]pyridin-7-yl)oxy)-2-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)quinoxaline (1.41 mg, 2.68 μmol, 16%) as a yellow solid. 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),2.2 8(s,3H),2.12(s,3H),1.87-1.73(m,3H),1.49(d,J＝11.2Hz,2H),1.29-1.2 3(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. At 0 ° C, NaOH (3M, 1.76 mL) was added dropwise 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), and the mixture was stirred at 25 ° C for 16 hours. 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 obtain tert-butyl 4-[(2E)-2-hydroxyiminoethyl]piperidine-1-carboxylate (1 g, 94%) as a colorless oil. 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. Add N-chlorosuccinimide (551mg, 4.13mmol) and pyridine (32.6mg, 412μmol) to the solution of 4-[(2E)-2-hydroxyiminoethyl]piperidine-1-carboxylic acid tert-butyl ester (1g, 4.13mmol) in dichloromethane (10mL). The mixture was stirred at 25°C for 16 hours. After completion, the mixture was poured into water (50mL) and extracted with ethyl acetate (30mL 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]piperidine-1-carboxylic acid tert-butyl ester (1.4g, crude product) as a white solid was obtained. ¹ HNMR (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 ° C 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 obtain 4-[[5-(7-bromoquinoxaline-2-yl)isoxazol-3-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (600 mg, 73%) as a white solid.

Step 4. To a solution of tert- _butyl 4-[[5-(7-bromoquinoxalin-2-yl)isoxazol-3-yl]methyl]piperidine-1-carboxylate (650 mg, 1.37 mmol) in dioxane (10 mL) and H 2 O (2 mL) was added KOH (770 mg, 13.7 mmol), t-BuXPhos (58.3 mg, 137 μmol) and Pd ₂ (dba) ₃ (125 mg, 137 μmol). The mixture was stirred at 100 °C under nitrogen 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 tert-butyl 4-[[5-(7-hydroxyquinoxalin-2-yl)isoxazol-3-yl]methyl]piperidine-1-carboxylate (270 mg, 47%) as a yellow solid. 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), 2.11-1.8 9(m,1H),1.78(d,J＝12.4Hz,2H),1.47(s,9H),1.33-1.15(m,2H).

Step 5. A solution of tert-butyl 4-[[5-(7-hydroxyquinoxaline-2-yl)isoxazol-3-yl]methyl]piperidine-1-carboxylate (220 mg, 535 μmol), N-chlorosuccinimide (85.8 mg, 643 μmol) in acetonitrile (1 mL) was stirred at 80 ° C 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 tert-butyl 4-[[5-(8-chloro-7-hydroxy-quinoxaline-2-yl)isoxazol-3-yl]methyl]piperidine-1-carboxylate (200 mg, 84%) as a yellow solid. 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), 2.11-1.8 9(m,1H),1.78(d,J＝12.4Hz,2H),1.47(s,9H),1.33-1.15(m,2H).

Step 6. Tert-butyl 4-[[5-(8-chloro-7-hydroxy-quinoxalin-2-yl)isoxazol-3-yl]methyl]piperidine-1-carboxylate (180 mg, 404 μmol), [2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]boronic acid (247 mg, 809 μmol), Cu(OAc) ₂ (36.7 mg, 202 μmol), MS (5mg, 405μmol) and a mixture of triethylamine (81.8mg, 809μmol) were stirred at 60°C for 16 hours under an _O atmosphere (15psi). 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]) to obtain 4-[[5-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]isoxazol-3-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (30mg, 42.5μmol, 11%) as a yellow oil. m/z ES+[M+H] ⁺ 705.2.

Step 7. A solution of 4-[[5-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]isoxazol-3-yl]methyl]-piperidine-1-carboxylic acid tert-butyl ester (25 mg, 35.4 μmol) in TFA (1 mL) was stirred at 25° C. for 10 min. Upon completion, the mixture was concentrated under reduced pressure to remove the solvent and 5-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]-3-(4-piperidinylmethyl)isoxazole (16 mg, crude) was obtained as a yellow oil. m/z ES+[M+H] ⁺ 475.1.

Step 8. To a solution of 5-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]-3-(4-piperidinylmethyl)isoxazole (16 mg, 33.7 μmol) in DMF (1 mL) was added formic acid (16.2 mg, 336 μmol), paraformaldehyde (10.1 mg, 336 μmol). The mixture was stirred at 60° C. for 16 hours. Upon 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-NXC18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 5%-35%, 7 min) to give 5-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]-3-[(1-methyl-4-piperidinyl)methyl]isoxazole (8.73 mg, 53%) as a yellow solid. 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-(tetrahydrofuran-3-ylmethyl)pyrazol-4-yl]quinoxaline

Step 1. Methanesulfonyl chloride (336 mg, 2.94 mmol) and triethylamine (594 mg, 5.87 mmol) were added to a solution of tetrahydrofuran-3-ylmethanol (200 mg, 1.96 mmol) in dichloromethane (3 mL). The mixture was stirred at 0 ° C for 1 hour. After completion, the reaction mixture was diluted with NaHCO ₃ solution (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tetrahydrofuran-3-ylmethyl methanesulfonate (400 mg, thick) 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50 mg, 98.6 μmol) in DMF (1 mL) was added K ₂ CO ₃ (40.8 mg, 295 μmol) and tetrahydrofuran-3-ylmethyl methanesulfonate (30 mg, 166 μmol). The mixture was stirred at 80° C. for 12 h. Upon 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]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50 mg, crude) as a white solid. m/z ES+[M+H] ⁺ 591.1.

Step 3. To a solution of 2-[[6-[5-chloro-3-[1-(tetrahydrofuran-3-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50 mg, 84.5 μmol) in TFA (0.5 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 15%-45%, 7 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-(tetrahydrofuran-3-ylmethyl)pyrazol-4-yl]quinoxaline (15.2 mg, 39%) as a yellow solid. m/z ES+[M+H] ⁺ 461.1; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.99 (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. 4-nitrophenyl 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-carboxylate

Under nitrogen, triethylamine (180 mg, 1.78 mmol) was added in one portion to a mixture of 2-[[6-[3-[1-(azetidin-3-yl)pyrazol-4-yl]-5-chloro-quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 889 umol) and (4-nitrophenyl) chloroformate (179 mg, 889 umol) in dichloromethane (10 mL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4-nitrophenyl 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-carboxylate (0.6 g, 578 umol, 65%) as a yellow solid. m/z ES+[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

A mixture of azetidine (118 mg, 2.06 mmol) and 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-carboxylic acid (4-nitrophenyl) ester (300 mg, 413 umol) in dichloromethane (5 mL) was stirred at 25° C. 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]methanone (70 mg, 86.8 umol, 21%) as a yellow solid. 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

A solution of azetidin-1-yl-[3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]methanone (70.0 mg, 108 umol) in trifluoroacetic acid (0.5 mL) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 11%-41%, 10min) to give azetidin-1-yl-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]methanone (16.8mg, 32.7umol, 30%) as an off-white solid. NMR (400MHz, CD3OD) δ9.18(s,1H),8.65(s,1H),8.41(s,1H),7.98(d,J＝9.2Hz,1H),7.74(d,J＝8.8Hz,1H),7.47(d,J＝9.2Hz,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. Synthesis of 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

Step 1. tert-Butyl 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

To the solution of 7- oxo -3- oxa -9- azabicyclo [3.3.1] nonane -9- carboxylic acid tert-butyl ester (450mg, 1.87mmol) in methanol (5mL) sodium borohydride (141mg, 3.73mmol) is added portionwise. The mixture is stirred at 0°C for 2 hours. The reaction mixture is quenched with saturated ammonium chloride (10mL) at 0°C, then diluted with water (20mL) and extracted with ethyl acetate (20mL x 3). The combined organic layer is washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 7- hydroxy -3- oxa -9- azabicyclo [3.3.1] nonane -9- carboxylic acid tert-butyl ester (400mg, 1.65mmol, 88%) as a white solid. 1H NMR (400MHz, CDCl3) δ = 5.59-5.43 (m, 1H), 4.15 (d, J = 2.4Hz, 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. tert-Butyl 7-methylsulfonyloxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate

At 0 ° C, triethylamine (83.1 mg, 822 umol) was added to a solution of 7-hydroxy-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl esters (100 mg, 411 umol) in dichloromethane (2 mL) at 0 ° C. Methanesulfonyl chloride (70.6 mg, 616 umol) was then added. The mixture was stirred at 0 ° C for 2 hours. The reaction mixture was quenched with water (10 mL) at 0 ° C, and then extracted with dichloromethane (20 mL x 3). The combined organic layer was 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 obtain 7-methylsulfonyloxy-3-oxa-9-azabicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl esters (60.0 mg, 187 umol, 45%) as a white solid. 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (47.3 mg, 93.3 umol) and tert-butyl 7-methylsulfonyloxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (36.0 mg, 112 umol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (60.8 mg, 186 umol) and 4-pyrrolidin-1-ylpyridine (13.8 mg, 93.3 umol). The mixture was stirred at 80° C. for 12 hours. The mixture was 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]; (B%: 46%-79%, 11 min) to give 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 (28.0 mg, 32.8 umol, 40%) as a yellow solid. m/z ES+[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

A solution of 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 (20.0 mg, 27.3 umol) in trifluoroacetic acid (1 mL) was stirred at 25°C for 0.5 hours. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 0%-26%, 10min) to give 7-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane (13.4 mg, 26.7 umol, 85%, formate) as an off-white solid. ¹ H NMR (400 MHz, 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 a solution of 2-[[6-[5-chloro-3-[1-(4-piperidinyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (170 mg, 288 umol) in dichloromethane (1.5 mL) was added chloroformic acid (4-nitrophenyl) ester (116 mg, 576 umol) and triethylamine (87.4 mg, 864 umol). The mixture was stirred at 25 ° C 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-nitrophenyl 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-carboxylate (190 mg, 242 umol, 84%) as a white solid. m/z ES+[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 a solution of 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 (170 mg, 225 umol) in tetrahydrofuran (1.5 mL) was added triethylamine (68.3 mg, 675 umol) and azetidine-3-ol (74.0 mg, 675 umol, HCl). The mixture was stirred at 60 ° C 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(3-hydroxyazetidin-1-yl)methanone (140 mg, 203 umol, 90%) as a yellow solid. m/z ES+[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

A solution of (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 (70.0 mg, 102 umol) in trifluoroacetic acid (0.5 mL) was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 9%-39%, 10min) to give (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 (24.8 mg, 44.2 umol, 44%) as a white solid. ¹ H NMR (400 MHz, 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,1 H),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 a solution of 2-[[6-[3-[1-(azetidin-3-yl)pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (130 mg, 230 umol) and 6-bromo-N,N-dimethyl-pyridin-2-amine (51.0 mg, 250 umol) in dioxane (3 mL) was added tris(dibenzylideneacetone)dipalladium (21.0 mg, 23.0 umol), (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane (13.0 mg, 23.0 umol) and cesium carbonate (151 mg, 460 umol). The mixture was stirred at 80° C. under nitrogen for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was 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] oxy-quinoxaline-2-yl] pyrazol-1-yl] azetidine-1-yl] -N, N- dimethyl -pyridine -2-amine (50.0 mg, 73.4 umol, 28%) as a white solid. m / z ES + [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

A solution of 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 (40.0 mg, 58.0 umol) in trifluoroacetic acid (0.5 mL) was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; (B%: 44%-74%, 10 min) to give 6-[3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]-N,N-dimethyl-pyridin-2-amine (2.68 mg, 4.86 umol, 7.9%) as a white solid. ¹ H NMR (400 MHz, 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-pyridyl)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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-bromopyridine (40.0 mg, 250 umol) and 2-[[6-[3-[1-(azetidin-3-yl)pyrazol-4-yl]-5-chloro-quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (130 mg, 230 umol) in dioxane (3 mL), tris(dibenzylideneacetone)dipalladium (21.0 mg, 23.0 umol), (5-diphenylphosphane-9,9-dimethylxanthen-4-yl)-diphenylphosphane (13.0 mg, 23.0 umol) and cesium carbonate (150 mg, 460 umol) were added. The mixture was stirred at 80 ° C for 12 hours under nitrogen. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 ml × 3). The combined organic layers were washed with brine (25 ml x 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-pyridyl)azetidin-3-yl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (70.0 mg, 110 umol, 34%) as a white solid. m/z ES+[M+H] ⁺ 639.3.

Step 2. 8-Chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[1-(2-pyridyl)azetidin-3-yl]pyrazol-4-yl]quinoxaline

A solution of 2-[[6-[5-chloro-3-[1-[1-(2-pyridinyl)azetidin-3-yl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (60.0 mg, 94.0 umol) in trifluoroacetic acid (0.6 mL) was stirred at 25 °C for 0.5 h. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 10 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[1-(2-pyridinyl)azetidin-3-yl]pyrazol-4-yl]quinoxaline (24.3 mg, 47.8 umol, 50%) as a white solid. ¹ H NMR (400 MHz, 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),2.5 7(s,3H)；m/z ES+[M+H] ⁺ 509.0.

Example 18. Synthesis of 5-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)-1,2-thiazinane 1,1-dioxide

Step 1. tert-Butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2-thiazinane-2-carboxylate 1,1-dioxide

At 25 ° C, to 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2-thiazinane 1,1-dioxide (300 mg, 743umol) and 4-dimethylaminopyridine (181 mg, 1.49mmol) in dichloromethane (10mL) was added dropwise di-tert-butyl dicarbonate (324mg, 1.49mmol). The mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2-thiazinane-2-carboxylic acid tert-butyl ester 1,1-dioxide (330mg, 655umol, 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. tert-Butyl 5-(hydroxymethyl)-1,2-thiazinane-2-carboxylate 1,1-dioxide

A solution of 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2-thiazinane-2-carboxylic acid tert-butyl ester 1,1-dioxide (270 mg, 536 umol) and tetrabutylammonium fluoride (1M in THF, 0.8 mL) in tetrahydrofuran (10 mL) was stirred at 25 ° C 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 obtain 5-(hydroxymethyl)-1,2-thiazinane-2-carboxylic acid tert-butyl ester 1,1-dioxide (150 mg, crude product) as a colorless oil.

Step 3. tert-Butyl 5-((p-toluenesulfonyloxy)methyl)-1,2-thiazinane-2-carboxylate 1,1-dioxide

4-Methylbenzenesulfonyl chloride (161 mg, 848 umol) and triethylamine (171 mg, 1.70 mmol) were added to a solution of 5-(hydroxymethyl)-1,2-thiazinane-2-carboxylic acid tert-butyl ester 1,1-dioxide (150 mg, 565 umol) in dichloromethane (5 mL). The mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to obtain 5-((p-toluenesulfonyloxy)methyl)-1,2-thiazinane-2-carboxylic acid tert-butyl ester 1,1-dioxide (140 mg, 333 umol, 59%) as a colorless oil. 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,1 H), 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. 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-thiazinane-2-carboxylate 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), tert-butyl 5-((p-toluenesulfonyloxy)methyl)-1,2-thiazinane-2-carboxylate 1,1-dioxide (70.0 mg, 166 umol), cesium carbonate (134 mg, 414 umol) in N,N-dimethylformamide (1 mL) was stirred at 80° C. for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed by 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-thiazinane-2-carboxylate 1,1-dioxide (70.0 mg, 92.0 umol, 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-thiazinane 1,1-dioxide

A solution of 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-thiazinane-2-carboxylate 1,1-dioxide (70 mg, 92.9 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 10 min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 22%-52%, 8min) to give 5-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)-1,2-thiazinane 1,1-dioxide (7.5mg, 14.2umol, 15%) as a white solid. ^1H 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＝2.4,8.4 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-pyridinyl)-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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-[1-(4-piperidinyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 254 umol) and 2-bromopyridine (40.2 mg, 254 umol) in dioxane (1.5 mL), methanesulfonic acid (2-dicyclohexylphosphino-2,6-di-isopropoxy-1,1-biphenyl) (2-amino-1,1-biphenyl-2-yl) palladium (II) (21.3 mg, 25.4 umol) and cesium carbonate (166 mg, 508 umol) were added. The mixture was degassed and purged with nitrogen 3 times, and then stirred at 80° C. 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-pyridinyl)-4-piperidinyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 150 umol, 59%) as a yellow oil. m/z ES+[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

A solution of 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 (65.0 mg, 97.4 umol) in trifluoroacetic acid (0.5 mL) was stirred for 1 hour at 25° C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 10min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[1-(2-pyridinyl)-4-piperidinyl]pyrazol-4-yl]quinoxaline (27.0 mg, 50.3 umol, 52%) as an off-white solid. ¹ H NMR (400 MHz, 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＝9.2 Hz,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 a solution of 2-[[6-[3-[1-(azetidin-3-yl)pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (130 mg, 231 umol) and 3-bromo-5-fluoro-pyridine (44.8 mg, 254 umol) in dioxane (2 mL), tris(dibenzylideneacetone)dipalladium (21.2 mg, 23.1 umol), (5-diphenylphosphane-9,9-dimethylxanthen-4-yl)-diphenylphosphane (13.4 mg, 23.1 umol) and cesium carbonate (151 mg, 463 umol) were added. The mixture was degassed and purged with a nitrogen atmosphere 3 times, and then stirred at 80° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was 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) azetidine -3-yl) -1H- pyrazole-4-yl) -7- ((2-methyl -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H- benzo [d] imidazole -6-yl) oxy) quinoxaline (30.0 mg, 42.5 umol, 18%) as a yellow oil. m / z ES + [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

A solution of 2-[[6-[5-chloro-3-[1-[1-(5-fluoro-3-pyridyl)azetidin-3-yl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (30.0 mg, 38.0 umol) in trifluoroacetic acid (0.5 mL) was stirred at 25° C. 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 C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 11%-41%, 10min) to give 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 (24.5mg, 46.2umol, 99%) as an off-white solid. ^1H 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-[1-(4-piperidinyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 339 umol) and 3-bromo-5-fluoro-pyridine (59.6 mg, 339 umol) in dioxane (2 mL), 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) were added. The mixture was degassed and purged with nitrogen 3 times, and then stirred at 80° C. for 16 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 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-pyridyl)-4-piperidyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (120 mg, 175 umol, 48%) as a yellow solid. m/z ES+[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

A solution of 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 (60.0 mg, 87.6 umol) in trifluoroacetic acid (0.5 mL) was stirred for 1 hour at 25° C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 7 min) to give 8-chloro-2-[1-[1-(5-fluoro-3-pyridinyl)-4-piperidinyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (24.2 mg, 40.1 umol, 39%) as an off-white solid. ¹ H NMR (400 MHz, 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),2.3 3-2.22(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 a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]ethyl methanesulfonate (200 mg, 318 umol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added triethylamine (96.5 mg, 954 umol) and azetidine-3-ol (69.7 mg, 636 umol, HCl). The mixture was stirred at 80 ° C 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)ethyl)azetidin-3-ol (100 mg, 124 umol, 39%) as a yellow solid. m/z ES+[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

A solution of 1-[2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl]azetidin-3-ol (80.0 mg, 132 umol) in trifluoroacetic acid (0.5 mL) was stirred for 0.5 hours at 20° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by SFC (column: Daicel Chiralcel OD (250 mm*30 mm*10 um); mobile phase: [0.1% ammonium hydroxide/methanol]; (B%: 45%-45%, 4.5 min, total run 50 min) and preparative HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (ammonium bicarbonate-acetonitrile]; (B%: 21%-51%, 10 min) to give 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 (6.6 mg, 13.4 umol, 10%) as a yellow solid. ¹ H NMR (400 MHz, 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＝2.0,8.8 Hz,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-fluorobuta-1,3-dienyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline

Step 1. (3,3-Difluorocyclobutyl) methanesulfonate

At 0 ° C, triethylamine (102 mg, 1.02 mmol) and methanesulfonyl chloride (116 mg, 1.02 mmol) were added to a solution of 3,3-difluorocyclobutanol (100 mg, 925 umol) in dichloromethane (2 mL). The mixture was stirred at 0 ° C for 0.5 hours. At 0 ° C, the reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (3,3-difluorocyclobutyl) methanesulfonate (172 mg, crude product) as a brown oil.

Step 2. 2-[[6-[5-chloro-3-[1-[(1E)-3-fluorobuta-1,3-dienyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 295 umol) in N,N-dimethylformamide (1.5 mL) was added cesium carbonate (192 mg, 591 umol), potassium iodide (9.82 mg, 59.1 umol) and (3,3-difluorocyclobutyl) methanesulfonate (82.6 mg, 443 umol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid) -acetonitrile ]; (B%: 46%-76%, 10min) to give 2-[[6-[5-chloro-3-[1-[(1E)-3-fluorobuta-1,3-dienyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (120mg, 208umol, 70%) as a white solid. 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] ⁺ 5 77.3.

Step 3. 8-Chloro-2-[1-[(1E)-3-fluorobuta-1,3-dienyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline

To a solution of 2-[[6-[5-chloro-3-[1-[(1E)-3-fluorobut-1,3-dienyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (90.0 mg, 155 umol) in tetrahydrofuran (0.5 mL) was added tetrabutylammonium fluoride (1 M in THF, 1.56 mL). The mixture was stirred at 80° C. 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*70*10um; mobile phase: [heptane-ethanol (0.1% ammonium hydroxide)]; (B%: 30%-70%, 15 min) and further purified by preparative HPLC (column: Shim-pack C18 150*25*10um; mobile phase: [water (0.225% formic acid) -acetonitrile ]; (B%: 15%-45%, 10 min) to give 8-chloro-2-[1-[(1E)-3-fluorobut-1,3-dienyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (26.1 mg, 58.5 umol, 36%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 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,1 H),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

4-methylbenzenesulfonyl chloride (102mg, 535umol), triethylamine (72.2mg, 714umol) and 4-dimethylaminopyridine (4.36mg, 35.7umol) were added to a solution of 3-(trifluoromethyl)cyclobutanol (50mg, 357umol) in dichloromethane (3mL). The mixture was stirred at 20°C 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 obtain 3-(trifluoromethyl)cyclobutyl 4-methylbenzenesulfonate (50.0mg, 170umol, 48%) as a yellow oil. 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (70.0 mg, 138 umol) in N,N-dimethylformamide (1 mL) was added cesium carbonate (135 mg, 414 umol) and [3-(trifluoromethyl)cyclobutyl]4-methylbenzenesulfonate (40.6 mg, 138 umol). The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was 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 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 (80.0 mg, crude) as a yellow oil. m/z ES ⁺ 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

A solution of 2-[[6-[5-chloro-3-[1-[3-(trifluoromethyl)cyclobutyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (80 mg, 127 umol) in trifluoroacetic acid (0.3 mL) was stirred for 0.5 hours at 20° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*15um; mobile phase: [water (0.2% formic acid)-acetonitrile]; (B%: 22%-52%, 10min) to give 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxaline (51.8mg, 104umol, 82%) as a white solid. ^1H 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-((1s,3s)-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-((1r,3r)-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 a solution of 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (150 mg, 337 umol) and 3-methoxyazetidine hydrochloride (125 mg, 1.01 mmol) in methanol (2 mL), diisopropylethylamine (131 mg, 1.01 mmol) and propan-2-ol titanium (IV) (192 mg, 674 umol) were added. The mixture was stirred at 60 ° C for 2 hours. Sodium cyanoborohydride (21 mg, 337 umol) was then added, and the reaction mixture was stirred at 25 ° C 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 layer was 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 C18 150×25 mm×10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10 min) to give 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 (60.0 mg, 112 umol, 33%) as a white solid m/z ES+[M+H] ⁺ 516.1.

Step 2. 8-Chloro-2-(1-((1s,3s)-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-((1r,3r)-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-benzoimidazol-5-yl)oxy]quinoxaline (60.0 mg, 116 umol) was purified by SFC (basic conditions, column: Daicel Chiralpak IE (50×250 mm, 10 um); mobile phase: [hexane-ethanol (0.1% ammonium hydroxide]); (B%: 80%-80%, 30, 120 min) to give 8-chloro-2-(1-((1s, 3s)-3-(3-methoxyazetidin-1-yl)cyclobutyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazole) as an off-white solid. The mixture was stirred at 4 ℃ for 2 h. In the mixture, 8-chloro-2-(1-((1r,3r)-3-(3-methoxyazetidin-1-yl)cyclobutyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (11.3 mg, 18.4 umol, 16%) and 8-chloro-2-(1-((1r,3r)-3-(3-methoxyazetidin-1-yl)cyclobutyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (6.0 mg, 11.3 umol, 9.8%) as a white solid.

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-((1r,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-((1s,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

Step 1. (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 a solution of 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (200 mg, 450 umol) and (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (180 mg, 1.35 mmol) in methanol (4 mL) was added diisopropylethylamine (174 mg, 1.35 mmol, 235 uL) and propan-2-ol titanium (IV) (256 mg, 900 umol). The mixture was stirred at 60 ° C for 2 hours. Then sodium cyanoborohydride (28 mg, 450 umol) was added, and the reaction mixture was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex LunaC18 150 x 25 mm x 10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10 min) to give (1S, 4S)-5-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]cyclobutyl]-2-oxa-5-azabicyclo[2.2.1]heptane (38.0 mg, 71.3 umol, 16%) as a colorless oil. m/z ES+[M+H] ⁺ 528.1.

Step 2. (1S,4S)-5-((1r,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-((1s,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 purified by SFC (basic conditions, column: Daicel Chiralpak IG (250 mm × 50 mm, 10 um); mobile phase: [hexane-ethanol (0.1% ammonium hydroxide)]; (B%: 80%-80%, 12 min) separation to obtain (1S, 4S)-5-((1r, 3S)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)cyclobutyl)-2-oxa-5-nitropropene as a white solid. Heterobicyclo[2.2.1]heptane (36.4 mg, 66.9 umol, 65%) and (1S,4S)-5-((1s,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, 14.6 umol, 14%) as white solids.

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 = 9.2 Hz,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＝9.2 Hz,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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

At 0°C, to a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (20.0 mg, 34.7 umol) in dichloromethane (0.5 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (76.9 mg, 347 umol). The mixture was stirred at 25°C for 1.5 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) at 0°C 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*50*10 um; mobile phase: [heptane-ethanol (0.1% ammonium hydroxide)]; (B%: 1%-35%, 15 min) to give 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 (20.0 mg, 33.6 umol, 91%) as a yellow solid. m/z ES+[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

A solution of 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 (17.0 mg, 28.4 umol) in trifluoroacetic acid (0.5 mL) was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid) -acetonitrile ]; (B%: 12%-42%, 10min) to give 8-chloro-2-[1-(3,3-difluorocyclobutyl)pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (11.4mg, 24.5umol, 85%) as a yellow solid. 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-((1r,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-((1s,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 a solution of 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (50.0 mg, 112 umol) and (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane; hydrochloride (45.7 mg, 337 umol) in methanol (2 mL) was added diisopropylethylamine (43.6 mg, 337 umol) and propan-2-ol titanium (IV) (63.9 mg, 225 umol). The mixture was stirred at 60 ° C for 2 hours. Sodium cyanoborohydride (7.06 mg, 112 umol) was then added, and the reaction mixture was stirred at 25 ° C 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 C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10min) to give (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, 21%) as a white solid. m/z ES+[M+H] ⁺ 528.3.

Step 2. (1R,4R)-5-((1r,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-((1s,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 purified by SFC (column: Daicel Chiralpak IG (250mm*50mm, 10um); mobile phase: [hexane-EtOH (0.1% ammonium hydroxide)]; (B%: 90%-90%, 30min) separation to obtain (1R,4R)-5-((1r,3R)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)cyclobutyl)-2-oxa-5-nitrogen as an off-white solid. Heterobicyclo[2.2.1]heptane (32.4 mg, 55.9 umol, 78%) and (1R,4R)-5-((1s,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, 12.3 umol, 17%) as off-white solids.

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 = 8.8 Hz,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-formamido-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-1-3-yl)ethanone

To a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetic acid (70.0 mg, 124 umol), 4,4-dimethyl-1,5-dihydroimidazole (15.8 mg, 161 umol) and diisopropylethylamine (64.0 mg, 495 umol) in N,N-dimethylamide (2 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethylammonium; hexafluorophosphate (236 mg, 619 umol). The mixture was stirred at 25 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-(5,5-dimethyl-4H-imidazo1-3-yl)ethanone (105 mg, crude) as a yellow solid. m/z ES+[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-formamido-2-methylpropyl)acetamide

A solution of 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 1-3-yl)ethanone (105 mg, 163 umol) in trifluoroacetic acid (2 mL) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 22%-52%, 10min) and re-purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 10%-30%, 10min) to give 2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-N-(2-formamido-2-methylpropyl)acetamide (6.58mg, 12.6umol, 7.6%) as an off-white solid. ^1HNMR (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 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 (300 mg, 592 umol) in acetonitrile (4 mL) was added scandium(III) trifluoromethanesulfonate (29.1 mg, 59.2 umol) and cyclopent-2-en-1-one (194 mg, 2.37 mmol). The mixture was stirred at 25 °C 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 condition, 50%-80% acetonitrile, 10 min) to give 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 (300 mg, 510 umol, 82%) as a yellow solid. ¹ H NMR (400 MHz, 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 a solution 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)cyclopentanone (280 mg, 475 umol) in dichloromethane (3 mL) at 0°C was slowly added bis(2-methoxyethyl)aminosulfur trifluoride (210 mg, 951 umol). The mixture was stirred at 25°C 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 concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% formic acid condition, 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]imidazol-6-yl)oxy)quinoxaline (140 mg, 230 umol, 48%) as an orange oil. m/z ES+[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

A solution of 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 (60.0 mg, 98.2 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. 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]; (B%: 15%-45%, 10min) to give 8-chloro-2-(1-(3,3-difluorocyclopentyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (27.7 mg, 57.5umol, 59%) as an off-white solid. ¹ H NMR (400 MHz, 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-(oxetane-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 a solution of 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 (90.0 mg, 153 umol) in tetrahydrofuran (2 mL) was added oxetanes-3-one (22.1 mg, 306 umol) and the mixture was stirred at 25 ° C for 0.5 hours. Sodium triacetoxyborohydride (97.4 mg, 459 umol) was then added to the mixture. The mixture was stirred at 25 ° C 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-((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 (40.0 mg, 61.5 umol, 40%) as a yellow oil. m/z ES+[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 a solution of 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 (35.0 mg, 54.4 umol) in tetrahydrofuran (1 mL) was added pyridine hydrofluoride (220 mg, 2.22 mmol). The mixture was stirred at 80 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Unisil 3-100C18 Ultra 150*50mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 10%-40%, 10 min) 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]imidazol-6-yl)oxy)quinoxaline (23.5 mg, 44.8 umol, 82%) as a white solid. ¹ H NMR (400 MHz, 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),5.11-4.9 0(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,3 H),2.17-2.04(m,4H); m/z ES+[M+H] ⁺ 514.1.

Example 32: Synthesis of 1-((1s,3s)-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-((1r,3r)-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 a solution of 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (150 mg, 340 umol) and azetidine-3-ol hydrochloride (111 mg, 1.01 mmol) in methanol (2 mL) was added propan-2-ol titanium (IV) (192 mg, 674 umol) and diisopropylethylamine (131 mg, 1.01 mmol). The mixture was stirred at 60 ° C for 2 hours. Sodium cyanoborohydride (21.0 mg, 337 umol) was then added, and the mixture was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with saturated sodium bicarbonate (20 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (25 mL x 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)azetidin-3-ol (30.0 mg, 60.0 umol, 18%) as a white solid. m/z ES+[M+H] ⁺ 502.3.

Step 2. 1-((1s,3s)-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-((1r,3r)-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-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]cyclobutyl]azetidin-3-ol (80.0 mg, 160 umol) was separated by SFC (basic conditions; column: Daicel Chiralpak IG (250 mm×50 mm, 10 um); mobile phase: [hexane-ethanol (0.1% ammonium hydroxide)]; (B%: 40%-40%, 22, 66 min) to give 1-((1s, 3s)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-1-yl)-1-yl)-2-ol as a yellow solid. 1-((1r,3r)-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, 77.1 umol, 48%) and 1-((1r,3r)-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 (18.6 mg, 36.4 umol, 23%) as a white solid.

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 = 9.2 Hz,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 (400 MHz, 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),2.3 1-2.21(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)ethyl methanesulfonate

To the solution of 1-(2-hydroxyethyl)pyrrolidin-2-one (500mg, 3.87mmol) in dichloromethane (5mL), triethylamine (1.18g, 11.6mmol) and methanesulfonyl chloride (665mg, 5.81mmol) are added. The mixture is stirred at 0°C for 1 hour. The reaction mixture is quenched with water (10mL) and extracted with dichloromethane (20mL x 3). The combined organic layer is washed with brine (10mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (700mg, crude product) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ4.28 (t, J = 5.2 Hz, 2H), 3.49 (t, J = 5.2 Hz, 2H), 3.40 (t, J = 7.2 Hz, 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 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 (200 mg, 394 umol) in N,N-dimethylformamide (2 mL) was added potassium acetate (164 mg, 1.18 mmol) and 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (163 mg, 789 umol). The mixture was stirred at 80 ° C for 12 hours. The reaction was then stirred at 100 ° C 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 condition, 80%-90% acetonitrile, 5 min) to give 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 (150 mg, 243 umol, 62%) as an orange oil. m/z ES+[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

A solution of 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 (50.0 mg, 80.9 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. 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]; (B%: 9%-39%, 10min) to give 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 (13.1 mg, 26.9umol, 33%) as a yellow solid. ¹ H NMR (400 MHz, 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

At 0°C, sodium hydride (15.2 mg, 381 umol, 60% in mineral oil) was added to a solution of 8-bromo-2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (100 mg, 190 umol) in tetrahydrofuran (2 mL). The mixture was stirred at 0°C for 30 min. Then 2-(chloromethoxy)ethyl-trimethyl-silane (47.6 mg, 286 umol) was added at 0°C. The mixture was stirred at 25°C 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 concentrated 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]imidazol-6-yl)oxy)quinoxaline (30.0 mg, 45.8 umol, 24%) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[5-bromo-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (25.0 mg, 38.1 umol) and cyclopropylboronic acid (32.8 mg, 381 umol) in dioxane (0.5 mL) and water (0.05 mL) was added sodium carbonate (12.1 mg, 114 umol) 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 umol). The mixture was stirred at 110° C. under nitrogen for 8 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was 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]imidazol-6-yl)oxy)quinoxaline (15.0 mg, 19.9 umol, 52%) as a yellow oil. m/z ES+[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

A solution of 2-[[6-[5-cyclopropyl-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (13.0 mg, 17.3 umol) in trifluoroacetic acid (0.5 mL) was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 20%-50%, 10min) to give 8-cyclopropyl-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (3.7 mg, 7.43umol, 43%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 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＝2.4,8.8 Hz,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 a mixture of 2-[1-(azetidine-3-yl)pyrazole-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (100 mg, 231 umol) in tetrahydrofuran (0.8 mL) and methanol (0.8 mL), triethylamine (46.8 mg, 463 umol) was added, followed by oxetane-3-ylmethyl methanesulfonate (38.4 mg, 231 umol). The reaction mixture was stirred at 80 ° C 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*25 mm*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 0%-24%, 10 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[1-(oxetan-3-ylmethyl)azetidin-3-yl]pyrazol-4-yl]quinoxaline (26.2 mg, 51.2 umol, 22%) as a white solid. ¹ H NMR (400 MHz, 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),6.9 4(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]heptane-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]heptane-6-yl]pyrazol-4-yl]quinoxaline

Step 1. tert-Butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (150 mg, 703 umol) in dichloromethane (3 mL) triethylamine (214 mg, 2.11 mmol) and methanesulfonyl chloride (161 mg, 1.41 mmol) were added, and the mixture was stirred at 0 ° C for 4 hours. The reaction mixture was quenched with water (5 mL) at 0 ° C and extracted with ethyl acetate (3 × 5 mL). The combined organic layer was washed with water (3 × 5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 6-methylsulfonyloxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (220 mg, 755 umol, 96%) as a yellow oil. 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50.0 mg, 98.6 umol), 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (43.1 mg, 148 umol) in N,N-dimethylformamide (5 mL), potassium carbonate (54.5 mg, 394 umol) was added. The mixture was stirred at 100 ° C for 16 hours. The reaction mixture was quenched with water (50 mL) at 20 ° C and extracted with ethyl acetate (3×20 mL). The combined organic layer was 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 tert-butyl 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-carboxylate (80.0 mg, 114 umol, 90%) as a yellow oil. m/z ES+[M+H] ⁺ 702.5.

Step 3. 2-[1-(2-Azaspiro[3.3]heptane-6-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline

A solution of 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 (80.0 mg, 114 umol) in trifluoroacetic acid (0.5 mL) was stirred for 2 hours at 20° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 3%-33%, 10min) to give 2-[1-(2-azaspiro[3.3]heptane-6-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (15.4 mg, 32.6 umol, 36%) as a yellow solid. ¹ H NMR (400 MHz, 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),4.2 4(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]heptane-6-yl]pyrazol-4-yl]quinoxaline

To a mixture of 2-[1-(2-azaspiro[3.3]heptane-6-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (100.0 mg, 212 umol) and oxetanes-3-one (30.6 mg, 424 umol) in methanol (1 mL), sodium cyanoborohydride (40.0 mg, 636 umol) and sodium acetate (87.9 mg, 1.06 mmol) were added. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 27%-57%, 8min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(oxetan-3-yl)-2-azaspiro[3.3]heptane-6-yl]pyrazol-4-yl]quinoxaline (17.7mg, 32.0umol, 15%) as a yellow solid. ^1H NMR (400MHz, CD ₃ OD) δ9.11 (d, J=1.6 Hz, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 7.86 (dd, J=1.6, 9.2 Hz, 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. Synthesis of 8-chloro-2-[1-[1-[(1-fluorocyclopropyl)methyl]azetidin-3-yl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline

Step 1. (1-Fluorocyclopropyl)methyl methanesulfonate

To the mixture of (1-fluorocyclopropyl)methanol (500mg, 5.55mmol) in dichloromethane (6mL), triethylamine (1.12g, 11.1mmol) is added, then methanesulfonyl chloride (953mg, 8.32mmol) is added at 0°C. The reaction mixture is stirred at 25°C for 2 hours. The reaction mixture is quenched with water (10mL) and extracted with dichloromethane (20mL x 2). The combined organic layer is washed with brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (petroleum ether/ethyl acetate=20/1 to 1/1) to obtain (1-fluorocyclopropyl) methyl methanesulfonate (400mg, 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 a mixture of 2-[1-(azetidine-3-yl)pyrazole-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazole-5-yl)oxy]quinoxaline (100 mg, 231 umol) and (1-fluorocyclopropyl)methyl methanesulfonate (38.9 mg, 231 umol) in tetrahydrofuran (1 mL) and methanol (1 mL), triethylamine (46.8 mg, 463 umol) was added, and the reaction mixture was stirred at 80 ° C for 12 hours. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was 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 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 0%-28%, 10min) to give 8-chloro-2-[1-[1-[(1-fluorocyclopropyl)methyl]azetidin-3-yl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (14.3 mg, 28.2 umol, 12%) as a white solid. ¹ H NMR (400 MHz, 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 a mixture of 2-[1-(azetidin-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (100 mg, 231 umol) and 2,2-difluoroethyl trifluoromethanesulfonate (49.5 mg, 231 umol) in acetonitrile (1.5 mL) was added potassium carbonate (96.0 mg, 694 umol) and potassium iodide (3.84 mg, 23.1 umol), and the reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was extracted with ethyl acetate (20 mL×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 C18 150*25 mm*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 0%-31%, 11 min) to give 8-chloro-2-[1-[1-(2,2-difluoroethyl)azetidin-3-yl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (25.2 mg, 50.4 umol, 22%) as a white solid. ¹ H NMR (400 MHz, 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 the solution of 2-benzyloxycyclobutanone (800mg, 4.54mmol) in methanol (8mL) sodium borohydride (258mg, 6.81mmol) is added. The mixture is stirred at 0°C for 2 hours. The reaction mixture is quenched by adding water (10mL) at 0°C, then diluted with water (30mL) and extracted with ethyl acetate (80mL x 3). The combined organic layer is washed with brine (30mL x3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 3/1) to obtain 2-benzyloxycyclobutanol (350mg, 1.96mmol, 43%) as a colorless oil. 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).

Step 2. (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), diisopropylethylamine (1.19 g, 9.20 mmol, 1.6 mL) and 4-dimethylaminopyridine (56.2 mg, 460 umol) were added. The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was 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 obtain (2-benzyloxycyclobutyl) 4-(trifluoromethyl)benzenesulfonate (400 mg, crude product) 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 umol), (2-benzyloxycyclobutyl) 4-(trifluoromethyl)benzenesulfonate (229 mg, 592 umol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (81.8 mg, 592 umol). The mixture was stirred at 80 ° C 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]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (90.0 mg, 135 umol, 68%) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[3-[1-(2-benzyloxycyclobutyl)pyrazol-4-yl]-5-chloro-quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (35.0 mg, 52.4 umol) in tetrahydrofuran (1 mL) was added tetrabutylammonium fluoride (1M in THF, 105 uL). The mixture was stirred at 40 ° C 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*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 40%-70%, 9min) to give 2-[1-[benzyloxy(cyclopropyl)methyl]pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (6.0mg, 11.2umol, 21%) as a white solid. ^1H 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. Synthesis of 2-[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 the solution of 8- oxo -3- azabicyclo [3.2.1] octane -3- carboxylic acid tert-butyl esters (500mg, 2.22mmol) in methanol (5mL), sodium borohydride (126mg, 3.33mmol) is added. The mixture is stirred at 0°C for 2 hours. The reaction mixture is quenched by adding water 2mL at 0°C, then diluted with water (3mL) and extracted with ethyl acetate (3mL x 3). The combined organic layer is washed with brine (3mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 8- hydroxy -3- azabicyclo [3.2.1] octane -3- carboxylic acid tert-butyl esters (440mg, 1.94mmol, 87%) as a white solid. ¹ HNMR (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. tert-Butyl 8-(trifluoromethylsulfonyloxy)-3-azabicyclo[3.2.1]octane-3-carboxylate

To 8-hydroxy-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester (200mg, 880umol), pyridine (696mg, 8.80mmol) in the mixture of -78 ℃ trifluoromethylsulfonyl trifluoromethanesulfonate (497mg, 1.76mmol).Mixture is slowly warmed to 0 ℃, and stirred at 0 ℃ for 1 hour.Reactant mixture is diluted with saturated sodium bicarbonate (5mL) and extracted with dichloromethane (3mL x 3).The organic layer merged is washed with salt water (3mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in a vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0 to 20/1) to give tert-butyl 8-(trifluoromethylsulfonyloxy)-3-azabicyclo[3.2.1]octane-3-carboxylate (230 mg, 640 umol, 73%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.04 (t, J=5.2 Hz, 1H), 3.85 (d, J=12.8 Hz, 1H), 3.70 (d, J=12.8 Hz, 1H), 3.31 (d, J=13.2 Hz, 1H), 3.21 (d, J=13.2 Hz, 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 296 umol) and 8-(trifluoromethylsulfonyloxy)-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (128 mg, 355 umol) in N,N-dimethylformamide (2 mL), cesium carbonate (193 mg, 592 umol) was added. The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layer was 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (90.0 mg, 126 umol, 43%) as a colorless oil. m/z ES+[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

A mixture of 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 (90.0 mg, 126 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 7 min) to give 2-[1-(3-azabicyclo[3.2.1]oct-8-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (34.6 mg, 71.0 umol, 57%) as a white solid. ¹ H NMR (400 MHz, 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. Synthesis of 8-chloro-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)oxy)quinoxaline

Step 1. N-tert-Butyloxycarbonyl-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 a solution of 5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazole-4-yl]quinoxaline-6-ol (250mg, 713umol) in N,N-dimethylformamide (3mL) was added potassium carbonate (197mg, 1.43mmol) and tert-butyl N-tert-butoxycarbonyl-N-(5-fluoro-2-nitro-phenyl)carbamate (508mg, 1.43mmol). The mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (10mL) and extracted with ethyl acetate (10mL 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 tert-butyl N-tert-butoxycarbonyl-N-[5-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-nitro-phenyl]carbamate (380 mg, 542 umol, 76%) as a yellow oil. m/z ES+[M+H] ⁺ 687.5.

Step 2. N-[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 a solution of N-tert-butyloxycarbonyl-N-[5-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-yl]oxy-2-nitro-phenyl]carbamic acid tert-butyl ester (330 mg, 480 umol) in ethanol (5 mL) and water (1 mL), iron powder (134 mg, 2.40 mmol) and ammonium chloride (257 mg, 4.80 mmol) were added. The mixture was stirred at 60 ° C 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]pyrazol-4-yl]quinoxaline-6-yl]oxy-phenyl]-N-tert-butyloxycarbonyl-carbamic acid tert-butyl ester (200 mg, crude product) as a yellow oil. m/z ES+[M+H] ⁺ 657.1.

Step 3. 4-((5-chloro-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)benzene-1,2-diamine

To a solution of N-[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 (200 mg, 304 umol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 20 ° C for 20 min. 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, 212 umol, 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° C. 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 C18 250*50mm*15um; mobile phase: [water (0.2% formic acid)-acetonitrile]; (B%: 50%-80%, 10min) to give 8-chloro-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-7-((2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)oxy)quinoxaline (38.5mg, 71.9umol, 66%) as a yellow solid. ^1H 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]heptane-5-yl]ethyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate (300 mg, 476 umol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (193 mg, 1.43 mmol) in acetonitrile (5 mL) was added sodium bicarbonate (200 mg, 2.38 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was concentrated in vacuo, and the residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate=0:1) to give 2-[[6-[5-chloro-3-[1-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl]ethyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 158 umol, 30%) as a yellow solid. m/z ES+[M+H] ⁺ 632.3.

Step 2. (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

A solution of 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 (90.0 mg, 142 umol) in trifluoroacetic acid (1 mL) was stirred at 25 °C for 6 hours. The mixture was 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]; (B%: 0%-29%, 11min), and re-purified by preparative TLC (dichloromethane: methanol = 10: 1) to give (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 (8.2 mg, 16.4 umol, 10%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 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. Ethyl 2-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]acetate

To a mixture of 2-[1-(azetidin-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (100 mg, 231 umol) in dichloromethane (1.5 mL) 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 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give ethyl 2-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]azetidin-1-yl]acetate (100 mg, 193 umol, 83%) as a white solid. 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 a mixture of ethyl 2-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]acetate (100 mg, 193 umol) in tetrahydrofuran (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (40.5 mg, 965 umol) and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched with 1N HCl solution to pH about 3. The mixture was directly purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 0%-28%, 10min) to give 2-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]acetic acid (50.0mg, 102umol, 52%) as a white solid. m/z ES+[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 a mixture of 3,3-difluoroazetidine hydrochloride (10.5 mg, 81.6 umol) and 2-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-yl]acetic acid (40.0 mg, 81.6 umol) in dichloromethane (1 mL), diisopropylethylamine (31.6 mg, 244 umol) was added and the reaction mixture was stirred at 25 ° C for 10 min. 3-(ethyliminomethyleneamino)propyl-dimethylammonium chloride (23.4 mg, 122 umol) and 1-hydroxybenzotriazole (16.5 mg, 122 umol) were then added and the reaction mixture was stirred at 40 ° C 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 C18 150*25 mm*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 0%-29%, 11 min) to give 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 (17.5 mg, 30.7 umol, 37%) as a white solid. ¹ H NMR (400 MHz, 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 a solution of 2-[1-(azetidin-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (50.0 mg, 116 umol), formaldehyde (69.5 mg, 2.32 mmol, 37% aqueous solution) and diisopropylethylamine (74.8 mg, 579 umol) in tetrahydrofuran (1.5 mL) was added sodium triacetoxyborohydride (49.1 mg, 232 umol). The mixture was stirred at 25 ° C 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 C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-29%, 10min) to give 8-chloro-2-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (26.9mg, 60.3umol, 52%) as a yellow gum. ^1H 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. Synthesis of 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

Step 1. Thietan-3-ylmethyl 4-methylbenzenesulfonate

At 0 ° C, 4-methylbenzenesulfonyl chloride (82.3 mg, 431 umol) was added to a solution of thietan-3-ylmethanol (30.0 mg, 287 umol) and triethylamine (87.4 mg, 863 umol) in dichloromethane (1 mL) at 0 ° C. The mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3: 1) to obtain thietan-3-ylmethyl 4-methylbenzenesulfonate (60.0 mg, 232 umol, 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

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 (100 mg, 197 umol), thietan-3-ylmethyl 4-methylbenzenesulfonate (50.9 mg, 197 umol) and cesium carbonate (128 mg, 394 umol) in N,N-dimethylformamide (1 mL) was stirred at 80 °C 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]imidazol-6-yl)oxy)-2-(1-(thietan-3-ylmethyl)-1H-pyrazol-4-yl)quinoxaline (100 mg, 168 umol, 85%) as a yellow oil. m/z ES+[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

3-Chlorobenzoic acid (116 mg, 505 umol) was added to a solution of 2-[[6-[5-chloro-3-[1-(thietan-3-ylmethyl)pyrazol-4-yl]quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 168 umol) in dichloromethane (1 mL). The mixture was stirred at 25 ° C for 16 hours. The mixture was poured into a 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)thietane 1,1-dioxide (80.0 mg, 127 umol, 75%) as a yellow solid. m/z ES+[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

A solution 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)thietane 1,1-dioxide (80 mg, 127 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 10 min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 10%-40%, 7min) and re-purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 25%-55%, 7min) to give 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 (8.9mg, 17.0umol, 14%) as an off-white solid. ^1H 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. Synthesis of 8-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 a solution of 5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-ol (150 mg, 427 umol) in N,N-dimethylformamide (3 mL) 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 ° C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-fluoro-6-nitro-aniline (180 mg, 357 umol, 66%) as a yellow solid. m/z ES+[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 a solution of 3-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-fluoro-6-nitro-aniline (150 mg, 297 umol) in ethanol (2 mL) and water (0.4 mL) 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 ° C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-3-fluoro-benzene-1,2-diamine (180 mg, crude) as a yellow solid. 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 1,1,1-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 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 29%-59%, 10min) to give 8-chloro-2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-7-[(4-fluoro-2-methyl-1H-benzimidazol-5-yl)oxy]quinoxaline (101 mg, 203 umol, 62%) as a yellow solid. ¹ H NMR (400 MHz, 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. tert-Butyl 3-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]azetidine-1-carboxylate

A mixture of 2-[1-(azetidine-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazole-5-yl)oxy]quinoxaline (100 mg, 231 umol), tert-butyl 3-oxoazetidine-1-carboxylate (51.5 mg, 301 umol), sodium triacetoxyborohydride (147 mg, 694 umol) in tetrahydrofuran (1 mL) was stirred at 25 ° C 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 Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 35%-65%, 9min) to give tert-butyl 3-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]azetidine-1-carboxylate (50.0mg, 85.3umol, 37%) as a white solid. m/z ES+[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 a solution of 3-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]azetidine-1-yl]azetidine-1-carboxylic acid tert-butyl ester (50 mg, 85.1 umol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 2-[1-[1-(azetidine-3-yl)azetidine-3-yl]pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (40.0 mg, crude) as a yellow solid. 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 a solution of 2-[1-[1-(azetidine-3-yl)azetidine-3-yl]pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (35.0 mg, 71.8 umol) in methanol (2 mL) was added formaldehyde (43.1 mg, 1.44 mmol, 37% aqueous solution) and sodium triacetoxyborohydride (76.1 mg, 359 umol). The mixture was stirred at 25 ° C 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 Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 24%-54%, 10min) to give 8-chloro-2-[1-[1-(1-methylazetidin-3-yl)azetidin-3-yl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (24.3mg, 48.6umol, 67%) as a white solid. ^1H 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,1 H),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

A solution of 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 (430 mg, 656 umol) in trifluoroacetic acid (5 mL) was stirred at 25 °C 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 x 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]imidazol-6-yl)oxy)quinoxaline (300 mg, crude) as a yellow solid. m/z ES+[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 a solution of 8-bromo-2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (100 mg, 190 umol) and potassium trifluoro(prop-1-ene-2-yl)borate (282 mg, 1.90 mmol) in dioxane (2 mL) and water (0.2 mL), sodium carbonate (60.5 mg, 571 umol) and methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (22.5 mg, 28.6 umol) were added. The mixture was stirred at 110 ° C for 2 hours under nitrogen. The reaction mixture was poured into 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 preparative HPLC (formic acid conditions; column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 19%-49%, 10min) to give 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 (17.8 mg, 35.8 umol, 18.8%) as a yellow solid. ¹ H NMR (400 MHz, 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.

The mixture was stirred for 2 hours at 0 ° C. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic layer was 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 obtain 3- [[4- [8- chloro-7- [2- methyl -3- (2- trimethylsilylethoxymethyl) benzimidazol-5-yl] oxy-quinoxaline-2-yl] pyrazole-1-yl] methyl] -1- methyl -cyclobutanol (35.0 mg, 57.2 umol, 33%) as a white solid. 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

A solution of 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-1-methyl-cyclobutanol (35.0 mg, 57.8 umol) in trifluoroacetic acid (2.16 g, 18.9 mmol) was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 7min) to give 3-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]-1-methyl-cyclobutanol (18.0 mg, 37.5 umol, 64%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 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. Synthesis of 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-thiazinane 1,1-dioxide

Step 1. 5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-methyl-1,2-thiazinane 1,1-dioxide

To a solution of tert-butyl-[(1,1-dioxothiazinan-5-yl)methoxy]-diphenyl-silane (1 g, 2.48 mmol) in tetrahydrofuran (20 mL) was added potassium carbonate (1.03 g, 7.43 mmol) and iodomethane (1.76 g, 12.4 mmol), and the mixture was stirred at 60 ° C 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-thiazinane 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-thiazinane 1,1-dioxide

A solution of tert-butyl-[(2-methyl-1,1-dioxo-thiazinane-5-yl)methoxy]-diphenyl-silane (500 mg, 1.20 mmol) in aqueous sodium hydroxide solution (5M, 10 mL) was stirred at 40 ° C 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 (12 M) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(hydroxymethyl)-2-methyl-1,2-thiazinane 1,1-dioxide (500 mg, crude) as a yellow oil. m/zES+[M+H] ⁺ 179.9.

Step 3. (2-Methyl-1,1-dioxido-1,2-thiazin-5-yl)methyl 4-methylbenzenesulfonate

4-Methylbenzenesulfonyl chloride (239 mg, 1.26 mmol) and triethylamine (254 mg, 2.51 mmol) were added to a solution of 5-(hydroxymethyl)-2-methyl-1,2-thiazinane 1,1-dioxide (500 mg, crude product) in dichloromethane (5 mL), and the mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid conditions) to obtain (2-methyl-1,1-dioxido-1,2-thiazinane-5-yl) methyl 4-methylbenzenesulfonate (100 mg, 299 umol, 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-thiazinane 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 (100 mg, 197 umol), (2-methyl-1,1-dioxido-1,2-thiazin-5-yl)methyl 4-methylbenzenesulfonate (80.0 mg, 240 umol), cesium carbonate (192 mg, 591 umol) in N,N-dimethylformamide (1 mL) was stirred at 80° C. 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 x 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)-2-methyl-1,2-thiazinane 1,1-dioxide (130 mg, crude) as a yellow oil. m/z ES+[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-thiazinane 1,1-dioxide

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-thiazinane 1,1-dioxide (130 mg, crude) in trifluoroacetic acid (2 mL) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 7min) to give 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-thiazinane 1,1-dioxide (74.9 mg, 139 umol, 71%) as an off-white solid. ¹ H NMR (400 MHz, 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. Ethyl 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-methylbutanoate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (700 mg, 1.38 mmol) and ethyl 3-methylbut-2-enoate (265 mg, 2.07 mmol, 288 μL) in N,N-dimethylformamide (14 mL) was added cesium carbonate (900 mg, 2.76 mmol) and the mixture was stirred at 25 ° C 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 ethyl 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-methylbutanoate (340 mg, 455 umol, 32%) as a yellow solid. 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 a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]-3-methyl-butyric acid ethyl ester (270 mg, 361 umol) in methanol (2.5 mL), tetrahydrofuran (2.5 mL) and water (2.5 mL) was added lithium hydroxide monohydrate (45.5 mg, 1.08 mmol). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was adjusted to pH = 5 with aqueous citric acid solution, then filtered and concentrated in vacuo to give 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 (150 mg, crude) as a yellow solid. m/z ES+[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 a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-3-methyl-butyric acid (150 mg, 247 umol) and ammonium chloride (132 mg, 2.47 mmol) in N,N-dimethylformamide (5 mL) was added diisopropylethylamine (95.8 mg, 741 umol, 129 μL) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium; hexafluorophosphate (141 mg, 371 umol) and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with water (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 to give 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 (180 mg, crude) as a yellow solid. m/z ES+[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

A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-3-methyl-butyramide (50.0 mg, 82.5 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. 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 C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 10%-40%, 10min) to give 3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-methylbutanamide (17.8 mg, 37.4 umol, 45%) as an off-white solid. ¹ H NMR (400 MHz, 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 a solution of 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-3-methyl-butyramide (8 mg, 16.8 umol) in acetonitrile (0.5 mL) was added methoxycarbonyl-(triethylamino)sulfonyl-azepanate (8.01 mg, 33.6 umol) and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated in vacuo to give a mixture. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 10%-40%, 10min) to give 4-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)quinuclidine (10.0mg, 16.6umol, 98%) as a yellow solid. m/z ES+[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-methylbutyronitrile

To a solution of methyl N-[6-[5-chloro-3-[1-(2-cyano-1,1-dimethyl-ethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]sulfonylcarbamate (8 mg, 13.4 umol) in dimethyl sulfoxide (0.5 mL) was added potassium carbonate (3.72 mg, 26.9 umol) and the mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered and concentrated in vacuo, and the residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 12%-42%, 10min) to give 3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-methylbutanenitrile (3.3mg, 6.80umol, 50%) as a yellow solid. ^1H 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]heptane-5-ylmethyl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

Step 1. Dimethyl 4-hydroxycyclopentane-1,2-dicarboxylate

At 0 ° C, sodium borohydride (3.64 g, 96.2 mmol) was added portionwise to a solution of 4-oxocyclopentane-1,2-dicarboxylic acid dimethyl ester (17.5 g, 87.4 mmol) in methanol (200 mL). The mixture was stirred at 0 ° C for 1 hour. At 0 ° C, the reaction mixture was quenched with brine (100 mL), and then extracted with ethyl acetate (3 × 100 mL). The combined organic layer was 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 obtain 4-hydroxycyclopentane-1,2-dicarboxylic acid dimethyl ester (10.0 g, 49.5 mmol, 56%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.50-4.32 (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. Dimethyl 4-(Benzyloxy)cyclopentane-1,2-dicarboxylate

At 0 ° C, sodium hydride (396 mg, 9.89 mmol, 60% in mineral oil) was added in batches to a solution of 4-hydroxycyclopentane-1,2-dicarboxylic acid dimethyl ester (2 g, 9.89 mmol) in N, N-dimethylformamide (20 mL), and the mixture was stirred at 20 ° C for 0.5 hours. Then benzyl bromide (1.69 g, 9.89 mmol, 1.17 mL) was slowly added, and the resulting mixture was stirred at 20 ° C for 0.5 hours. At 0 ° C, the reaction mixture was quenched with water (100 mL) and then extracted with ethyl acetate (3 × 100 mL). The combined organic layer was 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, 3.42 mmol, 35%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33-7.19 (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.

Step 3. (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) was added lithium aluminum hydride (493 mg, 13.0 mmol) in portions at 0° C., and the mixture was stirred at 20° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (0.5 mL), 10% aqueous sodium hydroxide solution (0.5 mL) and water (1.5 mL) at 0° C., 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。

Step 4. (4-(Benzyloxy)cyclopentane-1,2-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

To a solution of [4-benzyloxy-2-(hydroxymethyl)cyclopentyl]methanol (100 mg, 423 umol) in pyridine (2 mL) was added 4-methylbenzenesulfonyl chloride (242 mg, 1.27 mmol), and the mixture was stirred at 25 ° C 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 (4-(benzyloxy)cyclopentane-1,2-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (150 mg, 262 umol, 62%) as a colorless oil. 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.

Step 5. (4-Hydroxycyclopentane-1,2-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

Boron trichloride (1mL) was added to a solution of [4-benzyloxy-2-(tosyloxymethyl)cyclopentyl]methyl 4-methylbenzenesulfonate (140mg, 257umol) in dichloromethane (1mL). The mixture was stirred at 20°C for 0.5 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5mL) and extracted with ethyl acetate (3×5mL). 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 obtain (4-hydroxycyclopentane-1,2-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (80.0mg, 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]hept-5-ylmethyl 4-methylbenzenesulfonate

To a solution of [4-hydroxy-2-(p-tolylsulfonyloxymethyl)cyclopentyl]methyl 4-methylbenzenesulfonate (80.0mg, 176umol) in anhydrous tetrahydrofuran (1mL), sodium hydride (14.1mg, 352umol, 60% in mineral oil) was added, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (5mL) at 0°C and extracted with ethyl acetate (3x 5mL). The combined organic layer was 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 obtain 2-oxabicyclo[2.2.1]heptane-5-ylmethyl 4-methylbenzenesulfonate (45.0mg, 159umol, 91%) as a yellow oil. 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 umol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (54.5 mg, 394 umol) and 2-oxabicyclo[2.2.1]heptane-5-ylmethyl 4-methylbenzenesulfonate (44.6 mg, 158 umol), and the mixture was stirred at 80° C. 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]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 (120 mg, crude) as a black solid. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-(2-oxabicyclo[2.2.1]heptane-5-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (70.0 mg, 113 umol) in trifluoroacetic acid (0.5 mL) was stirred at 20° C. 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 150*25mm*10um; mobile phase: [water (0.2% formic acid)-acetonitrile]; (B%: 14%-44%, 10min) to give 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 (22.9mg, 45.7umol, 40%) as an off-white solid. ^1H 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 a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (100 mg, 174 umol) and azetidine (48.8 mg, 522 umol) in methanol (2 mL), tetraisopropoxytitanium (98.8 mg, 348 umol) and diisopropylethylamine (67.4 mg, 522 umol) were added, and the mixture was stirred at 60 ° C for 2 hours. Sodium cyanoborohydride (10.9 mg, 174 umol) was then added, and the mixture was stirred at 25 ° C 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 (3 × 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]imidazol-6-yl)oxy)quinoxaline (30.0 mg, 48.7 umol, 28%) as a white solid. m/z ES+[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]pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (25.0 mg, 40.6 umol) in trifluoroacetic acid (0.5 mL) was stirred at 25° C. for 0.5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPL (formic acid conditions; column: Unisil 3-100C18 Ultra 150*50mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 3%-33%, 10min) to give 2-[1-[3-(azetidin-1-yl)cyclobutyl]pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (12.4 mg, 23.9 umol, 60%) as a white solid. ¹ H NMR (400 MHz, 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (100 mg, 170 umol) and 3,3-difluoroazetidine (68.0 mg, 520 umol) in methanol (1.5 mL), diisopropylethylamine (67.0 mg, 520 umol) and tetraisopropoxytitanium (99.0 mg, 350 umol) were added and the mixture was stirred at 60 ° C for 2 hours. Sodium cyanoborohydride (11.0 mg, 170 umol) was then added. The mixture was stirred at 40 ° C for 12 hours. The reaction mixture was then filtered. The filtrate was washed with water (20 mL) and extracted with ethyl acetate (2×10 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (40.0 mg, 61.3 umol, 36%) as a white solid. m/z ES+[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

A solution of 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 (30.0 mg, 46.0 umol) in trifluoroacetic acid (0.2 mL) was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 35%-65%, 10min) to give 8-chloro-2-[1-[3-(3,3-difluoroazetidin-1-yl)cyclobutyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (13.7mg, 26.2umol, 56%) as a white solid. 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]cyclopropanol

Step 1. 1-[[4-[8-Chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclopropanol

A solution of 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 (190 mg, 287 umol) in trifluoroacetic acid (2 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was 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]; (B%: 8%-38%, 10min) to give 1-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclopropanol (74.6mg, 167umol, 58%) as a white solid. 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 a solution of 2-[[6-[5-chloro-3-(5-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 383 umol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (625 mg, 1.92 mmol) and tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate (409 mg, 1.15 mmol). The mixture was stirred at 100° C. 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 tert-butyl 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]-3-methyl-pyrazol-1-yl]piperidine-1-carboxylate (100 mg, 142 umol, 36%) as a yellow solid. m/z ES+[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

A solution of 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 (90.0 mg, 127 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 7min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[3-methyl-1-(4-piperidinyl)pyrazol-4-yl]quinoxaline (60.0mg, 126umol, 99%) as a white solid. m/z ES+[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 separated by SFC (column: Daicel ChiralPak IG (250*30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide/ethanol]; (B%: 70%-70%, 5.4 min, total running time 60 min) and then separated by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 7min) re-purify to give 8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]-2-[3-methyl-1-(4-piperidinyl)pyrazol-4-yl]quinoxaline (11.3mg, 23.8umol, 22%) as a white solid and 8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]-2-[5-methyl-1-(4-piperidinyl)pyrazol-4-yl]quinoxaline (8.3mg, 17.4umol, 16%) as a white solid.

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 1. N-tert-Butyloxycarbonyl-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 a solution of 5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-ol (200 mg, 570 umol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (236 mg, 1.71 mmol) and tert-butyl N-tert-butoxycarbonyl-N-(3,5-difluoro-2-nitro-phenyl)carbamate (320 mg, 855 umol). The mixture was stirred at 80° C. 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 tert-butyl N-tert-butoxycarbonyl-N-[5-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-3-fluoro-2-nitro-phenyl]carbamate (120 mg, 170 umol, 30%) as a yellow oil. m/z ES+[M+H] ⁺ 705.2.

Step 2. 5-((5-chloro-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-3-fluoro-2-nitroaniline

To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-3-fluoro-2-nitro-phenyl]carbamate (100 mg, 142 umol) in dichloromethane (0.9 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at 20 °C for 0.5 hours. 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/z ES+[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 a solution of 5-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-yl]oxy-3-fluoro-2-nitro-aniline (80 mg, 129 umol, trifluoroacetate) in ethanol (5 mL) and water (1 mL), iron powder (36.1 mg, 646 umol) and ammonium chloride (69.2 mg, 1.29 mmol) were added. The mixture was stirred at 60 ° C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.2% formic acid)-acetonitrile]; (B%: 28%-58%, 10min) to give 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 (29.0 mg, 58.1 umol, 45%) as an off-white solid. ¹ H NMR (400 MHz, 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

Step 1. tert-Butyl 4-(3-(methoxycarbonyl)-4-nitrophenyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate

To a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate (200 mg, 318 umol) in isopropanol (8 mL) was added azetidine (60.0 mg, 1.05 mmol), and the mixture was stirred at 80° C. 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]pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (35.0 mg, 59.3 umol, 19%) as a yellow solid. 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

A solution of 2-[[6-[3-[1-[2-(azetidin-1-yl)ethyl]pyrazol-4-yl]-5-chloro-quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (30.0 mg, 50.8 umol) in trifluoroacetic acid (2 mL) was stirred at 25 ° C 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]pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (11.8 mg, 24.4 umol, 48%) as a yellow gum. 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

A solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate (0.2 g, 317 umol), pyrrolidin-3-ol (83.0 mg, 953 umol), sodium bicarbonate (186 mg, 2.23 mmol) in acetonitrile (3 mL) was stirred at 80° C. 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 x 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)ethyl)pyrrolidin-3-ol (50 mg, 80.6 umol, 25%) as a yellow solid. m/z ES+[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

A solution of 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 (50 mg, 80.6 umol) in trifluoroacetic acid (45.9 mg, 403 umol) was stirred at 25 °C for 4 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(ammonium bicarbonate-acetonitrile]; (B%: 19%-49%, 8min) to give 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 (8.0 mg, 16.3 umol, 20%) as a yellow solid. ¹ H NMR (400 MHz, 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),4.3 3(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,1 H),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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate (200 mg, 318 umol) and 3-methoxypyrrolidine (131 mg, 954 umol) in acetonitrile (3 mL) was added sodium bicarbonate (134 mg, 1.59 mmol) and the mixture was stirred at 80° C. 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (45.0 mg, 70.9 umol, 22%) as a yellow solid. 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

A solution of 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 (39.0 mg, 61.5 umol) in trifluoroacetic acid (1.6 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 28%-58%, 10min) and re-purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 21%-51%, 9min) to give 8-chloro-2-[1-[2-(3-methoxypyrrolidin-1-yl)ethyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (1.5mg, 3.02umol, 4%) as an off-white solid. ^1HNMR (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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate (200 mg, 318 umol) and 3,3-difluoropyrrolidine hydrochloride (137 mg, 954 umol) in acetonitrile (3 mL) was added sodium bicarbonate (134 mg, 1.59 mmol) and the mixture was stirred at 80° C. 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-difluoropyrrolidin-1-yl)ethyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (41.0 mg, 64.0 umol, 20%) as a yellow solid. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methylbenzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (41.0 mg, 64.0 umol) in trifluoroacetic acid (1.6 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 10min) 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]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (2.5 mg, 4.88 umol, 7%) as a white solid. ¹ H NMR (400 MHz, 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,1 H), 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate (200 mg, 318 umol) and 3,3-difluoroazetidine hydrochloride (124 mg, 954 umol) in acetonitrile (3 mL) was added sodium bicarbonate (134 mg, 1.59 mmol) and the mixture was stirred at 80 °C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (37.0 mg, 59.1 umol, 19%) as a yellow solid. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-[2-(3,3-difluoroazetidin-1-yl)ethyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (37.0 mg, 59.1 umol) in trifluoroacetic acid (1.6 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 10min) 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]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (7.4 mg, 14.9 umol, 25%) as a white solid. ¹ H NMR (400 MHz, 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 a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (170 mg, 300 umol) in ethanol (2 mL) was added sodium borohydride (11.0 mg, 300 umol) at 0° C., and the mixture was stirred at 0° C. for 0.5 hours. At 0° C., the reaction mixture was quenched with saturated ammonium chloride solution (30 mL), then diluted with water (20 mL), and extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with water (2 x 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanol (180 mg, crude) as a yellow oil. m/z ES+[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

A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanol (170 mg, 300 umol) in trifluoroacetic acid (1.5 mL) was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions, column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; (B%: 22%-52%, 10 min) to give 3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]cyclobutanol (5.9 mg, 13.3 umol, 4.3%) as a white solid. ¹ H NMR (400 MHz, 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

At 0 ° C, methylmagnesium bromide (3M in THF, 170 μL) was added to a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (100 mg, 170 umol) in tetrahydrofuran (3 mL). The mixture was stirred at 0 ° C for 1 hour. At 0 ° C, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL), 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (40.0 mg, 67.7 umol, 32%) as a white solid. m/z ES+[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

A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (30.0 mg, 51.0 umol) in trifluoroacetic acid (0.3 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; (B%: 27%-57%, 10 min) to give 3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (15.0 mg, 32.5 umol, 64%) as a white solid. ¹ H NMR (400 MHz, 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),5.3 2(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) at 0°C was added triethylamine (25.7 mg, 254 umol) and dimethylcarbamoyl chloride (18.2 mg, 169 umol). The mixture was stirred at 25°C 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, 75.6 umol, 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

A solution of 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-N,N-dimethyl-piperidine-1-carboxamide (50.0 mg, 75.6 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.2% formic acid)-acetonitrile]; (B%: 14%-44%, 10min) to give 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 (13.4 mg, 25.2 umol, 32%) as a yellow solid. ¹ H NMR (400 MHz, 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

Step 1. (2-Cyano-2-methyl-propyl) methanesulfonate

To a solution of 3-hydroxy-2,2-dimethyl-propanenitrile (200 mg, 2.02 mmol) in ethyl acetate (3 mL) at 0°C, methanesulfonyl chloride (347 mg, 3.03 mmol) and triethylamine (612 mg, 6.05 mmol) were added and the mixture was stirred at 25°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 (2-cyano-2-methyl-propyl) methanesulfonate (310 mg, 1.75 mmol, 86%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.12 (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 a solution of (2-cyano-2-methyl-propyl) methanesulfonate (76.9 mg, 434 umol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 umol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (54.5 mg, 394 umol) and potassium iodide (32.7 mg, 197 umol). The mixture was stirred at 100 ° C 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 x 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-2,2-dimethyl-propanenitrile (100 mg, crude) as a yellow oil. m/z ES+[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 °C 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 C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 7min) to give 3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-2,2-dimethyl-propanenitrile (11.6 mg, 25.1 umol, 16%) as a white solid and 3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-2,2-dimethyl-propanamide (9.9 mg, 20.7 umol, 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. tert-Butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate

At 0 ° C, triethylamine (1.40 g, 13.8 mmol) was added to a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1 g, 4.60 mmol) in dichloromethane (10 mL), followed by methanesulfonyl chloride (1.05 g, 9.21 mmol). The mixture was stirred at 25 ° C for 1 hour. At 20 ° C, 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 tert-butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate (1.55 g, crude) as a yellow solid. ¹ HNMR (400MHz, CDCl ₃ ) δ = 4.24 (d, J = 4.8 Hz, 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (200 mg, 394 umol) and tert-butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate (175 mg, 592 umol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (164 mg, 1.18 mmol). The mixture was stirred at 80 ° C 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 x 100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]morpholine-4-carboxylate (315 mg, crude) as a yellow solid. m/z ES+[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

A solution of 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 (500 mg, 708 umol) in trifluoroacetic acid (5 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10min) to give 2-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]morpholine (227 mg, 477umol, 68%) as a yellow solid. 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),6.9 4(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 a solution of 2-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]morpholine (150 mg, 315 umol) in N,N-dimethylformamide (2 mL) was added paraformaldehyde (189 mg, 6.30 mmol) and formic acid (15.1 mg, 315 umol). The mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was filtered and concentrated in vacuo, and the residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 25%-55%, 10min) to give 2-[[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]-4-methyl-morpholine (15.2mg, 31.0umol, 9%) as a white solid. ^1H 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-(2,2,2-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-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

To a solution 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 (50.0 mg, 105 umol) in N,N-dimethylformamide (1 mL) was added diisopropylethylamine (27.0 mg, 209 umol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (29.1 mg, 126 umol) and the mixture was stirred at 25° C. 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 conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 45%-75%, 8min) to give 8-chloro-2-(1-((3S,4S)-3-fluoro-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (10.4mg, 18.0umol, 17%) as a yellow solid. ^1H 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),3.0 1(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: Synthesis of (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

Step 1. (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 a solution 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 (50.0 mg, 105 umol), 3-hydroxycyclobutanone (13.5 mg, 157 umol) in dichloromethane (1 mL) were added triethylamine (12.7 mg, 126 umol) and sodium triacetoxyborohydride (24.4 mg, 115 umol) and the mixture was stirred at 25° C. for 13 hours. The reaction mixture was quenched with methanol (0.2 mL) at 25° C. and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 27%-57%, 10min) to give (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 (16.4mg, 28.5umol, 27%) as a yellow solid. ^1H 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,2 H),2.15(s,3H); m/zES+[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

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 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 (100 mg, 169 umol), triethylamine (51.4 mg, 508 umol) in dichloromethane (1 mL) was added 4-nitrophenyl chloroformate (68.3 mg, 338 umol) and the mixture was stirred at 25°C 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-nitrophenyl 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-carboxylate (80.0 mg, 105 umol, 62%) as a colorless oil. m/z ES+[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

A solution of 4-nitrophenyl 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-carboxylate (80.0 mg, 105 umol), azetidine (19.8 mg, 211 umol), triethylamine (32.1 mg, 317 umol) in tetrahydrofuran (1 mL) was stirred at 60° C. 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methanone (70.0 mg, 103 umol, 98%) as a yellow oil. m/z ES+[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

A solution of 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 (70.0 mg, 103 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 10 min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 7min) to give 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 (20.5 mg, 37.7 umol, 36%) as an off-white solid. ¹ H NMR (400 MHz, 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

A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (30.0 mg, 52.2 umol) in trifluoroacetic acid (0.3 mL) was stirred for 0.5 hours at 25° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 9%-39%, 10 min) to give 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (12.5 mg, 27.5 umol, 52%) as a yellow gum. ¹ H NMR (400 MHz, 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

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

A solution of 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 (55.0 mg, 83.9 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. 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]; (B%: 16%-46%, 10min) to give 8-bromo-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (22.2 mg, 42.3 umol, 50%) as a white solid. ¹ H NMR (400 MHz, 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. 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)methyl)morpholine-4-carboxylate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (300 mg, 591 umol), 3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (154 mg, 709 umol) in toluene (5 mL), diisopropyl azodicarboxylate (179 mg, 887 umol) and triphenylphosphine (232 mg, 887 umol) were added, and the mixture was stirred at 60 ° C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (20 mL) at 25 ° C and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (3 × 10 mL), 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 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)methyl)morpholine-4-carboxylate (150 mg, 212 umol, 35%) as a yellow solid. m/z ES+[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

A solution of tert-butyl 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]morpholine-4-carboxylate (150 mg, 42.4 umol) in trifluoroacetic acid (7.70 g, 67.5 mmol) was stirred at 25°C for 3 hours. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 19%-49%, 8min) to give 3-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)morpholine (120mg, 252umol, 80%) as a white solid. ^1H 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

A solution of 3-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]morpholine (70.0 mg, 118 umol), formic acid (114 mg, 2.37 mmol), paraformaldehyde (71.2 mg, 2.37 mmol) in N,N-dimethylformamide (2 mL) was stirred at 60° C. for 16 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 23%-53%, 9min) to give 3-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)-4-methylmorpholine (16.0mg, 32.7umol, 27%) as a white solid. ^1H 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

A mixture of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (70.0 mg, 138 umol), (1-fluorocyclopropyl)methyl methanesulfonate (23.2 mg, 138 umol), potassium carbonate (57.2 mg, 414 umol) in N,N-dimethylformamide (1 mL) was stirred at 80 ° C for 12 hours under a nitrogen atmosphere. 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] pyrazol-4-yl] quinoxalin-6-yl] oxy-2-methyl-benzoimidazol-1-yl] methoxy] ethyl -trimethyl-silane (70.0 mg, 120 umol, 87%) as a yellow solid. m / z ES + [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

A mixture of 2-[[6-[5-chloro-3-[1-[(1-fluorocyclopropyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (65.0 mg, 112 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. 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*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 7 min) to give 8-chloro-2-[1-[(1-fluorocyclopropyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (44.0 mg, 98.0 umol, 85%) as a white solid. ¹ H NMR (400 MHz, 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]heptane-5-yl]ethyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a mixture of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]ethyl methanesulfonate (300 mg, 476 umol) and (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane; hydrochloride (193 mg, 1.43 mmol) in acetonitrile (5 mL) was added sodium bicarbonate (200 mg, 2.38 mmol) and the reaction mixture was stirred at 80 ° C for 12 hours. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (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-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl]ethyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (60.0 mg, 94.9 umol, 19%) as a yellow solid. m/z ES+[M+H] ⁺ 632.5.

Step 2. (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

A solution of 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 (50.0 mg, 79.0 umol) in trifluoroacetic acid (1 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 24%-54%, 10min) to give (1R,4R)-5-[2-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]ethyl]-2-oxa-5-azabicyclo[2.2.1]heptane (1.5mg, 2.93umol, 3%) as a yellow solid. ^1H 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 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 a solution of 2-[1-(azetidin-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (80.0 mg, 185 umol) and tetrahydropyran-4-one (24.1 mg, 241 umol) in tetrahydrofuran (2 mL), diisopropylethylamine (120 mg, 926 umol, 161) and sodium triacetoxyborohydride (78.5 mg, 371 umol) were added, and the mixture was stirred at 25° C. 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*25 mm*10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10 min) to give 8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]-2-[1-(1-tetrahydropyran-4-ylazetidin-3-yl)pyrazol-4-yl]quinoxaline (28.7 mg, 55.7 umol, 30%) as a yellow solid. ¹ H NMR (400 MHz, 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

A mixture of 2-[1-(azetidin-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (30 mg, 69.4 umol), 2-bromoacetonitrile (6.67 mg, 55.5 umol), potassium carbonate (20.5 mg, 148 umol) in acetonitrile (2 mL) was stirred at 25 ° C 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 C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 5min) and then re-purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 25%-55%, 7min) to give 2-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]azetidin-1-yl]acetonitrile (2.7mg, 5.69umol, 8%) as a white solid. ^1H 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,1 H), 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-(oxetane-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 a solution of 2-[1-(azetidine-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (50.0 mg, 115 umol) in tetrahydrofuran (3 mL) was added oxetane-3-one (16.7 mg, 231 umol) and the mixture was stirred at 25 ° C for 0.5 hours. Sodium triacetoxyborohydride (73.6 mg, 347 umol) was then added at 0 ° C. The mixture was stirred at 25 ° C 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 sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 22%-52%, 9min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[1-(oxetan-3-yl)azetidin-3-yl]pyrazol-4-yl]quinoxaline (26.9mg, 55.2umol, 47%) as a white solid. ^1H 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 a solution of 2-[1-(azetidine-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (50.0 mg, 115 umol) in 1-methylpyrrolidin-2-one (2 mL), potassium carbonate (48.0 mg, 347 umol) and 1-(azetidine-1-yl)-2-chloro-ethanone (15.1 mg, 113 umol) were added. The mixture was stirred at 25 ° C 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 C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 7 min) to give 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 (10.2 mg, 19.3 umol, 16%) as a white solid. ¹ H NMR (400 MHz, 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 a solution of 2-[1-(azetidine-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (50.0 mg, 115 umol) in 1-methylpyrrolidin-2-one (2 mL), potassium carbonate (48.0 mg, 347 umol) and 2-chloro-1-(3-hydroxyazetidine-1-yl)ethanone (15.5 mg, 104 umol) were added. The mixture was stirred at 25 ° C 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 Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 16%-46%, 9min) to give 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 (16.6mg, 30.5umol, 26%) as a white solid. ^1HNMR (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),5.1 6(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,3r)-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,3s)-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,3r)-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,3s)-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 purified by SFC (column: Daicel Chiralpak IG (250mm*30mm, 10um); mobile phase: [0.1% ammonium hydroxide, methanol]; (B%: 60%-60%, 4.6min) separation to obtain (1R, 3r)-3-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)methyl)-1-methylcyclobutanol (60.9mg, 127umol, 9.3%) and (1S, 3s)-3-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)methyl)-1-methylcyclobutanol (386mg, 773umol, 56%), both as green solids.

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/ zES+[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/ zES+[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. tert-Butyl 7-hydroxy-4-azaspiro[2.5]octane-4-carboxylate

At 0 ° C, sodium borohydride (25.2 mg, 666 μmol) was added portionwise to a solution of 7- oxo -4- azaspiro [2.5] octane -4- carboxylic acid tert-butyl esters (100 mg, 444 μmol) in methanol (1 mL). The mixture was stirred at 20 ° C 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 x3). The combined organic layer was 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 obtain 7- hydroxy -4- azaspiro [2.5] octane -4- carboxylic acid tert-butyl esters (90.0 mg, 396 μmol, 89%) as a colorless oil. 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. tert-Butyl 7-((methylsulfonyl)oxy)-4-azaspiro[2.5]octane-4-carboxylate

At 0 ° C, to a solution of 7-hydroxy-4-azaspiro [2.5] octane-4-carboxylic acid tert-butyl ester (90.0 mg, 396 μmol) and triethylamine (120 mg, 1.19 mmol) in dichloromethane (2 mL), methanesulfonyl chloride (68.0 mg, 594 μmol) was added, and the mixture was stirred at 20 ° C for 0.5 hours. After completion, the mixture was diluted with dichloromethane (20 mL) 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] octane-4-carboxylic acid tert-butyl ester (120 mg, 393 μmol, 99%) as a colorless oil. 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. tert-Butyl 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-carboxylate

To a mixture of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (120 mg, 237 μmol) and tert-butyl 7-methylsulfonyloxy-4-azaspiro[2.5]octane-4-carboxylate (108 mg, 355 μmol) in dimethyl sulfoxide (3 mL) was added potassium carbonate (65.4 mg, 473 μmol) and the mixture was stirred at 80° C. 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 tert-butyl 7-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylate (120 mg, 168 μmol, 70%) as a yellow solid. m/z ES+[M+H] ⁺ 716.3.

Step 4. 2-(1-(4-Azaspiro[2.5]octan-7-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

A solution of 7-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (120 mg, 167 μmol) in trifluoroacetic acid (3 mL) was stirred at 20 °C for 1 hour. After completion, the mixture was concentrated in vacuo, and the residue was purified by preparative HPLC [column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonium bicarbonate-acetonitrile]; (B%: 29%-59%, 9min] to give 2-[1-(4-azaspiro[2.5]octan-7-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (43.8 mg, 88.0 μmol, 52%) as a yellow solid. ¹ H NMR (400 MHz, 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,3r)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutanol and (1S,3s)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutanol

Step 1. (1R,3r)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutanol and (1S,3s)-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 μmol) was purified by SFC (column: Daicel Chiralpak IF (250mm*30mm, 10um); mobile phase: [hexane-EtOH (0.1% ammonium hydroxide)]; (B%: 35%-35%, 17min) separation to give (1R, 3r)-3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]cyclobutanol (102mg, 207μmol, 37%) as an off-white solid and (1S, 3s)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)cyclobutanol (5.8mg, 12.5μmol, 2.2%) as an off-white solid.

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＝6.8 Hz,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

At 0 ° C, methylmagnesium bromide (3M in THF, 170 μL) was added to a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (100 mg, 170 μmol) in tetrahydrofuran (3 mL). The mixture was stirred at 0 ° C for 1 hour. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) at 0 ° C, then diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layer was 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (40 mg, 67.8 μmol, 32%) as a white solid. m/z ES+[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

A mixture of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (30.0 mg, 51.0 μmol) in trifluoroacetic acid (0.3 mL) was stirred at 25° C. for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; (B%: 27%-57%, 10 min) to give 3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (15 mg, 33 μmol, 64%) as a white solid. ¹ H NMR (400 MHz, 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),5.3 2(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 ° C 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/z ES+[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-pyrazole-4-yl)quinoxaline (2.3 g, 8.36 mmol) in N,N-dimethylformamide (40 mL), potassium carbonate (2.31 g, 16.7 mmol) and (3,3-difluorocyclobutyl)methyl methanesulfonate (1.67 g, 8.36 mmol) were added. The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was 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 obtain a residue. The residue was triturated with petroleum ether:ethyl acetate (20:1, 60 mL) at 20 °C for 30 min to give 7-bromo-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxaline (800 mg, 2.12 mmol, 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

A mixture of 7-bromo-2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]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 (888 mg, 15.8 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. for 1 hour under a nitrogen atmosphere. 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, 1.27 mmol, 68%) as a yellow solid. m/z ES+[M+H] ⁺ 317.1.

Step 4. 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxalin-6-ol

To a solution of 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-ol (900 mg, 2.85 mmol) in chloroform (10 mL), nickel chloride (368 mg, 2.85 mmol), triethylamine (287 mg, 2.85 mmol) and N-iodosuccinimide (1.28 g, 5.69 mmol) were added. The mixture was stirred at 60 ° C for 2 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mL×3). The combined organic layer was 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 obtain 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxaline-6-ol (1.10 g, 2.43 mmol, 85%) as a red solid. m/zES+[M+H] ⁺ 442.9.

Step 5. N-tert-Butyloxycarbonyl-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 a solution of 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxalin-6-ol (1 g, 2.26 mmol) in N,N-dimethylformamide (10 mL) 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° C. 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]; (B%: 40% -60%, 7 min) to give tert-butyl N-tert-butoxycarbonyl-N-[5-[3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]oxy-2-nitro-phenyl]carbamate (1.20 g, 1.32 mmol, 58%) as a yellow solid. ¹ H NMR (400 MHz, 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 a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-[3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]oxy-2-nitro-phenyl]carbamate (1 g, 1.28 mmol) in dioxane (5 mL) was added hydrochloric acid/dioxane (4M, 10 mL). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give 5-[3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]oxy-2-nitro-aniline (1 g, crude) as a yellow solid. m/z ES+[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 a solution of 5-[3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxaline-6-yl]oxy-2-nitro-aniline (900 mg, 1.56 mmol) in ethanol (10 mL) and water (1 mL) was added iron powder (695 mg, 12.4 mmol) and ammonium chloride (665 mg, 12.4 mmol). The mixture was stirred at 60 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4-[3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxaline-6-yl]oxybenzene-1,2-diamine (1 g, crude) as a yellow solid. 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

To a solution of 4-[3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]oxybenzene-1,2-diamine (900 mg, 1.64 mmol) and 1,1,1-trimethoxyethane (986 mg, 8.21 mmol) in methanol (10 mL) was added sulfamic acid (318 mg, 3.28 mmol), and the mixture was stirred at 20° C. 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]pyrazol-4-yl]-8-iodo-7-[(2-methyl-1H-benzimidazol-5-yl)oxy]quinoxaline (600 mg, 1.05 mmol, 63%) as a yellow solid. 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-8-iodo-7-[(2-methyl-1H-benzimidazol-5-yl)oxy]quinoxaline (500 mg, 873 umol) in tetrahydrofuran (10 mL) was added sodium hydride (52.4 mg, 1.31 mmol, 60% in mineral oil) at 0°C, and the mixture was stirred at 0°C for 0.5 hours. A solution of 2-(chloromethoxy)ethyl-trimethylsilane (189 mg, 1.14 mmol) in tetrahydrofuran (2 mL) was then added dropwise, and the mixture was stirred at 0°C for 1 hour. 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]pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (550 mg, 782 umol, 89%) as a yellow solid. m/z ES+[M+H] ⁺ 703.0.

Step 10. 3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-N-(diphenylmethylene)-6-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-5-amine

To a solution of 2-[[5-[3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-5-iodo-quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50.0 mg, 71.2 μmol), diphenylmethaneimine (25.8 mg, 142 μmol) and cesium carbonate (69.6 mg, 213 μmol) in tert-amyl alcohol (0.5 mL) under nitrogen was added XantPhos Pd G4 (6.85 mg, 7.12 μmol), and the mixture was stirred at 90 °C for 16 hours. After completion, the mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (100% ethyl acetate) to give 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 mg, 42.0 μmol, 59%) as a yellow solid. m/z ES+[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 μmol) in hydrogen chloride/dioxane (4M, 0.1 mL) was stirred at 20° C. for 30 min. Upon 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

A solution of 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-6-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-5-amine (40.0 mg, 67.6 μmol) in trifluoroacetic acid (0.2 mL) was stirred at 20 °C for 10 min. After completion, the mixture was concentrated in vacuo, and the residue was purified by preparative HPLC [column: Phenomenex C18 75*30mm*3um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 15%-45%, 7min] and then re-purified by preparative TLC (dichloromethane:methanol=10:1) to give 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-6-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-5-amine (2 mg, 4.11 μmol, 6%) as a yellow solid. ¹ H NMR (400 MHz, 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-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxaline

Step 1. (1S,3s)-3-(Trifluoromethyl)cyclobutyl 4-methylbenzenesulfonate

To a solution of 3-(trifluoromethyl)cyclobutanol (50.0 mg, 357 umol) in dichloromethane (3 mL) was added triethylamine (72.7 mg, 718 umol), 4-dimethylaminopyridine (5.0 mg, 40.9 umol) and 4-methylbenzenesulfonyl chloride (170 mg, 892 umol). The mixture was stirred at 25 ° C 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 obtain (1S, 3s)-3-(trifluoromethyl)cyclobutyl 4-methylbenzenesulfonate (50 mg, 170 umol, 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-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxaline

To a solution of (1S, 3s)-3-(trifluoromethyl)cyclobutyl 4-methylbenzenesulfonate (20 mg, 68 umol) in N, N-dimethylformamide (1.2 mL), cesium carbonate (50 mg, 153 umol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (35 mg, 69 umol) were added. The mixture was stirred at 80 ° C 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]imidazol-6-yl)oxy)-2-(1-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxaline (62 mg, crude) as a yellow oil. m/z ES+[M+H] ⁺ 629.0.

Step 3. 8-Chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxaline

A solution of 8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)quinoxaline (60 mg, 95.4 umol) in trifluoroacetic acid (1.2 mL) was stirred at 25° C. for 2 hours. Upon completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 19%-49%, 10min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[3-(trifluoromethyl)cyclobutyl]pyrazol-4-yl]quinoxaline (23.9 mg, 48 umol, 50%) as a yellow solid. ¹ H NMR (400 MHz, 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/zES+[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. Ethyl 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)acetate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (4 g, 7.89 mmol) in acetonitrile (40 mL) was added ethyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (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° C. for 30 hours. After completion, the mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×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 ethyl 2-[8-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1,4-dioxaspiro[4.5]decane-8-yl]acetate (4.20 g, 5.73 mmol, 72%) as a yellow solid. m/z ES+[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 a solution of ethyl 2-[8-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]-1,4-dioxaspiro[4.5]decane-8-yl]acetate (1.5 g, 2.05 mmol) in dichloromethane (100 mL) was added diisobutylaluminum hydride (1 M, 10.2 mL) at -70°C, and the mixture was stirred at -70°C for 2 hours. After completion, the mixture was slowly quenched with methanol (50 mL) at -70°C, then slowly warmed to 20°C, and stirred at 20°C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1,4-dioxaspiro[4.5]decan-8-yl]acetaldehyde (1.40 g, crude) as a yellow solid, which was used directly in the next step. m/z ES+[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 a solution of 2-[8-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1,4-dioxaspiro[4.5]decan-8-yl]acetaldehyde (1.4 g, 2.03 mmol) in toluene (30 mL) under nitrogen was added Rh(PPh ₃ ) ₃ Cl (1.69 g, 1.83 mmol) and the mixture was stirred at 120° C. for 16 hours. Upon 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, the filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC [column: Phenomenex Synergi Max-RP 250*50mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 37%-67%, 21 min] to give 2-[[6-[5-chloro-3-[1-(8-methyl-1,4-dioxaspiro[4.5]decane-8-yl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (610 mg, 813 μmol, 40%) as a yellow solid. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-(8-methyl-1,4-dioxaspiro[4.5]decane-8-yl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (560 mg, 847 μmol) in formic acid (5 mL) and dichloromethane (5 mL) was stirred at 20° C. for 16 hours. Upon completion, the mixture was washed with saturated aqueous sodium bicarbonate solution (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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-4-methyl-cyclohexanone (310 mg, 490 μmol, 57%) as a yellow solid. m/z ES+[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

To a solution of 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-4-methyl-cyclohexanone (150 mg, 243 μmol) in dichloromethane (3 mL) was added diethylaminosulfur trifluoride (78.4 mg, 486 μmol) dropwise at 0° C., and the mixture was stirred at 35° C. for 2 hours. After completion, the mixture was poured into a saturated aqueous sodium bicarbonate solution (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]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (70 mg, 98.4 μmol, 40%) as a yellow solid. m/z ES+[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 °C for 1 hour. After completion, the mixture was concentrated in vacuo, and the residue was purified by preparative HPLC [column: Phenomenex C18 75*30mm*3um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 32%-42%, 7min] to give 8-chloro-2-[1-(4,4-difluoro-1-methyl-cyclohexyl)pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (51.4 mg, 98.6 μmol, 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-benzoimidazol-5-yl)oxy]quinoxaline (23.4 mg, 47.8 μmol, 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,3s)-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,3r)-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

At 0 ° C, methylmagnesium bromide (3M in THF, 185uL) was added to a solution of 3-[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (110mg, 185μmol) in anhydrous tetrahydrofuran (3mL). The mixture was stirred at 0 ° C for 2 hours. After completion, the mixture was quenched with saturated ammonium chloride (20mL) at 0 ° C, then diluted with water (20mL), and extracted with ethyl acetate (20mL×3). The combined organic layer was 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutanol (170 mg, 240 μmol, 65%) as a yellow oil. m/z ES+[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

A solution of 3-[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (140 mg, 198 μmol) in trifluoroacetic acid (2 mL) was stirred at 25° C. for 0.5 h. Upon completion, the 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(formic acid)-acetonitrile]; (B%: 19%-49%, 10 min) to give 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 μmol, 74%) as a white solid. m/z ES+[M+H] ⁺ 479.1.

Step 3. (1S,3s)-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,3r)-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 μmol) was separated by SFC (basic conditions; column: Daicel Chiralpak AD (250 mm*30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide/methanol]; (B%: 45%-45%, 3.6 min, total run 50 min) to give (1S,3s)-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 as a white solid. The mixture was stirred at room temperature for 2 h and then dried over medium (40 °C) for 2 h. The mixture was stirred at room temperature for 2 h. (1R,3r)-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 μmol, 64%) and (1R,3r)-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 (3.8 mg, 7.89 μmol, 5.4%) as a white solid.

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,3s)-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,3r)-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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (270 mg, 514 μmol) and (3,3-dimethoxycyclobutyl)methyl methanesulfonate (138 mg, 617 μmol) in N,N-dimethylformamide (5 mL), potassium carbonate (142 mg, 1.03 mmol) and potassium iodide (85.4 mg, 514 μmol) were added. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layer was 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]imidazol-6-yl)oxy)quinoxaline (280 mg, 416 μmol, 81%) as a yellow oil. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-[(3,3-dimethoxycyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (260 mg, 398 μmol) in dichloromethane (2.5 mL) and formic acid (2.5 mL) was stirred at 25 ° C 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclobutanone (230 mg, 364 μmol, 91%) as a white solid. m/z ES+[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

At 0 ° C, methylmagnesium bromide (3M in THF, 346 μL) was added to a solution of 3-[[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]cyclobutanone (210 mg, 346 μmol) in anhydrous tetrahydrofuran (5 mL). The mixture was stirred at 0 ° C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) at 0 ° C, then diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)-1-methylcyclobutanol (65.0 mg, 83.4 μmol, 24%) as a yellow oil. m/z ES+[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

A solution of 3-[[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-1-methyl-cyclobutanol (65.0 mg, 83.4 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 h. Upon completion, the 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(formic acid)-acetonitrile]; (B%: 21%-51%, 10 min) to give 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 mg, 59.0 μmol, 71%) as a white solid. m/z ES+[M+H] ⁺ 493.2.

Step 5. (1S,3s)-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,3r)-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 mg, 59.0 μmol) was separated by SFC (column: Daicel Chiralpak IE (250 mm*30 mm, 10 um); mobile phase: [hexane-EtOH (0.1% ammonium hydroxide)]; (B%: 55%-55%, 15 min) to give (1S,3s)-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 as a brown solid. The results were as follows: (1R,3r)-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 μmol, 18%) and (1R,3r)-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 (25.6 mg, 51.3 μmol, 84%) as off-white solids.

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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (130 mg, 248 μmol) in anhydrous tetrahydrofuran (6 mL) was added sodium hydride (29.7 mg, 743 μmol, 60% in mineral oil). The mixture was stirred at 25 ° C for 0.5 hours. Then 2-bromoacetic acid (51.6 mg, 371 μmol, 26.7 μL) was added. The mixture was stirred at 60 ° C for 1 hour. After completion, the mixture was quenched with water (2 mL) at 25 ° C and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and then acidified by saturated citric acid aqueous solution until pH was 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)acetic acid (140 mg, crude) as a yellow solid. 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 a solution of 2-[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]acetic acid (130 mg, 223 μmol) and 3,3-difluoropyrrolidine hydrochloride (48.0 mg, 334 μmol) in dichloromethane (5 mL) was added diisopropylethylamine (86.5 mg, 669 μmol, 117 μL). Then EDCI (64.1 mg, 334 μmol) and HOBt (45.2 mg, 334 μmol) were added. The mixture was stirred at 25 ° C 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-1-(3,3-difluoropyrrolidin-1-yl)ethanone (160 mg, crude) as a yellow oil. m/z ES+[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

A solution of 2-[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-(3,3-difluoropyrrolidin-1-yl)ethanone (150 mg, 223 μmol) in trifluoroacetic acid (3 mL) was stirred at 25° C. for 0.5 h. Upon completion, the 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(formic acid)-acetonitrile]; (B%: 20%-50%, 10 min) to give 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 (33.8 mg, 62.3 μmol, 28%) as a white solid. 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. Synthesis of 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)cyclopropanol

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]imidazol-6-yl)oxy)-2-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methyl)-1H-pyrazol-4-yl)quinoxaline (150 mg, 227 μmol), 2-(cyclopent-1-en-1-yl ... -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88.1 mg, 454 μmol), [2-(2-aminophenyl)phenyl]palladium (1+); bis(1-adamantyl)-butyl-phosphine; mesylate (16.5 mg, 22.7 μmol), cesium carbonate (222 mg, 681 μmol) mixture was degassed and purged with nitrogen three times, and then the mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere. 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]imidazol-6-yl)oxy)-2-(1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methyl)-1H-pyrazol-4-yl)quinoxaline (120 mg, 173 μmol, 76%) as a yellow solid. m/z ES+[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)cyclopropanol

A solution of 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 (120 mg, 173 μmol) in trifluoroacetic acid (0.5 mL) was stirred at 25° C. for 1 hour. Upon completion, 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(formic acid)-acetonitrile]; (B%: 14%-44%, 10 min) to give 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)cyclopropanol (44.3 mg, 90.8 μmol, 52%) as a yellow solid. ¹ H NMR (400 MHz, 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＝2.4,8.8 Hz,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. Synthesis of 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

Step 1. (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) was added methanesulfonyl chloride (296 mg, 2.58 mmol) at 0° C., and the mixture was stirred for 1 hour at 0° C. The mixture was quenched with water (5 mL) and extracted with dichloromethane (8 mL×3), and 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 light red solid. ¹ H NMR (400MHz, CDCl ₃ ) δ = 4.09 (d, J = 6.0 Hz, 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 a solution of (4,4-difluorocyclohexyl)methyl methanesulfonate (100 mg, 438 umol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (230 mg, 438 umol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (180 mg, 1.30 mmol). The mixture was stirred at 80 ° C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-7-fluoro-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (310 mg, crude) as a yellow oil. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-[(4,4-difluorocyclohexyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-7-fluoro-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (300 mg, 456 umol) in trifluoroacetic acid (3 mL) was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 35%-65%, 10min) to give 8-chloro-2-[1-[(4,4-difluorocyclohexyl)methyl]pyrazol-4-yl]-7-[(4-fluoro-2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (206 mg, 390 umol, 85%) as a yellow solid. ¹ H NMR (400 MHz, 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,3r)-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,3s)-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. 2-(1-(5,8-dioxaspiro[3.4]octan-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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (3.50 g, 6.90 mmol) and 2-bromo-5,8-dioxaspiro[3.4]octane (2.13 g, 11.0 mmol) in N,N-dimethylformamide (50 mL), potassium carbonate (2.86 g, 20.7 mmol) and potassium iodide (115 mg, 690 μmol) were added. The mixture was stirred at 100 ° C 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 layer was 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]octan-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, 5.43 mmol, 79%) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[5-chloro-3-[1-(5,8-dioxaspiro[3.4]octan-2-yl)pyrazol-4-yl]quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (3.5 g, 5.65 mmol) in dichloromethane (18 mL) and water (1 mL) was added formic acid (42.7 g, 928 mmol, 35 mL). The mixture was stirred at 40 ° C 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 solution until pH = 8-9. The mixture was extracted with ethyl acetate (100 mL×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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutanone (2.5 g, 4.26 mmol, 75%) as a white solid. m/z ES+[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

At 0 ° C, methylmagnesium bromide (3M in THF, 522 μL) was added to a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (300 mg, 522 μmol) in anhydrous tetrahydrofuran (3 mL). The mixture was then stirred at 0 ° C for 2 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) at 0 ° C, diluted with water (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layer was 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutanol (750 mg, 1.27 mmol, 49%) as a white solid. m/z ES+[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

A mixture of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (750 mg, 1.27 mmol) in trifluoroacetic acid (7.5 mL) was stirred at 25° C. for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. Then, the crude product was purified by preparative HPLC (formic acid conditions; column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (formic acid)-acetonitrile]; (B%: 10%-40%, 10 min) to give 3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (470 mg, 1.02 mmol, 80%) as a white solid. m/z ES+[M+H] ⁺ 461.1.

Step 5. (1R,3r)-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,3s)-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-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (470 mg, 1.02 mmol) was purified by SFC (basic conditions, column: Daicel Chiralpak IG (250mm×30mm, 10um); mobile phase: [heptane-ethanol (0.1% ammonium hydroxide)]; (B%: 40%-40%, 15min) separation to obtain (1R, 3r)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)-1-methylcyclobutanol (330mg, 715μmol, 70%) as a white solid and (1S, 3s)-3-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]-1-methyl-cyclobutanol (28.0mg, 54.7μmol, 5.4%) 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＝9.6 Hz,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 a solution of 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-ol (900 mg, 2.85 mmol) in chloroform (15 mL) was 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 ° C 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 obtain 5-bromo-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxaline-6-ol (1.6 g, crude) as a yellow solid. m/zES+[M+H] ⁺ 397.1.

Step 2. N-[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 a solution of 5-bromo-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-ol (1.25 g, 3.16 mmol) in N,N-dimethylformamide (20 mL) was 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 was stirred at 80 ° C 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 layer was 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-nitro-phenyl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (2.4 g, 2.62 mmol, 83%) as a brown oil. m/z ES+[M+H] ⁺ 732.9.

Step 3. 5-((5-Bromo-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-2-nitroaniline

To a solution of N-[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 (2.2 g, 3.01 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at 20 ° C for 0.5 hours. 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, 1.86 mmol, 62%) as a yellow solid. m/z ES+[M+H] ⁺ 533.0.

Step 4. 4-((5-Bromo-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)benzene-1,2-diamine

To a solution of 5-[5-bromo-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-yl]oxy-2-nitro-aniline (1 g, 1.88 mmol) in ethanol (20 mL) and water (2 mL), iron powder (526 mg, 9.41 mmol) and ammonium chloride (1.01 g, 18.8 mmol) were added. The mixture was stirred at 60 ° C 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 layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4-((5-bromo-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxaline-6-yl)oxy)benzene-1,2-diamine (1 g, crude) as a yellow solid. 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 a solution of 4-[5-bromo-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline-6-yl]oxybenzene-1,2-diamine (1 g, 1.99 mmol) in methanol (20 mL) was added sulfamic acid (387 mg, 3.99 mmol) and 1,1,1-trimethoxyethane (1.20 g, 9.97 mmol). The mixture was stirred at 20 ° C 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]imidazol-5-yl)oxy)quinoxaline (800 mg, 1.43 mmol, 72%) as a red solid. 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 a solution of 8-bromo-2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-7-[(2-methyl-1H-benzimidazol-5-yl)oxy]quinoxaline (560 mg, 1.07 mmol) in anhydrous tetrahydrofuran (10 mL) was added sodium hydride (85.3 mg, 2.13 mmol, 60% in mineral oil). The mixture was stirred at 0 ° C for 0.5 hours. (2-(chloromethoxy)ethyl)trimethylsilane (355 mg, 2.13 mmol) was then added dropwise, and the resulting mixture was stirred at 20 ° C 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-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)oxy)quinoxaline (170 mg, 246 μmol, 23%) as a yellow solid. ¹ H NMR (400 MHz, 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[5-[5-bromo-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50.0 mg, 76.3 umol) in dioxane (1 mL) and water (0.2 mL) was added 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (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 at 100 ° C for 1 hour under nitrogen. 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]pyrazol-4-yl]-5-(2,5-dihydrofuran-3-yl)quinoxaline-6-yl]oxy-2-methylbenzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50.0 mg, 69.8 umol, 92%) as a yellow solid. 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

A solution of 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 (30 mg, 46.5 μmol) in trifluoroacetic acid (0.5 mL) was stirred at 20° C. for 0.5 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 16%-46%, 10 min) to give 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 (8.8 mg, 17.1 μmol, 36.7%) as a yellow solid. ¹ H NMR (400 MHz, 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/zES+[M+H] ⁺ 5 15.0.

Example 95. 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)quinoxaline

Step 1. 3-(Benzyloxy)-N-methoxy-N-methylcyclobutanecarboxamide

To a solution of 3-benzyloxycyclobutanecarboxylic acid (5 g, 24.2 mmol) and N-methoxymethylamine (3.55 g, 36.3 mmol, HCl salt) in N,N-dimethylformamide (50 mL) was added N,N-diisopropylacetyleneamine (12.5 g, 96.9 mmol) and HATU (13.8 g, 36.3 mmol). The mixture was stirred at 25 ° C 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 obtain 3-benzyloxy-N-methoxy-N-methyl-cyclobutanecarboxamide (5 g, 19.0 mmol, 78%) as a colorless 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,2 H),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 methylmagnesium bromide (1 M, 26 mL, 26 mmol). The mixture was stirred at 0 ° C for 2 hours under a nitrogen atmosphere. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) at 0 ° C and diluted with water (50 mL). The mixture was 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 to give 1-(3-benzyloxycyclobutyl)ethanone (4 g, 17.6 mmol, 88%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.27 (m, 5H), 4.49-4.39 (m, 2H), 4.04-3.94 (m, 1H), 2.73 (dd, J=8.0, 9.6 Hz, 1H), 2.53-2.40 (m, 2H), 2.30-2.14 (m, 2H), 2.11 (s, 3H).

Step 3. (E)-3-(3-(Benzyloxy)cyclobutyl)but-2-enoic acid ethyl ester

To a solution of ethyl 2-diethoxyphosphoryl acetate (4.74 g, 21.1 mmol) in tetrahydrofuran (36 mL) was added sodium hydride (845 mg, 21.1 mmol, 60% in mineral oil), and the mixture was stirred at 0 ° C for 0.5 hours. Then 1- (3-benzyloxycyclobutyl) ethanone (3.60 g, 17.6 mmol) was added. The mixture was stirred at 25 ° C for 11.5 hours under a nitrogen atmosphere. After completion, at 0 ° C, the reaction mixture was quenched with water (50 mL), and then extracted with ethyl acetate (3 × 50 mL). The combined organic layer was 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 (E)-ethyl 3-(3-benzyloxycyclobutyl)but-2-enoate (4.30 g, 15.3 mmol, 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,1 H),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. Ethyl 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)butanoate

1,8-diazabicyclo[5.4.0]undec-7-ene (720 mg, 4.73 mmol) and (E)-3-(3-benzyloxycyclobutyl)but-2-enoic acid ethyl ester (1.30 g, 4.73 mmol) were added to a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (2 g, 3.94 mmol) in acetonitrile (20 mL). The mixture was stirred at 60 ° C 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 ethyl 3-(3-benzyloxycyclobutyl)-3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]butanoate (1.70 g, 2.15 mmol, 54%) as a yellow solid. m/z ES+[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 a solution of 3-(3-benzyloxycyclobutyl)-3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]butyric acid ethyl ester (1.50 g, 1.92 mmol) in dichloromethane (75 mL) was added diisobutylaluminum hydride (1 M, 9.6 mL, 9.6 mmol) dropwise at -70°C. The mixture was stirred at -70°C for 1 hour under a nitrogen atmosphere. Upon completion, the reaction mixture was slowly quenched with methanol (5 mL) at -70°C and then warmed to 25°C. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3-(3-benzyloxycyclobutyl)-3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]butanal (1.40 g, 1.54 mmol, 80%) as a yellow solid. m/z ES+[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 a solution of 3-(3-benzyloxycyclobutyl)-3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]butanal (1.40 g, 1.90 mmol) in toluene (14 mL) was added Rh(PPh ₃ ) ₃ Cl (1.76 g, 1.90 mmol). The mixture was stirred at 120° C. for 12 hours under nitrogen atmosphere. Upon 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 condition) to give 2-[[6-[3-[1-[1-(3-benzyloxycyclobutyl)-1-methyl-ethyl]pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (320 mg, 365 μmol, 19%) as a white solid. m/z ES+[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

To a solution of 2-[[6-[3-[1-[1-(3-benzyloxycyclobutyl)-1-methyl-ethyl]pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (300 mg, 422 μmol) in dichloromethane (3 mL) at 0° C., tribromoborane (317 mg, 1.27 mmol) was added. The mixture was stirred at 0° C. for 0.5 hours under a nitrogen atmosphere. Upon completion, the reaction mixture was quenched with water (5 mL) at 0° C. 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]quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-ethyl]cyclobutanol (130 mg, 263 μmol, 62%) as a ^white solid. 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,1 H),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 a solution of 3-[1-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-ethyl]cyclobutanol (95.0 mg, 194 μmol) in dichloromethane (1 mL) and N,N-dimethylformamide (0.1 mL) at 0°C was added Dess-Martin bivalent iodide (123 mg, 291 μmol). The mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. Upon completion, the reaction mixture was quenched at 0°C with saturated aqueous sodium thiosulfate solution (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL), 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]; (B%: 11%-41%, 10 min) to give 3-[1-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-ethyl]cyclobutanone (70.0 mg, 143 μmol, 73%) as a ^white solid. 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 a solution of 3-[1-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-methyl-ethyl]cyclobutanone (40.0 mg, 82.1 μmol) in dichloromethane (1 mL) at 0°C was added bis(2-methoxyethyl)aminosulfur trifluoride (181 mg, 821 μmol). The mixture was stirred at 0°C for 0.1 hours under a nitrogen atmosphere. Upon completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL) at 0°C, 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 C18150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 25%-45%, 10 min) to give 8-chloro-2-[1-[1-(3,3-difluorocyclobutyl)-1-methyl-ethyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (26.5 mg, 51.6 μmol, 62%) as a ^white solid. 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

A mixture of 3-[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (30.0 mg, 51.0 μmol) in trifluoroacetic acid (0.5 mL) was stirred at 25° C. 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 C18 150×25 mm×10 um; mobile phase: [water (formic acid)-acetonitrile]; (B%: 19%-49%, 10 min) to give 3-[4-[8-chloro-7-[(4-fluoro-2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (15.3 mg, 32.7 μmol, 65%) as a white solid. ¹ H NMR (400 MHz, 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,3s)-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

At 0 ° C, sodium borohydride (19 mg, 506 μmmol) was added to a solution of 3-[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (300 mg, 506 μmol) in ethanol (3 mL). The mixture was stirred at 0 ° C for 0.5 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) at 0 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanol (200 mg, 333 μmol, 66%) as a ^white solid. 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.

Step 2. (1S,3s)-3-(4-(8-chloro-7-((7-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutanol

A solution of 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 (200 mg, 340 μmol) in trifluoroacetic acid (2 mL) was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (formic acid)-acetonitrile]; (B%: 16%-46%, 10 min) to give (1S,3s)-3-[4-[8-chloro-7-[(4-fluoro-2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]cyclobutanol (84.5 mg, 0.18 mmol, 54%) as a ^white solid. 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)ethyl methanesulfonate

At 0 ° C, N, N- diisopropylacetyl amine (111 mg, 1.10 mmol) and methanesulfonyl chloride (100 mg, 881 μmol) were added to a solution of 1- (3,3- difluorocyclobutyl) ethanol (100 mg, 734 μmol) in dichloromethane (1 mL). The mixture was stirred at 25 ° C for 0.5 hours. After completion, the reaction mixture was quenched with water (10 mL) at 0 ° C and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 1- (3,3- difluorocyclobutyl) ethyl methanesulfonate (157 mg, crude product) 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 394 μmol) and 1-(3,3-difluorocyclobutyl)ethyl methanesulfonate (118 mg, 552 μmol) in N,N-dimethylformamide (2 mL), potassium carbonate (109 mg, 788 μmol) and potassium iodide (6.55 mg, 39.4 μmol) were added. The mixture was stirred at 100 ° C 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]imidazol-6-yl)oxy)quinoxaline (130 mg, 204 μmol, 51%) as a brown solid. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-[1-(3,3-difluorocyclobutyl)ethyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (130 mg, 207 μmol) in trifluoroacetic acid (1 mL) was stirred at 25 °C 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*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 16%-46%, 10 min) to give 8-chloro-2-[1-[1-(3,3-difluorocyclobutyl)ethyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (41.9 mg, 84.7 μmol, 40%) as a ^white solid. 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

Step 1. 4-nitrophenyl 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-carboxylate

Under nitrogen, triethylamine (180 mg, 1.78 mmol) was added in one portion to a mixture of 2-[[6-[3-[1-(azetidin-3-yl)pyrazol-4-yl]-5-chloro-quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 889 umol) and (4-nitrophenyl) chloroformate (179 mg, 889 umol) in dichloromethane (10 mL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4-nitrophenyl 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-carboxylate (0.6 g, 578 umol, 65%) as a yellow solid. m/z ES+[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 25 ° C, to a mixture of 3- [4- [8-chloro-7- [2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl] oxy-quinoxaline-2-yl] pyrazol-1-yl] azetidine-1-carboxylic acid (4-nitrophenyl) ester (300 mg, 413 μmol) and azetidine-3-ol hydrochloride (135.58 mg, 1.24 mmol) in dichloromethane (5 mL) was added N, N-diisopropylacetyl amine (41.7 mg, 413 μmol, 57.4 μL) in one portion. The mixture was stirred at 25 ° C 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]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%) as a yellow solid. m/z ES+[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

A solution 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)azetidin-1-yl)(3-hydroxyazetidin-1-yl)methanone (80 mg, 121 μmol) in trifluoroacetic acid (3 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 7%-37%, 10 min) to give (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 (26.4 mg, 49.8 μmol, 41%) as a yellow solid. ¹ H NMR (400 MHz, 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-dimethylazetidine-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 a mixture of 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 (150 mg, 267 μmol) and N,N-dimethylcarbamoyl chloride (28.7 mg, 267 μmol, 24.5 μL) in dichloromethane (4 mL) was added N,N-diisopropylacetylamine (81.0 mg, 801 μmol, 111 μL) at 0°C. The mixture was stirred at 0°C for 30 min. Upon completion, the reaction mixture was quenched with water (5 mL) at 20°C and then extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with brine (5 mL x 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-N,N-dimethylazetidine-1-carboxamide (80 mg, 125 μmol, 47%) as a yellow solid. m/z ES+[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

A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-N,N-dimethyl-azetidine-1-carboxamide (70 mg, 111 μmol) in trifluoroacetic acid (3 mL) was stirred at 25° C. for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 11%-41%, 10 min) to give 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-N,N-dimethyl-azetidine-1-carboxamide (25.3 mg, 50.1 μmol, 45%) as an off-white solid. ¹ H NMR (400 MHz, 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. Synthesis of 1-((4-(7-((5,7-difluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropanol

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

A mixture of 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (80.0 mg, 157 μmol), (1-tetrahydropyran-2-yloxycyclopropyl)methanol (32.5 mg, 189 μmol), diisopropyl azodicarboxylate (47.7 mg, 236 μmol), triphenylphosphine (61.9 mg, 236 μmol) in toluene (2 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 60 °C under nitrogen atmosphere 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]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%) as a yellow solid. m/z ES+[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

A solution of 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 (50 mg, 75.4 μmol) in trifluoroacetic acid (1 mL) was stirred at 20° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 17%-44%, 9 min) to give 1-((4-(7-((5,7-difluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropanol (10.4 mg, 23.3 μmol, 31%) as a white solid. ¹ H NMR (400 MHz, 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 a solution of 2-[[5,7-difluoro-2-methyl-6-[3-(1H-pyrazol-4-yl)quinoxalin-6-yloxy-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (70 mg, 138 μmol) in N,N-dimethylformamide (1.5 mL) was added 1,3-dioxolane-2-one (36.4 mg, 413 μmol). The mixture was stirred at 140 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give 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 (70 mg, crude) as a brown oil. m/z ES+[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

A solution of 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 (70 mg, 127 μmol) in trifluoroacetic acid (1 mL) was stirred at 20° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 17%-47%, 10 min) to give 2-(4-(7-((5,7-difluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)ethanol (30.1 mg, 70.6 μmol, 56%) as a white solid. ¹ H NMR (400 MHz, 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 a solution of 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (60 mg, 118 μmol) in N,N-dimethylformamide (1 mL) was added cesium carbonate (76.9 mg, 236 μmol) and 2,2-dimethyloxirane (25.5 mg, 354 μmol). The mixture was stirred at 100 °C for 1 hour. Upon 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (60 mg, crude) as a brown solid. m/z ES+[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

A solution of 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 (60 mg, 103 μmol) in trifluoroacetic acid (0.5 mL) was stirred at 20° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 22%-52%, 7 min) to give 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 (22.1 mg, 48.0 μmol, 47%) as a white solid. ¹ H NMR (400 MHz, 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. Synthesis of 1-((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

The solution of lithium aluminum hydride (653mg, 17.2mmol) in tetrahydrofuran (5mL) is degassed and purged with nitrogen 3 times. Then 1-hydroxycyclobutanecarboxylic acid (500mg, 4.31mmol) in tetrahydrofuran (5mL) is added dropwise at 25°C. The mixture is then stirred at 70°C for 1 hour. After completion, the mixture is quenched with sodium sulfate tetrahydrate (20g). The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1 to 0/1) to obtain 1- (hydroxymethyl) cyclobutanol (350mg, 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

A mixture of 8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (100 mg, 197 μmol), 1-(hydroxymethyl)cyclobutanol (40 mg, 391 μmol), triphenylphosphine (77.6 mg, 295 μmol) and diisopropyl azodicarboxylate (59.8 mg, 295 μmol) in toluene (1 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 60° C. for 16 hours under a nitrogen atmosphere. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (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] imidazol-6-yl) oxy) quinoxalin-2-yl) -1H-pyrazol-1-yl) methyl) cyclobutanol (100 mg, 169 μmol, 85%) as a yellow solid. m / z ES + [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

A solution of 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 (100 mg, 169 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 10 min. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 25%-35%, 7 min) to give 1-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclobutanol (36.2 mg, 77.2 μmol, 45%) as an off- ^white solid. 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-morpholinethanone

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-morpholinethanone

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 190 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (53 mg, 381 μmol) and 2-chloro-1-morpholine-ethanone (34 mg, 210 μmol). The mixture was stirred at 80 ° C 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 x 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-morpholine-ethanone (150 mg, crude) as a yellow solid. m/z ES+[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-morpholinethanone

A solution of 2-[4-[8-chloro-7-[4-fluoro-2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-morpholine-ethanone (150 mg, 230 μmol) in trifluoroacetic acid (1.8 mL) was stirred at 25° C. 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: Shim-pack C18 150*25*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 12%-42%, 10 min) to give 2-(4-(8-chloro-7-((7-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-1-morpholinoethanone (30.9 mg, 0.059 mmol, 26%) as a ^white solid. 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/zES+[M+H] ⁺ 521.9.

Example 106. Synthesis of 8-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 a solution of 8-chloro-7-((7-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (150 mg, 285 μmol) and 4,4-difluorocyclohexyl methanesulfonate (122 mg, 571 μmol) in dimethyl sulfoxide (1 mL) was added cesium carbonate (186 mg, 571 μmmol) and potassium iodide (47.4 mg, 285 μmol). The mixture was then stirred at 80 °C for 16 hours. Upon 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-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (180 mg, 279 μmol, 97%) as a yellow oil. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-(4,4-difluorocyclohexyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-7-fluoro-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (180 mg, 279 μmol) in trifluoroacetic acid (1 mL) was stirred for 10 min at 25° C. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 33%-63%, 10 min) to give 8-chloro-2-(1-(4,4-difluorocyclohexyl)-1H-pyrazol-4-yl)-7-((7-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (100 mg, 190 μmol, 68%) as a white solid. ¹ H NMR (400 MHz, 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. Synthesis of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-(oxetane-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 a solution of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (50 mg, 108 umol) and oxetanes-3-one (23.5 mg, 326 umol) in methanol (1 mL) was added sodium acetate (11.6 mg, 141 umol) and sodium cyanoborohydride (20.5 mg, 326 umol). The mixture was stirred at 25 ° C for 6 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 18%-48%, 9min) to give 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 (47.6 mg, 92.4 umol, 77%) as an off-white solid. ¹ H NMR (400 MHz, 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＝2.4,8.8 Hz,1H),4.7 7-4.68(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]heptane-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]heptane-5-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

Step 1. tert-Butyl 5-methylsulfonyloxy-2-azabicyclo[2.2.1]heptane-2-carboxylate

Methanesulfonyl chloride (403mg, 3.52mmol) and triethylamine (712mg, 7.03mmol) are added to a solution of 5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl esters (500mg, 2.34mmol) in dichloromethane (5mL). The mixture is stirred at 0°C for 1 hour. After completion, the reaction mixture is quenched with water (40mL) and extracted with dichloromethane (40mL × 3). The combined organic layer is washed with brine (30mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 5-methylsulfonyloxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl esters (550mg, crude product) as an orange oil.

Step 2. 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)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To 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 (400 mg, 789 umol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (327 mg, 2.37 mmol) and tert-butyl 5-((methylsulfonyl)oxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (460 mg, 1.58 mmol). The mixture was stirred at 80° C. 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 condition, 90%-95%, 5 min) 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)-2-azabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 0.29 mmol, 36%) as an orange oil. m/z ES+[M+H] ⁺ 702.6.

Step 3. 2-(1-(2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

A solution of 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)-2-azabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 283 umol) in trifluoroacetic acid (1 mL) was stirred at 30° C. for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 3%-33%, 10min) to give 2-(1-(2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (39.3 mg, 83.4 umol, 29%) as an off-white solid. ¹ H NMR (400 MHz, 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,1 H),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,2 H), 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]heptane-5-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

To a solution of 2-(1-(2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (60.0 mg, 127 umol), acetone (22.2 mg, 381 umol) in methanol (1 mL) 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 ° C 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 ° C for 2 hours. Upon 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 C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 10min) to give 8-chloro-2-(1-(2-isopropyl-2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (9.0 mg, 17.5 umol, 14%) as a white solid. ¹ H NMR (400 MHz, 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),7.2 1(s,1H),6.94(dd,J＝2.4,8.4Hz,1H),4.79(dd,J＝3.6,7.6Hz,1 H),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

Step 1. (3,3-Dimethoxycyclobutane-1,1-diyl)dimethanol

At 0 ° C, lithium aluminum hydride (3.95g, 104mmol) was added to a solution of 3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diisopropyl ester (10g, 34.68mmol) in tetrahydrofuran (100mL) in batches. The mixture was stirred at 25 ° C for 12 hours. The mixture was diluted with tetrahydrofuran (100mL), then carefully quenched by dropping water (4mL), 15% sodium hydroxide (4mL) and water (12mL). 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 obtain (3,3-dimethoxycyclobutane-1,1-diyl) dimethanol (3.89g, 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).

Step 2. (3,3-Dimethoxycyclobutane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

At 0 ° C, to a solution of [1-(hydroxymethyl)-3,3-dimethoxy-cyclobutyl]methanol (3.89 g, 22.08 mmol) in pyridine (40 mL) was added 4-methylbenzenesulfonyl chloride (12.6 g, 66.23 mmol). The mixture was stirred at 0 ° C 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 obtain (3,3-dimethoxycyclobutane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (4.5 g, 12.13 mmol, 55%) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 7.74 (d, J = 8.2 Hz, 4H), 7.49 (d, J = 8.1 Hz, 4H), 3.93 (s, 4H), 2.89 (s, 6H), 2.43 (s, 6H), 1.85 (s, 4H).

Step 3. (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 ° C 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 = 8.2 Hz, 4H), 7.55 (d, J = 8.1 Hz, 4H), 4.23 (s, 4H), 2.92 (s, 4H), 2.49 (s, 6H).

Step 4. (3-Hydroxycyclobutane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

At 0 ° C, sodium borohydride (148 mg, 3.92 mmol) was added to a solution of (3-oxocyclobutane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (860 mg, 1.96 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 25 ° C 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 layer was 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 obtain (3-hydroxycyclobutane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (790 mg, 1.79 mmol, 91%) as a white solid. ^1. 99-1.93(m,2H),1.64-1.57(m,2H).

Step 5. 2-Oxabicyclo[2.1.1]hexan-4-ylmethyl 4-methylbenzenesulfonate

At 0 ° C, sodium hydride (215 mg, 5.38 mmol, 60% in mineral oil) was added to a solution of (3-hydroxycyclobutane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (790 mg, 1.79 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 25 ° C 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 layer was 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 obtain 2-oxabicyclo[2.1.1]hexane-4-ylmethyl 4-methylbenzenesulfonate (140 mg, 490 umol, 27%) as a white solid. . ¹ HNMR (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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 98.6 umol) and 2-oxabicyclo[2.1.1]hexane-4-ylmethyl 4-methylbenzenesulfonate (63.5 mg, 118 umol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (81.8 mg, 296 umol). The mixture was stirred at 80 ° C for 3 hours. The reaction mixture was quenched 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 to give 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 (150 mg, crude) as a yellow oil. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-(2-oxabicyclo[2.1.1]hexan-4-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (140 mg, 232 umol) in trifluoroacetic acid (3 mL) was stirred for 1 hour at 25° C. 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]; (B%: 13%-43%, 10min) to give 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 (22.7mg, 47.9umol, 21%) as a ^yellow solid. 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] ⁺ 4 73.1.

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

Step 1. (1-tritylaziridin-2-yl)methanol

At 0 ° C, lithium borohydride (164 mg, 7.54 mmol) was added to a solution of 1-trityl aziridine-2-carboxylic acid methyl ester (700 mg, 2.04 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for 2 hours at 20 ° C. After completion, the reaction mixture was quenched with saturated ammonium chloride (10 mL) at 0 ° C, then diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1-trityl aziridine-2-yl) methanol (900 mg, crude product) 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), 1.8 6(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 a solution of (1-tritylaziridin-2-yl)methanol (280 mg, 887 umol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (300 mg, 592 umol) in dichloromethane (6 mL) was added triphenylphosphine (233 mg, 887 umol). Diisopropyl azodicarboxylate (179 mg, 887 umol) was then added at 0° C., and the mixture was stirred at 25° C. for 1 hour. Upon 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]imidazol-6-yl)oxy)-2-(1-((1-tritylaziridin-2-yl)methyl)-1H-pyrazol-4-yl)quinoxaline (350 mg, 0.44 mmol, 66%) as a ^yellow solid. 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(d d,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 a solution of 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 (100 mg, 124 umol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 20° C. for 1 hour. Upon 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]imidazol-6-yl)oxy)quinoxaline (100 mg, crude) as a yellow solid. m/z ES+[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

A solution of 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 (60 mg, 107 umol) in trifluoroacetic acid (1 mL) was stirred at 20° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-25%, 10min) and re-purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 17%-47%, 9min) to give 2-(1-(aziridin-2-ylmethyl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (14.6mg, 33.9umol, 32%) as a ^white solid. 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] ⁺ 43 2.1.

Example 111. Synthesis of 2-(1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

Step 1. 2-(1-(5,8-dioxaspiro[3.4]octan-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 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 (500 mg, 980 umol) and 2-bromo-5,8-dioxaspiro[3.4]octane (210 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (408 mg, 3.0 mmol) and potassium iodide (16 mg, 99 umol). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 2). 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]octan-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, 0.58 mmol, 52%) as a yellow solid. m/z ES+[M+H] ⁺ 619.3.

Step 2. 2-(1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

A solution of 2-(1-(5,8-dioxaspiro[3.4]octan-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) in trifluoroacetic acid (0.5 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 35%-65%, 9min) to give 2-(1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (8.7mg, 17.7umol, 22%) as a ^white solid. 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-benzimidazol-1-yl]methoxy]ethyl-trimethylsilane

To a mixture of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (100 mg, 197 umol) in N,N-dimethylformamide (2 mL) at 0°C, sodium hydride (15.8 mg, 394 umol, 60% in mineral oil) was added. The mixture was stirred at 0°C for 0.5 hours. 3-bromoprop-1-ene (40.0 mg, 330.65 umol) was then added, and the mixture was stirred at 20°C for 1.5 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 2-[[6-[3-(1-allylpyrazol-4-yl)-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethylsilane (120 mg, crude) as a yellow solid. m/z ES+[M+H] ⁺ 547.1.

Step 2. 2-(1-allylpyrazol-4-yl)-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline

A solution of 2-[[6-[3-(1-allylpyrazol-4-yl)-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 183 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 7 min) to give 2-(1-allylpyrazol-4-yl)-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (50.4 mg, 0.12 mmol, 66%) as a yellow solid. ¹ H NMR (400 MHz, 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

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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 394 umol) in tetrahydrofuran (8 mL) was added sodium hydride (50.0 mg, 1.25 mmol, 60% in mineral oil). The mixture was stirred at 25 ° C for 0.5 hours. 2-bromoacetic acid (80.0 mg, 576 umol) was then added and the mixture was stirred at 60 ° C for 1.5 hours. After completion, the reaction mixture was quenched with water (2 mL) at 25 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetic acid (200 mg, 0.35 mmol, 86%) as a yellow solid. m/z ES+[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 a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetic acid (100 mg, 177 umol) in acetonitrile (3 mL) was added tris(2,2,2-trifluoroethyl)borate (120 mg, 390 umol) and 2-aminoethanol (17 mg, 278 umol). The mixture was stirred at 100° C. 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]; (B%: 45% -80%, 6 min) to give 2- [4- [8-chloro-7- [2-methyl-3- (2-trimethylsilylethoxymethyl) benzimidazol-5-yl] oxy-quinoxalin-2-yl] pyrazol-1-yl] -N- (2-hydroxyethyl) acetamide (60 mg, 98.8 umol, 55%) as a yellow solid. m / z ES + [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

A solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-N-(2-hydroxyethyl)acetamide (35 mg, 58 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 8%-38%, 7 min) to give 2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-N-(2-hydroxyethyl)acetamide (23.6 mg, 49.5 umol, 86%) as a white solid. ¹ H NMR (400 MHz, 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

A mixture of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]ethyl methanesulfonate (500 mg, 795 umol) and 2-aminoethanol (971 mg, 15.9 mmol) was stirred at 80 ° C 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]oxy-quinoxaline-2-yl]pyrazol-1-yl]ethylamino]ethanol (0.22 g, 296 umol, 37%) as a yellow solid. 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

A mixture of 2-[2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethylamino]ethanol (0.22 g, 370 umol) in trifluoroacetic acid (3 mL) was stirred at 20° C. for 2 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure to get a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10min) to give 2-[2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]ethylamino]ethanol (63.6mg, 137umol, 37%) as a yellow solid. ^1H 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. Synthesis of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(2-methyl-2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)quinoxaline

Step 1. 8-Chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(2-methyl-2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)quinoxaline

To a solution of 2-(1-(2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (60.0 mg, 127 umol) in N,N-dimethylformamide (1 mL) was added formic acid (122 mg, 2.54 mmol) and paraformaldehyde (76.4 mg, 2.54 mmol). The mixture was stirred at 60 ° C for 13 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.2% formic acid)-acetonitrile]; (B%: 3%-33%, 10min) to give 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(2-methyl-2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)quinoxaline (55.5mg, 114umol, 89%) as a yellow solid. ^1H 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,1 H),6.94(dd,J＝2.0,8.8 Hz,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

Step 1. (3-Methyloxetan-3-yl)methyl methanesulfonate

To a solution of (3-methyloxetane-3-yl)methanol (300mg, 2.94mmol) in dichloromethane (5mL), triethylamine (891mg, 1.23mL) and methanesulfonyl chloride (504mg, 4.41mmol) were added. The mixture was stirred at 0°C for 1 hour. After completion, at 25°C, the reaction mixture was quenched with saturated sodium bicarbonate solution (10mL), and then extracted with ethyl acetate (25mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (3-methyloxetane-3-yl)methyl methanesulfonate (500mg, crude product) as a yellow oil. ¹ HNMR (400MHz, CDCl ₃ ) δ4.51 (d, J = 6.4 Hz, 2H), 4.43 (d, J = 6.4 Hz, 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 295 umol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (122 mg, 887 umol), potassium iodide (49.1 mg, 295 umol) and (3-methyloxetane-3-yl)methyl methanesulfonate (90.0 mg, 499 umol). The mixture was stirred at 80 ° C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (220 mg, crude) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[5-chloro-3-[1-[(3-methyloxetan-3-yl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 253 umol) in trifluoroacetic acid (1 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 ° C for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NXC18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 7 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(3-methyloxetan-3-yl)methyl]pyrazol-4-yl]quinoxaline (65.6 mg, 142 umol, 56%) as a yellow solid. ¹ H NMR (400 MHz, 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＝1 2.0Hz, 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

At 0°C, to a solution of 2-[[6-[5-chloro-3-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 330 umol) and diisopropylethylamine (130 mg, 990 umol) in dichloromethane (2 mL) was added isocyanato(trimethyl)silane (46 mg, 400 umol, 53 μL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with dichloromethane (25 mL×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]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxamide (100 mg, 155 umol, 46%) as a white solid. m/z ES+[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

A solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxamide (70 mg, 108 umol) in trifluoroacetic acid (0.7 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (basic conditions: column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 15%-45%, 9 min) to give 4-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxamide (27.6 mg, 53.5 umol, 48%) as ^{a white} solid. 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-((1s,4s)-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-((1r,4r)-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]decane-8-yl methanesulfonate

Methanesulfonyl chloride (543 mg, 4.74 mmol, 367 μL) and triethylamine (640 mg, 6.32 mmol, 880 μL) were added to a solution of 1,4-dioxaspiro [4.5] decan-8-ol (500 mg, 3.16 mmol) in dichloromethane (6 mL). The mixture was stirred at 0 ° C 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 layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1,4-dioxaspiro [4.5] decane-8-yl methanesulfonate (800 mg, crude product) as a yellow solid. 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-(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

2-[[6-[5-chloro-3-(1H-pyrazole-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (400mg, 789umol), potassium iodide (131mg, 789umol) and cesium carbonate (771mg, 2.37mmol) are added to a solution of 1,4-dioxaspiro[4.5]decane-8-yl methanesulfonate (373mg, 1.58mmol) in N,N-dimethylformamide (6mL). The mixture is stirred at 80°C for 12 hours. After completion, the reaction mixture is diluted with water (50mL) and extracted with dichloromethane (50mL x 3). The combined organic layer is 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-(1,4-dioxaspiro[4.5]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) as a yellow oil. m/z ES+[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 a solution of 2-(1-(1,4-dioxaspiro[4.5]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, 927 umol) in dichloromethane (6 mL) was added formic acid (3 mL). The mixture was stirred at 40 °C for 16 hours. Upon 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclohexanone (600 mg, crude) as a yellow oil. m/z ES+[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 a solution of 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclohexanone (250 mg, 414 umol) and azetidine (116 mg, 1.24 mmol, HCl salt) in methanol (5 mL) was added triethylamine (126 mg, 1.24 mmol) and acetic acid (373 mg, 6.22 mmol). Sodium triacetoxyborohydride (176 mg, 829 umol) was then added in two portions at 0° C. (slightly exothermic). The reaction mixture was stirred at 40° C. for 16 hours. Upon 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]imidazol-6-yl)oxy)quinoxaline (100 mg, 156 umol, 36%) as a yellow oil. m/z ES+[M+H] ⁺ 644.2.

Step 5. 2-(1-((1s,4s)-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-((1r,4r)-4-(azetidin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

A solution of 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 (65 mg, 101 umol) in trifluoroacetic acid (1 mL) was stirred at 20° C. for 30 min. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.2% formic acid)-acetonitrile]; (B%: 10%-20%, 12min) and further separated by SFC (column: Daicel ChiralPak IG (250*30mm, 10um); mobile phase: [0.1% NH ₃ H ₂ O MEOH]; (B%: 55%-55%, 6.1min; 60min) to give 2-(1-((1s,4s)-4-(azetidin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (9.1mg, 17.7umol, 18%) as a yellow gum. solid and 2-(1-((1r,4r)-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, 32.7 umol, 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),4.33-4.1 9(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-methyltetrahydrofuran-3-yl)methyl]pyrazol-4-yl]quinoxaline

Step 1. (3-Methyltetrahydrofuran-3-yl)methyl methanesulfonate

At 0 ° C, triethylamine (1.31 g, 12.9 mmol) and methanesulfonyl chloride (739 mg, 6.46 mmol) were added to a solution of (3-methyltetrahydrofuran-3-yl)methanol (500 mg, 4.30 mmol) in dichloromethane (5 mL). The mixture was stirred at 0 ° C for 2 hours. The reaction mixture was quenched with water (15 mL) at 0 ° C, and then extracted with dichloromethane (10 mL × 3). The combined organic layer was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain (3-methyltetrahydrofuran-3-yl)methyl methanesulfonate (600 mg, 3.09 mmol, 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 296 umol) and (3-methyltetrahydrofuran-3-yl)methyl methanesulfonate (74.7 mg, 385 umol) in N,N-dimethylformamide (1.5 mL), cesium carbonate (289 mg, 887 umol) and potassium iodide (49.1 mg, 296 umol) were added. The mixture was stirred at 80 ° C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, crude) as a yellow oil. m/z ES+[M+H] ⁺ 605.3.

Step 3. 8-Chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(3-methyltetrahydrofuran-3-yl)methyl]pyrazol-4-yl]quinoxaline

A solution of 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 (130 mg, 215 umol) in trifluoroacetic acid (1 mL) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 22%-32%, 7 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(3-methyltetrahydrofuran-3-yl)methyl]pyrazol-4-yl]quinoxaline (43.5 mg, 91.2 umol, 43%) as an off-white solid. ¹ H NMR (400 MHz, 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 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 (100 mg, 197 umol), 4,4-difluorocyclohexyl methanesulfonate (84.5 mg, 394 umol) in dimethyl sulfoxide (1 mL) was added cesium carbonate (192 mg, 591 umol) and potassium iodide (32.7 mg, 197 umol). The mixture was stirred at 80 °C for 12 hours. Upon 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]imidazol-6-yl)oxy)quinoxaline (90 mg, 144 umol, 73%) as a yellow solid. m/z ES+[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

A solution of 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 (85 mg, 135 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 10 min. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 20%-50%, 7 min) to give 8-chloro-2-(1-(4,4-difluorocyclohexyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (33.5 mg, 67.9 umol, 49%) as a yellow solid. ¹ H NMR (400 MHz, 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＝2.0 Hz,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. Methyl 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-methylpropanoate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (400mg, 789umol) and 2-bromo-2-methyl-propionic acid methyl ester (171mg, 947umol) in N,N-dimethylformamide (6mL), cesium carbonate (514mg, 1.58mmol) was added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (30mL) and extracted with ethyl acetate (20mL×3). The combined organic layer was 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 methyl 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-methylpropanoate (410 mg, 628 umol, 79%) as a yellow solid. m/z ES+[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

At 0°C, sodium borohydride (76.6 mg, 2.03 mmol) was added to a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]-2-methyl-propionic acid methyl ester (410 mg, 675 umol) in ethanol (6 mL). The mixture was stirred at 25°C 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (280 mg, 377 umol, 56%) as a yellow oil. m/z ES+[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

A solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-2-methyl-propan-1-ol (80 mg, 108 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. 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 C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 10min) to give 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 (33.5mg, 74.7umol, 69%) as a yellow solid. 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 a solution of 2-[[6-[5-chloro-3-[1-[(3S,4S)-3-fluoro-4-piperidinyl]pyrazol-4-yl]quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 329 umol) in tetrahydrofuran (5 mL) was added oxetanes-3-one (47.4 mg, 658 umol). The mixture was stirred at 25 ° C for 0.5 hours. Sodium triacetoxyborohydride (209 mg, 987 umol) was then added at 0 ° C. The mixture was stirred at 25 ° C 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-((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 (230 mg, crude) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[5-chloro-3-[1-[(3S,4S)-3-fluoro-1-(oxetanes-3-yl)-4-piperidinyl]pyrazol-4-yl]quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (210 mg, 316 umol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in THF, 632 μL). The mixture was stirred at 80 ° C 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*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 11%-41%, 10 min) and re-purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; (B%: 27%-57%, 10 min), which was re-purified by preparative HPLC (formic acid conditions; column: Shim-pack C18 150*25*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 10min) was further purified to obtain 8-chloro-2-(1-((3S,4S)-3-fluoro-1-(oxetane-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (6.12mg, 11.5umol, 3.7%) as a ^yellow solid. 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),2.4 9(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

Step 1. tert-Butyl 5-methylsulfonyloxy-2-azabicyclo[2.2.1]heptane-2-carboxylate

Methanesulfonyl chloride (302 mg, 2.64 mmol) was added to a solution of 5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (500 mg, 2.20 mmol) and triethylamine (569 mg, 4.40 mmol) in dichloromethane (5 mL). The mixture was stirred at 25 ° C for 1 hour. After completion, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate was 6/1 to 3/1) to obtain 5-methylsulfonyloxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (500 mg, 1.64 mmol, 74%) as a colorless oil. 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. 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)-8-azabicyclo[3.2.1]octane-8-carboxylate

To 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 (300 mg, 592 μmol) in N-methylpyrrolidone (10 mL) was added cesium carbonate (245 mg, 0.79 mmol) and tert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylate (217 mg, 0.71 mmol). The mixture was stirred at 80 °C for 1 hour. Upon 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 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)-8-azabicyclo[3.2.1]octane-8-carboxylate (450 mg, crude) as a yellow oil. m/z ES+[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

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)-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 558 umol) in trifluoroacetic acid (1 mL) was stirred at 30° C. for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure to give 2-(1-(8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (270 mg, crude) as a yellow oil. m/z ES+[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]octan-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 LunaC18 150*25mm*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]octan-3-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline as a yellow solid. )oxy)quinoxaline (24.9 mg, 51.3 umol, 31%) and 2-(1-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (23.4 mg, 48.2 umol, 29%) as an off-white solid.

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. 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-(1-((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]octan-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 °C for 13 hours. Upon completion, the reaction mixture was filtered and 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]; (B%: 4%-34%, 10min) purification to obtain 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazole as an off-white solid -4-yl)quinoxaline (9.3 mg, 18.6 umol, 9%) 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]octan-3-yl)-1H-pyrazol-4-yl)quinoxaline (11.1 mg, 22.2 umol, 11%) 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 (400 MHz, 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. Synthesis of 8-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-ylmethanol

At 0 ° C, lithium aluminum hydride (333 mg, 8.78 mmol) was added to a solution of 3- oxabicyclo [3.1.0] hexane -6- carboxylic acid (750 mg, 5.85 mmol) in tetrahydrofuran (10 mL) in batches. The mixture was stirred at 25 ° C for 1 hour. After completion, the mixture was carefully quenched with sodium sulfate dodecahydrate (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 obtain 3- oxabicyclo [3.1.0] hexane -6- ylmethanol (250 mg, 2.19 mmol, 37%) as a colorless oil. 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]hexan-6-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 umol) in dichloromethane (1 mL) was added 3-oxabicyclo[3.1.0]hexane-6-ylmethanol (27.0 mg, 236 umol) and triphenylphosphine (77.6 mg, 295 umol). Diisopropyl azodicarboxylate (59.8 mg, 295 umol) was then added at 0° C., and the mixture was stirred at 25° C. for 12 hours. Upon 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]hexan-6-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (25 mg, 41.5 umol, 21%) as a white solid. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-(3-oxabicyclo[3.1.0]hexan-6-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (25 mg, 41.5 umol) in trifluoroacetic acid (0.6 mL) was stirred at 25° C. for 0.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 8 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-(3-oxabicyclo[3.1.0]hexan-6-ylmethyl)pyrazol-4-yl]quinoxaline (6.4 mg, 13.6 umol, 32%) as an off-white solid. ¹ H NMR (400 MHz, 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),7.2 0(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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-[1-[(4-methylsulfanylcyclohexyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (20.0 mg, 30.8 umol) in acetonitrile (1 mL) and water (1 mL) at 0° C. was added oxadiazol (56.8 mg, 92.4 umol). The mixture was stirred at 0° C. for 1 hour. Upon completion, the mixture was poured into saturated sodium sulfate (10 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 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 (20 mg, crude) as a yellow oil. m/z ES+[M+H] ⁺ 681.1.

Step 2. 8-Chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(4-methylsulfonylcyclohexyl)methyl]pyrazol-4-yl]quinoxaline

A solution of 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 (20.0 mg, 29.4 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 7 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(4-methylsulfonylcyclohexyl)methyl]pyrazol-4-yl]quinoxaline (6.0 mg, 10.9 umol, 37%) as an off-white solid. ¹ H NMR (400 MHz, 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. tert-Butyl 3-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate

To a solution of 3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl esters (500mg, 2.14mmol) in dichloromethane (5mL), triethylamine (651mg, 6.43mmol) and methanesulfonyl chloride (368mg, 3.22mmol) are added. The mixture is stirred at 0°C for 1 hour. The reaction mixture is quenched with water (4mL) at 0°C and extracted with dichloromethane (3mL×3). The combined organic layers are washed with brine (5mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 3-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl esters (600mg, crude product) as a yellow oil. ¹ HNMR (400MHz, CDCl ₃ ) δ 4.62-3.94 (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. tert-Butyl 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-carboxylate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 394 umol) in N,N-dimethylformamide (2 mL), potassium carbonate (164 mg, 1.18 mmol) and tert-butyl 3-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (184 mg, 591 umol) were added. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layer was 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)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (190 mg, 263 umol, 67%) as a yellow oil. m/z ES+[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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 69.2 umol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (2 mL) at 25 ° C, 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (40 mg, crude) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[5-chloro-3-[1-[(3-fluoro-4-piperidinyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (40 mg, 64.3 umol) in tetrahydrofuran (0.5 mL) was added tetrabutylammonium fluoride (1 M in THF, 129 μL). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 7 min) to give 8-chloro-2-[1-[(3-fluoro-4-piperidinyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (2.6 mg, 5.27 umol, 8.2%) as a yellow solid. ¹ H NMR (400 MHz, 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° C. for 12 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; (B%: 20%-50%, 10 min) and purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 10min) was further purified to obtain 8-chloro-2-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazole-6 -yl)oxy)quinoxaline (4.1 mg, 7.84 umol, 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 (19.9 mg, 39.1 umol, 32%) as an off-white solid.

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. Synthesis of 4-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclohexan-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 a solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]cyclohexanone (150 mg, 243 umol) in methanol (2 mL) was added sodium cyanoborohydride (37.0 mg, 589 umol) and acetic acid (42.0 mg, 699 umol). The mixture was stirred at 25 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclohexanol (150 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, 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),1.4 6-1.38(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)cyclohexan-1-ol

A solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclohexanol (90.0 mg, 145 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1.5 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 16%-46%, 8min) to give 4-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclohexan-1-ol (18.5mg, 37.9umol, 26%) as a white solid. ^1HNMR (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

A solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclohexanone (60 mg, 97.2 umol) in trifluoroacetic acid (2 mL) was stirred at 25° C. 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*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 7 min) to give 4-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclohexanone (22.6 ^mg , 46.4 umol, 48%) as an off-white solid. 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. Synthesis of 3-((4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclobutanol

Step 1. (3-(Benzyloxy)cyclobutyl)methanol

The solution of lithium aluminum hydride (736mg, 19.4mmol) in anhydrous tetrahydrofuran (10mL) is degassed and purged with nitrogen 3 times, then at 0°C, 3-benzyloxycyclobutanecarboxylic acid (1g, 4.85mmol) in anhydrous tetrahydrofuran (5mL) is added. Under a nitrogen atmosphere, the mixture is stirred at 25°C for 16 hours. After completion, the reaction mixture is quenched by adding water (1mL), 15% sodium hydroxide (1mL) and water (3mL) at 0°C. The mixture is filtered. The filtrate is dried over anhydrous sodium sulfate, and the filtrate is concentrated in vacuo to obtain (3- (benzyloxy) cyclobutyl) methanol (900mg, 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), 1.71-1.6 2(m,2H).

Step 2. (3-(Benzyloxy)cyclobutyl)methyl methanesulfonate

At 0 ° C, triethylamine (790 mg, 7.80 mmol) and methanesulfonyl chloride (447 mg, 3.90 mmol) were added to a solution of (3-benzyloxycyclobutyl)methanol (500 mg, 2.60 mmol) in dichloromethane (5 mL). The mixture was stirred for 1 hour at 0 ° C. After completion, the reaction mixture was quenched by adding water (3 mL) and extracted with dichloromethane (3 mL x 3). The combined organic layer was washed with brine (3 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain (3-benzyloxycyclobutyl) methyl methanesulfonate (600 mg, 2.22 mmol, 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 μmol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 986 μmol). The mixture was stirred at 80 ° C 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]imidazol-6-yl)oxy)quinoxaline (780 mg, crude) as a yellow oil. m/z ES+[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 a mixture of 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 (50 mg, 73.4 μmol) was added boron trichloride (1 M in toluene, 734 μL) at 0°C. The mixture was stirred at 0°C for 2 hours. Upon completion, the reaction was poured into water (3 mL) and adjusted to pH ~7 with saturated sodium bicarbonate. The mixture was 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, and the residue was purified twice by preparative HPLC (column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 10%-40%, 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)cyclobutanol (12.8 mg, 27.5 μmol, 37%) as an ^off -white solid. 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. Synthesis of 3-((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 μmol) in trifluoroacetic acid (0.5 mL) was stirred at 25 °C for 2 hours. After completion, the reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*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.

(3.2 mg, 6.71 μmol, 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＝6.4 Hz,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. Synthesis of 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

Step 1. 7-Bromo-6-methyl-quinoxalin-2-ol and 6-bromo-7-methylquinoxalin-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 ° C for 16 hours. The mixture was diluted with petroleum ether (200 mL) and stirred at 25 ° C for 0.5 hours. The formed solid was separated by filtration and dried in vacuo to obtain a mixture of 7-bromo-6-methyl-quinoxaline-2-ol and 6-bromo-7-methylquinoxaline-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-quinoxaline-2-ol (2 g, 8.37 mmol, mixture of regioisomers) in toluene (15 mL) was added phosphorus oxychloride (12.8 g, 83.6 mmol), and the mixture was stirred at 100 ° C 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, 3.84 mmol, 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

A solution of 7-bromo-2-chloro-6-methyl-quinoxaline (1 g, 3.88 mmol), tert-butyl 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (1.52 g, 3.88 mmol), cyclopenta-2,4-dien-1-yl(diphenyl)phosphane; dichloropalladium; iron (284 mg, 388 umol) and potassium acetate (762 mg, 7.77 mmol) in dioxane (10 mL) and water (2.5 mL) was stirred at 60° C. for 12 hours under nitrogen. The reaction mixture was quenched with water (20 mL) at 25° C. 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 column chromatography (petroleum ether/ethyl acetate=20/1 to 0/1) to give tert-butyl 4-[[4-(7-bromo-6-methyl-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (0.90 g, 1.85 mmol, 40%) as a brown solid. m/z ES+[M+1] ⁺ 488.1.

Step 4. tert-Butyl 4-((4-(7-hydroxy-6-methylquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

A solution of tert-butyl 4-((4-(7-bromo-6-methylquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (1.5 g, 3.08 mmol), tris(dibenzylideneacetone)dipalladium (282 mg, 308 μmol), t-Bu XPhos (130 mg, 308 μmol), potassium hydroxide (1.73 g, 30.8 mmol) in dioxane (16 mL) and water (8 mL) was stirred at 100 ° C for 3 hours under a nitrogen atmosphere. After completion, the reaction mixture was quenched by the addition of water (20 mL) at 25 ° C and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (10 mL×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, 3.08 mmol, 99%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6): δ=10.48 (d, J=30 Hz, 2H), 9.03 (d, J=29.6 Hz, 2H), 8.52 (d, J=21.6 Hz, 2H), 8.22 (d, J=15.2 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.23 (d, J=16.8 Hz, 1H), 4.0 9(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. tert-Butyl 4-((4-(8-chloro-7-hydroxy-6-methylquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

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 ° C for 12 hours. Upon completion, the reaction mixture was quenched by the addition of water (20 mL) at 25 ° C 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 condition) and SFC (column: Daicel Chiralcel OJ (250 mm*30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide/methanol]; (B%: 70%-70%, 5.5 min; 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, 0.66 mmol, 25%) as a yellow solid. 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. tert-Butyl 4-((4-(7-(3-amino-4-nitrophenoxy)-8-chloro-6-methylquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

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 μmol), tert-butyl N-tert-butoxycarbonyl-N-(5-fluoro-2-nitro-phenyl)carbamate (350 mg, 982 μmol), potassium carbonate (181 mg, 1.31 mmol) and potassium iodide (10.8 mg, 65.5 μmol) in N,N-dimethylformamide (5 mL) was stirred at 100° C. for 16 hours. Upon completion, the reaction mixture was quenched by the addition of water (20 mL) at 25° C. 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 condition) to give tert-butyl 4-((4-(7-(3-amino-4-nitrophenoxy)-8-chloro-6-methylquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (0.2 g, 0.34 mmol, 51%) as a yellow solid. m/z ES+[M+H] ⁺ 594.3.

Step 7. tert-Butyl 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-carboxylate

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 μmol) 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° C. for 12 hours. Upon completion, the mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified by reverse phase HPLC (0.1% formic acid conditions) to give tert-butyl 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-carboxylate (0.13 g, 0.22 mmol, 77%) as a green solid. m/z ES+[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 a solution of tert-butyl 4-[[4-[8-chloro-6-methyl-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (0.1 g, 170 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol). The mixture was stirred at 25 °C for 1 hour. Upon completion, the mixture was concentrated in vacuo to give 8-chloro-6-methyl-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)quinoxaline (0.1 g, TFA salt, crude) as a yellow solid. m/z ES+[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

A solution of 8-chloro-6-methyl-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (0.09 g, 149 μmol, TFA salt), paraformaldehyde (89.7 mg, 2.99 mmol) and formic acid (143 mg, 2.99 mmol) in N,N-dimethylformamide (3 mL) was stirred at 60 °C for 16 hours. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 7min) to give 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 (16 mg, 31.8 μmol, 21%) as a ^white solid. 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. Synthesis of 4-((1r,3r)-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-((1s,3s)-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 a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (65 mg, 110 μmol) and morpholine (30 mg, 340 μmol, 30 μL) in dichloromethane (1 mL) was added acetic acid (9.5 mg, 160 μmol, 9 μL) and Molecular sieves (100 mg). The reaction was then cooled to 0 ° C, and sodium cyanoborohydride (14 mg, 230 μmol) was added. The mixture was stirred at 25 ° C for 2 hours. 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 layer was 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 obtain 2- [[6- [5- chloro-3- [1- (3- morpholine cyclobutyl) pyrazole-4-yl] quinoxaline-6-yl] oxy-2-methyl-benzimidazol-1-yl] methoxy] ethyl-trimethyl-silane (30 mg, 46.4 μmol, 41%) as a white solid. m / zES + [M + H] ⁺ 646.3.

Step 2. 4-((1r,3r)-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-((1s,3s)-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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (30 mg, 46 μmol) in trifluoroacetic acid (0.3 mL) was stirred at 25° C. 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 C18150×25mm×10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 30%-33%, 10min) purification to obtain 4-((1r,3r)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)morpholine (7.6mg, 14.7μmol, 32%) as a white solid and 4-((1s,3s)-3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)morpholine (1.9mg, 3.7μmol, 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-(((1s,4s)-4-methoxycyclohexyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline and 8-chloro-2-(1-(((1r,4r)-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 a mixture of 1-(bromomethyl)-4-methoxy-cyclohexane (45 mg, 217 umol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 umol) in N,N,N-dimethylformamide (2 mL), potassium carbonate (54.5 mg, 394 umol) was added, and the mixture was stirred at 80° C. 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, crude) as a yellow solid. m/z ES+[M+H] ⁺ 633.2.

Step 2. 8-Chloro-2-(1-(((1s,4s)-4-methoxycyclohexyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline and 8-chloro-2-(1-(((1r,4r)-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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (140 mg, 221 umol) in trifluoroacetic acid (2 mL) was stirred at 20° C. 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%, 10min) purification to give 8-chloro-2-(1-(((1s,4s)-4-methoxycyclohexyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (29.5mg, 58.6μmol, 27%) as a yellow solid and 8-chloro-2-(1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (57mg, 113μmol, 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. Synthesis of 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

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 a solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]cyclohexanone (100 mg, 162 umol) in methanol (2 mL) was added N-methylmethylamine hydrochloride (75.0 mg, 920 umol). The mixture was stirred at 25 ° C for 0.2 hours. Sodium cyanoborohydride (25.0 mg, 398 umol) was then added, and the mixture solution was stirred at 40 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-N,N-dimethyl-cyclohexylamine (60 mg, 92.9 μmol, 57%) as a yellow solid. m/z ES+[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

A solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-N,N-dimethyl-cyclohexylamine (30 mg, 46.4 umol) in trifluoroacetic acid (0.8 mL) was stirred at 25° C. 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]; (B%: 5%-35%, 10 min) to give 4-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]-N,N-dimethyl-cyclohexylamine (9.1 mg, 17.6 μmol, 38%) as a ^yellow solid. 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 a solution of 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (90.0 mg, 123 μmol) in acetonitrile (1 mL) was added hydrochloric acid (6 M, 1 mL) The mixture was stirred at 60° C. for 3 hours. After completion, the reaction mixture was concentrated in vacuo and purified by preparative HPLC (formic acid conditions; column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10min) to give 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 (31.7 mg, 55.3 μmol, 45%, formate) as an ^off -white solid. 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] ⁺ 5 04.1.

Example 137. Synthesis of 2-(1-((1s,4s)-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

Step 1. (1s,4s)-1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane

To the solution of (3-methylenecyclobutyl)methanol (200mg, 2.04mmol) in methyl tert-butyl ether (2mL) and water (1mL), sodium bicarbonate (342mg, 4.08mmol) and iodine (1.03g, 4.08mmol) are added. The mixture is stirred at 25 ° C for 16 hours. After completion, the mixture is quenched with sodium thiosulfate (100mg) and extracted with ethyl acetate (30mLx 3). The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 10/1) to obtain (1S, 4s) -1- (iodomethyl) -2- oxabicyclo [2.1.1] hexane (70mg, 0.31mmol, 15%) as a yellow oil. 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-((1s,4s)-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 a solution of (1S,4s)-1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane (53.0 mg, 236 μmol) and 8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (100 mg, 197 μmol) in N,-N1-dimethylformamide was added cesium carbonate (192 mg, 591 μmol). The mixture was stirred at 80 °C for 16 hours. Upon completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed by 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-((1s,4s)-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 (110 mg, 182 μmol, 92%) as a yellow solid. m/z ES+[M+H] ⁺ 603.2.

Step 3. 2-(1-((1s,4s)-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

A solution of 2-(1-((1s,4s)-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 (110 mg, 182 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 10 min) to give 2-(1-((1s,4s)-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 (50.1 mg, 106 μmol, 58%) as a white solid. ¹ H NMR (400 MHz, 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,2 H), 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

Step 1. (1,1-dioxytetrahydrothiophen-3-yl)methyl 4-methylbenzenesulfonate

At 0 ° C, 4-dimethylaminopyridine (80 mg, 655 umol) and 4-methylbenzenesulfonyl chloride (126 mg, 661 umol) were added to a solution of (1,1-dioxothiane-3-yl)methanol (100 mg, 666 umol) in dichloromethane (5 mL) at 0 ° C. Then triethylamine (138 mg, 1.37 mmol, 190 μL) was added and the mixture was stirred at 25 ° C for 1 hour. After completion, the mixture was quenched with water (6 mL) and then extracted with dichloromethane (8 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/2) to obtain (1,1-dioxothiane-3-yl) methyl 4-methylbenzenesulfonate (120 mg, 395 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-dioxothiane-3-yl)methyl 4-methylbenzenesulfonate (80 mg, 263 umol) in N,N-dimethylformamide (3 mL), cesium carbonate (170 mg, 522 umol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (135 mg, 266 umol) were added. The mixture was stirred at 80 ° C 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-dioxothian-3-yl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (220 mg, crude) as a yellow oil. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-[(1,1-dioxothian-3-yl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (220 mg, 344 umol) in trifluoroacetic acid (3 mL) was stirred at 25° C. for 2 hours. Upon 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]; (B%: 30% - 62%, 8 min) to give 3-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]thiazane 1,1-dioxide (120 mg, 236 umol, 67%) as a yellow solid. m/z ES+ [M+H] ⁺ 509.3.

Step 4. (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 separated by SFC (column: Daicel Chiralcel OJ (250 mm*30 mm*10 um); mobile phase: [0.1% ammonium hydroxide/ethanol]; (B%: 60%-60%, 3.5 min, total run 40 min) and further separated by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 7min) purification to obtain (3R)-3-[[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]methyl]thiazane 1,1-dioxide (58.9mg, 116umol, 49%) as a yellow solid and (3S)-3-[[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline-2-yl]pyrazol-1-yl]methyl]thiazane 1,1-dioxide (28mg, 55umol, 23%) as an off-white solid.

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＝4.8 Hz,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 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 (70.0 mg, 118 μmol) and 2-bromoacetamide (18.0 mg, 130 μmol) in acetonitrile (1 mL) was added sodium iodide (1.8 mg, 11.8 μmol) and potassium carbonate (32.8 mg, 237 μmol). The mixture was stirred at 60° C. for 3 hours. Upon 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)acetamide (75 mg, 116 μmol, 97%) as a yellow oil. m/z ES+[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

A solution of 2-[4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-piperidinyl]acetamide (75 mg, 115 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 5 min) to give 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 (25.5 mg, 49.3 μmol, 42%) as a yellow solid. ¹ H NMR (400 MHz, 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

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 (70 mg, 118 μmol), 2-chloro-N-methylacetamide (14.0 mg, 130 μmol) and potassium phosphate (50.3 mg, 237 μmol) in acetonitrile (1 mL) was stirred at 40 °C 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-methylacetamide (75 mg, crude) as a yellow oil. m/z ES+[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

A solution of 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 (75 mg, crude) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 7 min) to give 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 (38.0 mg, 71.6 μmol, 62%) as an off-white solid. ¹ H NMR (400 MHz, 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 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 (70 mg, 118 μmol) and triethylamine (36.0 mg, 355. μmol) in dichloromethane (1 mL) was added methylaminocarbonyl chloride (13.3 mg, 142 μmol). The mixture was stirred at 25 °C for 1 hour. Upon 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-N-methylpiperidine-1-carboxamide (75 mg, crude) as a yellow oil. m/z ES+[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

A solution of 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 (75 mg, 115 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 7 min) to give 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 (34.4 mg, 66.5 μmol, 57%) as a white solid. ¹ H NMR (400 MHz, 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. Synthesis of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(2-(oxetan-3-yl)-2-azabicyclo[2.2.1]heptane-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]heptane-5-yl)-1H-pyrazol-4-yl)quinoxaline

To a solution of 2-(1-(2-azabicyclo[2.2.1]heptane-5-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (40.0 mg, 84.8 μmol) in methanol (1 mL) was added sodium cyanoborohydride (6.92 mg, 110 μmol), oxetanes-3-one (18.3 mg, 254 μmol) and sodium acetate (9.04 mg, 110 μmol). The mixture was stirred at 25 °C for 12 hours. Upon completion, the reaction mixture was quenched with water (0.2 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 28%-58%, 10min) and re-purified by preparative HPLC (basic conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 20%-50%, 8min) to give 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 (33.7mg, 63.9μmol, 75%) as a white solid. 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]heptane-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 a solution of 2-(1-(2-azabicyclo[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 (100 mg, 162 μmol) in N,N-dimethylformamide (1 mL) was added cesium carbonate (159 mg, 487 μmol) and 2-bromoacetamide (22.4 mg, 162 μmol). The mixture was stirred at 25° C. for 13 hours. After completion, the reaction mixture was quenched with water (0.2 mL) and concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (column: Phenomenex LunaC18150*25 mm*10 um; mobile phase: [water(formic acid)-acetonitrile]; (B%: 1%-30%, 10 min) to give 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]heptane-2-yl)acetamide (40 mg, 59.4 μmol, 32%) as a yellow oil. m/z ES+[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

A solution of 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 (40.0 mg, 59.4 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex LunaC18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10 min) to give 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 (20.2 mg, 37.3 μmol, 63%) as an ^off -white solid. 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(d d,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. Synthesis of 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

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 a solution of 2-(1-(2-azabicyclo[2.2.1]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 (130 mg, 211 μmol) in dichloromethane (1 mL) was added diisopropylethylamine (81.8 mg, 633 μmol) followed by isocyanato(trimethyl)silane (29.2 mg, 253 μmol) at 0°C. The mixture was stirred at 25°C for 12 hours. Upon 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]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%) as a yellow oil. m/z ES+[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

A solution of 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 (100 mg, 152 μmol) in trifluoroacetic acid (1 mL) was stirred at 25 °C for 1 hour. Upon 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 conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 21%-51%, 10min) to give 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 (11.1mg, 21.0μmol, 14%) as a ^white solid. 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. Synthesis of 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

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 a solution of 2-(1-(2-azabicyclo[2.2.1]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 (80.0 mg, 130 μmol) in dichloromethane (1 mL) was added triethylamine (39.4 mg, 389 μmol) and methylcarbamoyl chloride (14.6 mg, 156 μmol). The mixture was stirred at 25 °C for 13 hours. Upon 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]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%) as a yellow oil. m/z ES+[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

A solution of 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 (80.0 mg, 119 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex LunaC18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 10%-40%, 10 min) to give 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 (23.0 mg, 42.3 μmol, 36%) as ^{an off} -white solid. 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),4.3 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 a solution of 2-[1-(azetidin-3-ylmethyl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (50 mg, 102 umol, formic acid) in tetrahydrofuran (3 mL), triethylamine (31.7 mg, 314 umol), potassium iodide (33.8 mg, 203 umol) and 2-chloro-N-methyl-acetamide (10 mg, 93 umol) were added. The mixture was stirred at 25 ° C for 20 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 15%-42%, 8min) to give 2-[3-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]azetidin-1-yl]-N-methyl-acetamide (17.9 mg, 34.6 umol, 34%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6): δ＝9.31 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 7.95 (d, J＝9.2 Hz, 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 a solution of 2-[1-(azetidin-3-ylmethyl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (55 mg, 123 umol) in N,N-dimethylformamide (1.5 mL), potassium carbonate (55.0 mg, 398 umol), 1-(azetidin-1-yl)-2-chloro-ethanone (16 mg, 120 umol) and potassium iodide (55.0 mg, 331 umol) were added. The mixture was stirred at 25 ° C for 2 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 15%-45%, 8min) and re-purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 8min) to give 1-(azetidin-1-yl)-2-[3-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]azetidin-1-yl]ethanone (10.0mg, 18.4umol, 14%, formate) as an ^off -white solid. 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,1 H),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 a solution of 2-[1-(azetidin-3-ylmethyl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (60 mg, 122 umol, formic acid) in 1-methyl-2-pyrrolidinone (1 mL), sodium phosphate (58 mg, 354 umol) and 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone (18.0 mg, 120 umol) were added. The mixture was stirred at 40 ° C for 2.5 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 15%-42%, 8min) to give 2-[3-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]azetidin-1-yl]-1-( ³ -hydroxyazetidin-1-yl)ethanone (29.8mg, 53.3umol, 44%) as a white solid. 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 a solution of 2-[1-(azetidin-3-ylmethyl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (55 mg, 112 umol, formate) in acetonitrile (2 mL), potassium carbonate (33 mg, 239 umol) and 2-bromoacetonitrile (11 mg, 91.7 umol, 6.1 μL) were added. The mixture was stirred at 25 ° C 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]quinoxalin-2-yl]pyrazol-1-yl]methyl]azetidin-1-yl]acetonitrile (34.9 mg, 72 umol, 63%) as an off-white solid. 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

At 25 ° C, 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)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 200 μmol) in tetrahydrofuran (2 mL). The mixture was stirred at 25 ° C for 0.5 hours. Then 1-(azetidine-1-yl)-2-chloro-ethanone (38 mg, 290 μmol) was added. The reaction mixture was stirred at 60 ° C 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 x 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)benzoimidazol-5-yl]

[0266]Oxy-quinoxalin-2-yl]pyrazol-1-yl]ethanone (220 mg, crude). m/z ES+[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

A solution of 1-(azetidin-1-yl)-2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethanone (200 mg, 330 μmol) in trifluoroacetic acid (2 mL) was stirred at 25 ° C for 0.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane: methanol = 10: 1) to give 1-(azetidin-1-yl)-2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]ethanone (17.8 mg, 37.6 μmol, 11.3%) as a white solid. 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

At 25 ° C, sodium hydride (17.7 mg, 443 umol, 60% in mineral oil) was added to a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 295 μmol) in tetrahydrofuran (3 mL). The mixture was stirred at 25 ° C for 0.5 hours. Then 2-chloro-1-(3-hydroxyazetidine-1-yl)ethanone (66.4 mg, 443 μmol) was added. The resulting mixture was stirred at 60 ° C for 1.5 hours. After completion, the reaction mixture was quenched with water (20 mL) at 25 ° C. Then the mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% ammonium hydroxide conditions) to give 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]

Pyrazol-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone (80.0 mg, 129 μmol, 40%). ¹ H NMR (400 MHz, CDCl ₃ ): δ＝9 (d, J＝4.0 Hz, 1H), 8.41 (d, J＝2.8 Hz, 1H), 8.29 (d, J＝2.0 Hz, 1H), 7.90-7.83 (m, 1H), 7.68 (d, J＝8.8 Hz, 1H), 7.45-7.38 (m, 1H), 7.15 (d, J＝2.4 Hz, 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

A solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone (75.0 mg, 120 μmol) in trifluoroacetic acid (0.5 mL) was stirred for 1 hour at 25° C. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 14%-44%, 8 min) to give 2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone (22.1 mg, 45 μmol, 36%) as an ^off -white solid. 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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 umol) in acetonitrile (3 mL), cesium carbonate (200 mg, 614 umol), potassium iodide (70 mg, 422 umol) and 2-bromoacetamide (30.0 mg, 218 umol) were added. The mixture was stirred at 80 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetamide (110 mg, crude) as a yellow solid. m/z ES+[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

A solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetamide (110 mg, 195 umol) in trifluoroacetic acid (3 mL) was stirred at 25° C. 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*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 8%-38%, 7 min) to give 2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]acetamide (45.5 mg, 105 μmol, 54 ^% ) as a white solid. 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. Ethyl 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)acetate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (500 mg, 986 μmol) in tetrahydrofuran (20 mL) was added sodium hydride (118 mg, 2.96 mmol, 60% in mineral oil), and the mixture was stirred at 25 ° C for 0.5 hours. Then ethyl 2-bromoacetate (247 mg, 1.48 mmol, 164 μL) was added, and the mixture was stirred at 60 ° C for 1.5 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) at 20 ° C, 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 ethyl 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)acetate (280 mg, 0.47 mmol, 48%) as a ^yellow solid. 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/zES+[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 μmol) in ethanol (2 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (46.9 mg, 337 μmol) and ethyl 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetate (100 mg, 169 μmol). The mixture was stirred at 25° C. for 2 hours. After completion, the 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] oxy-quinoxalin-2-yl] pyrazol-1-yl] -1- (3-hydroxypyrrolidin-1-yl) ethanone (38 mg, 60 μmol, 36%) as a yellow solid. m / z ES + [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

A solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-(3-hydroxypyrrolidin-1-yl)ethanone (35.0 mg, 55.2 μmol) in trifluoroacetic acid (0.8 mL) was stirred at 25° C. for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 3%-33%, 10 min) to give 2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-(3-hydroxypyrrolidin-1-yl)ethanone (7.7 mg, 15.3 μmol, 28%) as a ^yellow gum. 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

A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]cyclobutanone (130 mg, 230 μmol), azetidine-3-ol hydrochloride (74 mg, 680 μmol), titanium tetraisopropoxide (130 mg, 450 μmol, 130 μL) and diisopropylethylamine (88 mg, 680 μmol, 120 μL) in methanol (2 mL) was stirred at 60 ° C for 2 hours. Sodium cyanoborohydride (14 mg, 230 μmol) was then added, and the reaction mixture was stirred at 25 ° C 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutyl)azetidin-3-ol (25 mg, 40 μmol, 17%) as a white solid. m/z ES+[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

A solution of 1-[3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutyl]azetidin-3-ol (20 mg, 31 μmol) in trifluoroacetic acid (0.3 mL) was stirred for 0.5 h at 25° C. 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]; (B%: 2%-32%, 10 min) to give 1-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]cyclobutyl]azetidin-3-ol (8.4 mg, 16 μmol, 44%, formate) as a ^yellow solid. 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[6-[5-chloro-3-(5-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 383 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (159 mg, 1.15 mmol) and (3,3-difluorocyclobutyl)methyl methanesulfonate (99.8 mg, 498 μmol). The mixture was stirred at 80° C. 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]-5-methyl-pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (mixture of regioisomers, 70.0 mg, 111 μmol, 28%) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]-5-methyl-pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (60.0 mg, 95.9 μmol) in trifluoroacetic acid (0.5 mL) was added trifluoroacetic acid (923 mg, 8.10 mmol). The mixture was stirred at 25 °C for 0.5 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 20%-50%, 7 min) to give 8-chloro-2-[1-[(3,3-difluorocyclobutyl)methyl]-5-methyl-pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (mixture of regioisomers, 45.0 mg, 90.9 μmol, 94%) as a white solid. m/z ES+[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, 90.9 μmol) was purified by SFC (column: Daicel Chiralpak AD (250mm*30mm, 10um); mobile phase: [methanol-acetonitrile]; (B%: 60%-60%, 6min, total run 60min) separation to obtain 8-chloro-2-[1-[(3,3-difluorocyclobutyl)methyl]-3-methyl-pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (21.3mg, 43.0μmol, 47%) as a white solid and 8-chloro-2-[1-[(3,3-difluorocyclobutyl)methyl]-5-methyl-pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (15.9mg, 32.1μmol, 34%) 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 a mixture of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetic acid (100 mg, 176 μmol), 3-methoxypyrrolidine (36.0 mg, 265 μmol) and 3-(ethyliminomethyleneamino)propyl-dimethylammonium chloride (50.8 mg, 265 μmol) in dichloromethane (1.5 mL) was added hydroxybenzotriazole (35.8 mg, 265 μmol) and diisopropylethylamine (68.6 mg, 530 μmol). The reaction mixture was stirred at 25° C. for 2 hours. Upon completion, the reaction mixture was extracted with ethyl acetate (2× 20 mL). The combined organic layers were washed with brine (2 x 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-(3-methoxypyrrolidin-1-yl)ethanone (110 mg, 169 μmol, 96%) as a yellow solid. m/z ES+[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

A mixture of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-(3-methoxypyrrolidin-1-yl)ethanone (90.0 mg, 138 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 hours. After completion, the reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 25%-55%, 8min) to give 2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-(3-methoxypyrrolidin- ¹ -yl)ethanone (23.5mg, 45.5μmol, 33%) as a white solid. 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. Synthesis of 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

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 a solution of 2-[[6-[5-bromo-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (30.0 mg, 54.4 μmol) and tetrahydrothiopyran-4-ylmethyl methanesulfonate (14.9 mg, 70.7 μmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (22.6 mg, 163 μmol). The mixture was stirred at 80° C. 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]imidazol-6-yl)oxy)-2-(1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-4-yl)quinoxaline (35.0 mg, crude) as a yellow oil. m/z ES+[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 a solution of 2-[[6-[5-bromo-3-[1-(tetrahydrothiopyran-4-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (35.0 mg, 52.6 μmol) in dichloromethane (1 mL) at 0° C., m-chloroperbenzoic acid (23.5 mg, 116 μmol, 85% purity) was added. The mixture was stirred at 25° C. for 2 hours. The mixture was poured into an 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (36.0 mg, crude) as a yellow oil. m/z ES+[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-dioxothiani-4-yl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (36.0 mg, 51.6 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. 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]; (B%: 11%-41%, 10min) purification to obtain 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 (3.8mg, 6.6μmol, 13%) as a white solid 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 (8.2mg, 14.3μmol, 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),4.3 1(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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 μmol) in N,N-dimethylformamide (1.5 mL) was added cesium carbonate (193 mg, 592 μmol) and 2,2-dimethyloxirane (15.6 mg, 217 μmol). The mixture was stirred at 100 ° C 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 sodium sulfate, filtered and concentrated in vacuo to give 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 (200 mg, crude) as a yellow oil. 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(brdd,J＝2.0,8.8Hz,1 H),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)benzimidazol

A solution of 5-[5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-2-methyl-propan-2-ol (200 mg, 345 μmol) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 10 min) and then re-purified by preparative HPLC (column: Shim-pack C18 150*25*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10 min) to give 1-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-2-methyl-propan-2-ol (42.4 mg, 94.4 μmol, 27%) as a ^white solid. 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 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 (140 mg, 238 μmol) in ethanol (1.5 mL) was added sodium borohydride (18.0 mg, 475 μmol). The mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with water (3 mL) at 0° C. and then extracted with ethyl acetate (3 mL×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-(trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclobutanol (110 mg, 186 μmol, 78%) as a yellow oil. m/z ES+[M+H] ⁺ 591.1.

Step 2. 2-[[6-[5-chloro-3-[1-[(3-methoxycyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

At 0°C, to a solution of 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]cyclobutanol (100 mg, 169 μmol) in tetrahydrofuran (1 mL) was added aqueous sodium hydroxide solution (10.2 mg, 254 μmol, 60 wt%). The mixture was stirred at 0°C for 0.5 hours. Iodomethane (24.0 mg, 169 μmol) was then added. The mixture was stirred at 25°C for 1.5 hours. The reaction mixture was quenched with water (6 mL) at 0°C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (140 mg, crude) as a brown solid. m/z ES+[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

A mixture of 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 (140 mg, 231 μmol) in trifluoroacetic acid (1.5 mL) was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 10 min) to give 8-chloro-2-[1-[(3-methoxycyclobutyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (26.3 mg, 55.4 μmol, 24%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J=1.6 Hz, 1H), 8.77-8.66 (m, 1H), 8.35 (s, 1H), 8.14 (d, J=2.0 Hz, 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

Step 1. Ethyl 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-methylbutanoate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (700 mg, 1.38 mmol) and ethyl 3-methylbut-2-enoate (265 mg, 2.07 mmol, 288 μL) in N,N-dimethylformamide (14 mL), cesium carbonate (900 mg, 2.76 mmol) was added. The mixture was stirred at 25 ° C for 48 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL×3). The combined 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 1/9) to give ethyl 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-methylbutanoate (340 mg, 455 μmol, 33%) as a yellow solid. 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).

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 a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-3-methyl-butyric acid ethyl ester (270 mg, 361 μmol, 85% purity) in methanol (2.5 mL), tetrahydrofuran (2.5 mL) and water (2.5 mL) was added lithium hydroxide monohydrate (45.5 mg, 1.08 mmol). The mixture was stirred at 25° C. 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-methylbutanoic acid (150 mg, crude) as a yellow solid. m/z ES+[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 a solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]-3-methyl-butyric acid (150 mg, 247 μmol) and ammonium chloride (132 mg, 2.47 mmol) in N,N-dimethylformamide (5 mL) was added diisopropylethylamine (95.8 mg, 741 μmol, 129 μL) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (141 mg, 371 μmol). The mixture was stirred at 25 ° C 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]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-methylbutanamide (180 mg, crude) as a yellow oil. m/z ES+[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

A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-3-methyl-butyramide (50.0 mg, 82.5 μmol) in trifluoroacetic acid (1 mL) was stirred for 0.5 hours at 25° C. 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]; (B%: 10%-40%, 10 min) to give 3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-methylbutanamide (17.8 mg, 37.4 μmol, 45%) as an ^off -white solid. HNMR (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

Step 1. (3,3-Difluorocyclopentyl)methyl methanesulfonate

To a solution of (3,3-difluorocyclopentyl)methanol (100 mg, 735 umol) in dichloromethane (3 mL), triethylamine (145 mg, 1.44 mmol, 200 μL) and methyl methane disulfonyl chloride (104 mg, 904 umol, 70 μL) were added. The mixture was stirred at 0 ° C for 1 hour. After completion, the mixture was quenched with water (3 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain (3,3-difluorocyclopentyl) methyl methanesulfonate (200 mg, crude product) 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of (3,3-difluorocyclopentyl)methyl methanesulfonate (66.4 mg, 310 umol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 umol) in N,N-dimethylformamide (2 mL), potassium carbonate (75.0 mg, 543 umol) was added. The mixture was stirred at 80 ° C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 160 μmol, 80%) as a yellow oil. m/z ES+[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

A solution of 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 (100 mg, 160 umol) in trifluoroacetic acid (2 mL) was stirred at 20° C. 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 C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 20%-50%, 7 min) and re-purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; (B%: 33%-63%, 9 min) to give 8-chloro-2-[1-[(3,3-difluorocyclopentyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (27 mg, 54 μmol, 34%) as a white ^solid . 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 a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]acetic acid (100 mg, 177 μmol), 3,3-difluoropyrrolidine hydrochloride (38.1 mg, 265 μmol) and diisopropylethylamine (68.6 mg, 531 μmol, 92.5 μL) in dichloromethane (2 mL) was added 3-(ethyliminomethyleneamino)propyl-dimethylammonium chloride; chloride (50.9 mg, 265 μmol) and hydroxybenzotriazole (35.9 mg, 265 μmol). The mixture was stirred at 25 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-(3,3-difluoropyrrolidin-1-yl)ethanone (121 mg, crude) as a yellow solid. m/z ES+[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

A solution of 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 (112 mg, 171 μmol) in trifluoroacetic acid (1.8 mL) was stirred at 25° C. for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 9%-39%, 10 min) to give 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 (41.6 mg, 79 μmol, 46%) as a ^white solid. 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),7.2 2(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 a solution of 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 (145 mg, 247 μmol) in tetrahydrofuran (2 mL) was added pyridine hydrofluoride (244 mg, 2.47 mmol, 0.22 mL). The mixture was stirred at 80 °C for 0.5 h. Upon completion, 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]; (B%: 4%-34%, 10 min) to give 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 (26.4 mg, 57.6 μmol, 23%) as an ^off- white solid. 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. Synthesis of 8-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-carboxylate

To a solution of tert-butyl 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-carboxylate (70 mg, 101 μmol), cyclopropylboronic acid (87.1 mg, 1.01 mmol) in dioxane (1 mL) and water (0.1 mL) was added XPhos Pd G2 (8.0 mg, 10.1 μmol) and sodium carbonate (21.5 mg, 202 μmol). The mixture was stirred at 100 °C under nitrogen for 5 hours. Upon 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 tert-butyl 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-carboxylate (70 mg, 10.1 μmol, 99%) as a yellow oil. m/z ES+[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

A solution of tert-butyl 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-carboxylate (70 mg, 100 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 7 min) to give 8-cyclopropyl-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (12.5 mg, 26.8 μmol, 26%) as a yellow solid. ¹ H NMR (400 MHz, 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,1 H),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 a solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]acetic acid (100 mg, 177 μmol), 3-fluoropyrrolidine hydrochloride (33.3 mg, 265 μmol) and diisopropylethylamine (68.6 mg, 531 μmol, 92.5 μL) in dichloromethane (2 mL) was added 3-(ethyliminomethyleneamino)propyl-dimethylammonium chloride (50.9 mg, 265 μmol) and hydroxybenzotriazole (35.9 mg, 265 μmol). The mixture was stirred at 25 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-(3-fluoropyrrolidin-1-yl)ethanone (113 mg, crude) as a yellow solid. m/z ES+[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

A solution of 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 (100 mg, 157 μmol) in trifluoroacetic acid (1.8 mL) was stirred at 25° C. for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 11%-31%, 10 min) to give 2-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-(3-fluoropyrrolidin-1-yl)ethanone (35.9 mg, 70.9 μmol, 45%) as a ^white solid. 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

A solution of 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]cyclobutanone (160 mg, 272 μmol), azetidine hydrochloride (140 mg, 1.49 mmol) and acetic acid (1.6 mg, 27.2 μmol) in methanol (1.5 mL) was stirred at 25 ° C for 0.2 hours. Sodium cyanoborohydride (34.1 mg, 543 μmol) was then added and the mixture was stirred at 40 ° C 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]methyl]pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (130 mg, 206 μmol, 76%) as a yellow oil. m/z ES+[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

A mixture of 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 (120 mg, 190 μmol) in trifluoroacetic acid (1 mL) was stirred for 1 hour at 25° C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 5%-35%, 7 min) to give 2-[1-[[3-(azetidin-1-yl)cyclobutyl]methyl]pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (32.7 mg, 64.8 μmol, 34%) as a ^brown solid. 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. Synthesis of 8-methyl-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)quinoxaline

Step 1. tert-Butyl 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-carboxylate

To a solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (1 g, 1.40 mmol) and methylboric acid (850 mg, 14.0 mmol) in dioxane (10 mL) and water (1 mL), sodium carbonate (450 mg, 4.30 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (170 mg, 210 μmol) were added. The mixture was stirred at 110 ° C under nitrogen 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 x 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]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (620 mg, 907 μmol, 65%) as a white solid. m/z ES+[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

A solution of tert-butyl 4-[[4-[8-methyl-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (620 mg, 906 μmol) in trifluoroacetic acid (6 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 1.4 g of crude product as a yellow oil. 100 mg of the crude product was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; (B%: 23%-53%, 10 min) to give 8-methyl-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline (17.7 mg, 39.1 μmol, 18%) as a ^white solid. 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),6.8 7(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. Synthesis of 8-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-carboxylate

To a solution of tert-butyl 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-carboxylate (100 mg, 144 μmol), methylboronic acid (26.0 mg, 434 μmol) in dioxane (1 mL) and water (0.1 mL) was added XPhos Pd G2 (11.4 mg, 14.4 μmol) and sodium carbonate (46.0 mg, 434 μmol). The mixture was stirred at 110 °C under nitrogen for 5 hours. Upon 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 tert-butyl 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-carboxylate (90 mg, 134 μmol, 93%) as a yellow oil. m/z ES+[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

A solution of tert-butyl 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-carboxylate (90 mg, 134 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 7%-37%, 10 min) to give 8-methyl-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (35.0 mg, 79.6 μmol, 59%) as an off-white solid. ¹ H NMR (400 MHz, 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-(oxetane-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 a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline (200 mg, 409 μmol) in methanol (5 mL) was added sodium cyanoborohydride (33.4 mg, 532 μmol), sodium acetate (43.7 mg, 532 μmol) and oxetane-3-one (295 mg, 4.10 mmol). The mixture was stirred at 20° C. for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 31%-61%, 8min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-[1-(oxetan-3-yl)-4-piperidinyl]ethyl]pyrazol-4-yl]quinoxaline (38.7mg, 71.1μmol, 17%) as an ^off -white solid. 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. Synthesis of 4-(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 a solution of 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 136 μmol) in acetonitrile (3 mL) was added hydrochloric acid (6M, 1 mL). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 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 (90 mg, crude) as a yellow oil. m/z ES+[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

A solution of 2-[4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-4-piperidinyl]ethanol (80.0 mg, 126 μmol) in hydrobromic acid (4.47 g, 26.5 mmol, 3 mL, 48%) was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 21%-51%, 10min) and re-purified by preparative HPLC (formic acid conditions; column: Shim-packC18 150*25*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-10%, 10min) to give 4-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)quinuclidine (13.0mg, 22.7μmol, 18%) as an ^orange gum. 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-(2,2,2-trifluoroethyl)-4-piperidinyl]ethyl]pyrazol-4-yl]quinoxaline

Step 1. 8-Chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-[1-(2,2,2-trifluoroethyl)-4-piperidinyl]ethyl]pyrazol-4-yl]quinoxaline

To a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline (200 mg, 409 μmol) in N,N-dimethylformamide (2 mL) was added diisopropylethylamine (158 mg, 1.23 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (142 mg, 614 μmol). The mixture was stirred at 25 ° C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 10%-40%, 7 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-[1-(2,2,2-trifluoroethyl)-4-piperidinyl]ethyl]pyrazol-4-yl]quinoxaline (31.8 mg, 55.8 μmol, 13%) as an ^off -white solid. 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),7.0 3-6.97 (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-cyclobutylamine

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-cyclobutaneamine

To a solution of 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]methyl]cyclobutanone (120 mg, 204 μmol) in methanol (1.5 mL) was added N-methylmethylamine hydrochloride (94.7 mg, 1.16 mmol) and sodium acetate (167 mg, 2.04 mmol). The mixture was stirred at 25 ° C for 0.2 hours. Sodium cyanoborohydride (32.0 mg, 509 μmol) was then added and the mixture was stirred at 40 ° C for 1.8 hours. The reaction mixture was quenched with saturated sodium bicarbonate (2 mL) at 25 ° C, 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-N,N-dimethyl-cyclobutanamine (80 mg, 129 μmol, 63%) as a yellow solid. m/z ES+[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

A mixture of 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-N,N-dimethyl-cyclobutanamine (70 mg, 113 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 0%-30%, 10 min) to give 3-[[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]-N,N-dimethyl-cyclobutanamine (26.7 mg, 54.7 μmol, 48%) as a yellow solid. ¹ H NMR (400 MHz, 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

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 a mixture of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 986 μmol) and 2-bromo-1,1-diethoxy-ethane (389 mg, 1.97 mmol) in N,N-dimethylformamide (8 mL) was added cesium carbonate (964 mg, 2.96 mmol). The mixture was heated to 100 ° C and stirred for 4 hours. After completion, the reaction mixture was quenched with water (50 mL) at 20 ° C 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]imidazol-6-yl)oxy)quinoxaline (600 mg, 866 μmol, 88%) as a yellow oil. m/z ES+[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 a mixture of 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 (200 mg, 321 μmol) and 2-(bromomethyl)-2-(hydroxymethyl)propane-1,3-diol (128 mg, 642 μmol) in toluene (5 mL) was added p-toluenesulfonic acid (11.1 mg, 64.2 μmol). The mixture was then heated to 100° C. and stirred for 16 hours. Upon 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-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]methyl]-1,3-dioxan-5-yl]methanol (90 mg, 144 μmol, 45%) as a yellow solid. m/z ES+[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]quinoxaline-2-yl]pyrazol-1-yl]methyl]-1,3-dioxane-5-yl]methanol (70 mg, 117 μmol) in tetrahydrofuran (4 mL) was added aqueous sodium hydroxide solution (18.7 mg, 468 μmol, 60 wt%). The mixture was heated to 60 ° C and stirred for 2 hours. After completion, the reaction mixture was quenched by adding water (5 mL) at 0 ° C, and then extracted with ethyl acetate (10 mL×3). The combined organic layer was 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 C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 11%-41%, 10min) and then repurified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 27%-57%, 10min) purification 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 (8.5mg, 16.4μmol, 14%) as a white solid and compound 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-((5-methylene-1,3-dioxane-2-yl)methyl)-1H-pyrazol-4-yl)quinoxaline (19.8mg, 40.6μmol, 35%) as a yellow solid.

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 a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline (120 mg, 245 μmol) in tetrahydrofuran (2 mL) and water (1 mL) was added sodium bicarbonate (61.9 mg, 737 μmol) and propionyl chloride (45.5 mg, 491 μmol). The mixture was stirred at 25° C. for 0.5 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NXC18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 7 min) to give 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 (44.6 mg, 82.0 μmol, 33%) as a yellow solid. 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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

To a solution of 2-[[5-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 394 μmol), (3,3-difluorocyclobutyl)methyl methanesulfonate (94.8 mg, 473 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (164 mg, 1.18 mmol). The mixture was stirred at 80° C. 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (250 mg, crude) as a yellow oil. m/z ES+[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-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

A mixture of methylboronic acid (245 mg, 4.09 mmol), 2-[[5-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (250 mg, 409 μmol), XPhos Pd G2 (32.2 mg, 40.9 μmol), sodium carbonate (130 mg, 1.23 mmol) in dioxane (3 mL) and water (0.6 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. 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]pyrazol-4-yl]-5-methyl-quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (160 mg, 261 μmol, 64%) as a yellow oil. m/z ES+[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

A solution of 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 (160 mg, 271 μmol) in trifluoroacetic acid (2 mL) was stirred for 2 hours at 25° C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 20%-50%, 7 min) to give 2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-8-methyl-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (59.3 mg, 128 μmol, 47%) as a ^yellow solid. 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),7.1 4(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. Synthesis of 2-(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 a solution of 8-bromo-2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (50.0 mg, 95.2 μmol) and methylboronic acid (57.0 mg, 952 μmol) in dioxane (1 mL) and water (0.1 mL) was added sodium carbonate (30.3 mg, 286 μmol) and XPhos Pd G2 (11.2 mg, 14.3 μmol). The mixture was stirred at 110 ° C for 12 hours under nitrogen. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layer was dried over sodium sulfate, filtered, and 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]; (B%: 17%-47%, 10 min) to give 2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-8-methyl-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (11.0 mg, 23.9 μmol, 25%) as an off-white solid. ¹ H NMR (400 MHz, 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. Synthesis of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-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-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline

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 mg, 84.7 μmol) in N,N-dimethylformamide (1 mL) was added diisopropylethylamine (21.9 mg, 169 μmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (23.6 mg, 102 μmol). The mixture was stirred at 25° C. 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]imidazol-6-yl)oxy)-2-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (50 mg, 74.4 μmol, 88%) as a yellow oil. m/z ES+[M+H] ⁺ 672.5.

Step 2. 8-Chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline

A solution of 8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (50.0 mg, 74.4 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 18%-48%, 7 min) to give 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (20.3 mg, 37.4 μmol, 49% yield) as an off-white solid. ¹ H NMR (400 MHz, 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/zES+[M+H] ⁺ 542.1.

Example 178. Synthesis of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(4-piperidinyl)ethyl]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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (832 mg, 1.64 mmol) in N,N-dimethylformamide (10 mL) 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 ° C 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 tert-butyl 4-[2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate (1.20 g, crude) as a yellow oil. m/z ES+[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

A solution of 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 (100 mg, 139 umol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; 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-[1-[2-(4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline (26.1 mg, 53.6 umol, 38%) as a yellow solid. ¹ H NMR (400 MHz, 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, m/z ES+[M+H] ⁺ 488.1.

Example 179. Synthesis of 8-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 a solution of 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline (200 mg, 409 μmol) in N,N-dimethylformamide (3 mL) was added paraformaldehyde (123 mg, 4.10 mmol) and formic acid (196 mg, 4.10 mmol). The mixture was stirred at 60° C. for 12 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 0%-30%, 10 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[2-(1-methyl-4-piperidinyl)ethyl]pyrazol-4-yl]quinoxaline (26.6 mg, 53.0 μmol, 12%) as ^{a yellow} gum. 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),3.1 3(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. Synthesis of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline

Step 1. tert-Butyl 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-carboxylate

A solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 986 μmol), 4-iodopiperidine-1-carboxylic acid tert-butyl ester (1.53 g, 4.93 mmol), cesium carbonate (642 mg, 1.97 mmol) in N,N-dimethylformamide (5 mL) was stirred at 100 ° C for 1 hour. Then 4-iodopiperidine-1-carboxylic acid tert-butyl ester (920 mg, 2.96 mmol) was added and the mixture was stirred at 100 ° C for 1 hour. In addition, 4-iodopiperidine-1-carboxylic acid tert-butyl ester (920 mg, 2.96 mmol) was added and the mixture was stirred at 100 ° C 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 tert-butyl 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-carboxylate (320 mg, 463 μmol, 47%) as a yellow solid. m/z ES+[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

A solution of tert-butyl 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-carboxylate (320 mg, 463 μmol) in trifluoroacetic acid (5 mL) was stirred at 25° C. for 10 min. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 10 min) to give 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (150 mg, 0.324 mmol, 70%) as a yellow solid. ¹ H NMR (400 MHz, 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＝4.8,1 0.0Hz, 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 a solution of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (50 mg, 109 μmol) in N,N-dimethylformamide (1 mL) was added paraformaldehyde (32.6 mg, 1.09 mmol) and formic acid (52.2 mg, 1.09 mmol). The mixture was stirred at 60 °C for 16 hours. Upon completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 0%-29%, 10 min) to give 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline (36.2 mg, 0.076 mmol, 70%) as a yellow solid. ¹ H NMR (400 MHz, 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. Synthesis of 8-chloro-2-(1-(1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

Step 1. 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)azetidine-1-carboxylate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazole-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 394 μmol) and 3-iodoazetidine-1-carboxylic acid tert-butyl ester (123 mg, 433 μmol) in N,N-dimethylformamide (4 mL), cesium carbonate (257 mg, 789 μmol) was added. The mixture was stirred at 50 ° C for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layer was 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 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)azetidine-1-carboxylate (210 mg, 314 μmol, 80%) as a yellow solid. m/z ES+[M+H] ⁺ 662.3.

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

To a solution of tert-butyl 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]azetidine-1-carboxylate (190 mg, 287 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL). The mixture was stirred at 25 ° C 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]imidazol-6-yl)oxy)quinoxaline (300 mg, crude) as a yellow solid. m/z ES+[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 a solution of 2-[[6-[3-[1-(azetidin-3-yl)pyrazol-4-yl]-5-chloro-quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (300 mg, 534 μmol) in dichloromethane (5 mL) was added diisopropylethylamine (207 mg, 1.60 mmol, 279 μL). Then ethanesulfonyl chloride (103 mg, 800 μmol, 75.7 μL) was added at 0°C. The mixture was stirred at 25°C 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]imidazol-6-yl)oxy)quinoxaline (350 mg, crude) as a yellow oil. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-(1-ethylsulfonylazetidin-3-yl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (350 mg, 535 μmol) in trifluoroacetic acid (5 mL) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenex Luna C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 10 min) to give 8-chloro-2-(1-(1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (48.0 mg, 91.2 μmol, 17%) ^as an off-white solid. 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. 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

To 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 (500 mg, 986 μmol) and tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (551 mg, 1.97 mmol) in dimethyl sulfoxide (10 mL) was added cesium carbonate (964 mg, 2.96 mmol) and potassium iodide (164 mg, 986 μmol). The mixture was stirred at 80 °C for 12 hours. Upon 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 afford 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 (430 mg, 0.62 mmol, 57%) as an orange solid. m/z ES+[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

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 (165 mg, 239 μmol) in trifluoroacetic acid (1 mL) was stirred at 30 °C for 1 hour. Upon 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 (110 mg, crude) as an orange oil. m/z ES+[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 a solution of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)quinoxaline (100 mg, 217 μmol) in dichloromethane (1 mL) was added triethylamine (66.0 mg, 652 μmol, 90.8 μL) and acetyl chloride (15.4 mg, 196 μmol, 14.0 μL). The mixture was stirred at 0 °C for 20 min. Acetyl chloride (17.0 mg, 217 μmol, 15.5 μL) was then added and the mixture was stirred at 0 °C for 10 min. In addition, acetyl chloride (17.0 mg, 217 μmol, 15.5 μL) was added and the mixture was stirred at 0 °C for 10 min. Upon 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 C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 13%-43%, 10 min) to give 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, 0.091 mmol, 42%) as off-white. ¹ H NMR (400 MHz, DMSO-d6) δ 12.32 (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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 197 μmol) in acetonitrile (2 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (30.0 mg, 197 μmol) and 2- (1- ethylsulfonylazetidine -3- subunit) acetonitrile (40.0 mg, 214 μmol). The mixture was stirred at 30 ° C 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 layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- [3- [4- [8- chloro-7- [2- methyl -3- (2- trimethylsilylethoxymethyl) benzimidazol-5-yl] oxy-quinoxaline-2-yl] pyrazole-1-yl] -1- ethylsulfonyl -azetidine -3- base] acetonitrile (120 mg, crude) as a yellow solid. 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

A solution of 2-[3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-ethylsulfonyl-azetidin-3-yl]acetonitrile (70.0 mg, 100 μmol) in trifluoroacetic acid (1 mL) was stirred for 0.5 hours at 25° C. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 22%-52%, 8min) to give 2-[3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-ethylsulfonyl-azetidin-3-yl]acetonitrile (18.7mg, 0.033mmol, 32%) as a gray solid. ¹ H NMR (400MHz, DMSO-d6) δ 12.31 (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-(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)ethyl methanesulfonate

To the solution of 2-(2,5-dihydrofuran-2-yl) ethane-1-ol (260mg, 2.28mmol) in dichloromethane (1mL), triethylamine (921mg, 9.11mmol) and methanesulfonyl chloride (782mg, 6.83mmol) are added. The mixture is stirred at 25 ° C for 1 hour. The mixture is poured into water (10mL) and extracted with ethyl acetate (30mL x 3). The combined organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to obtain 2-(2,5-dihydrofuran-2-yl) ethyl methanesulfonate (100mg, 520μmol, 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-(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 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 (100 mg, 197 μmol) in N,N-dimethylformamide (1 mL) was added 2-(2,5-dihydrofuran-2-yl)ethyl methanesulfonate (53.0 mg, 276 μmol) and potassium carbonate (81.7 mg, 591 μmol). The mixture was stirred at 80 °C for 12 hours. Upon 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-(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 (80 mg, 132 μmol, 67%) as a white solid. m/z ES+[M+H] ⁺ 603.2.

Step 3. 8-Chloro-2-(1-(2-(2,5-dihydrofuran-2-yl)ethyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

A solution of 8-chloro-2-(1-(2-(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 (80 mg, 132 μmol) in trifluoroacetic acid (2 mL) was stirred at 25 °C for 0.5 h. Upon 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. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 14%-44%, 10 min) to give 8-chloro-2-(1-(2-(2,5-dihydrofuran-2-yl)ethyl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (38.9 mg, 82.1 μmol, 61%) as an ^off -white solid. 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. Synthesis of 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

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 a mixture of 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 (0.20 g, 322 μmol) in dichloromethane (4 mL) at 0°C was added 3-chloroperoxybenzoic acid (144 mg, 708 μmol, 85% purity). The mixture was then stirred at 25°C for 2 hours. Upon 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 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 (170 mg, 0.26 mmol, 64%) as a white solid. m/z ES+[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

A solution of 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 (0.17 g, 260 μmol) in trifluoroacetic acid (2 mL) was stirred at 15° C. for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 11%-41%, 10 min) to give 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 (40.0 mg, 76.5 μmol, 29%) as a white solid. ¹ H NMR (400 MHz, 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＝8.4,2.4 Hz,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. Synthesis of 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

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

A solution of 2-[[6-[5-chloro-3-[1-(tetrahydrothiopyran-4-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (60 mg, 96.5 μmol) in trifluoroacetic acid (1 mL) was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 20%-50%, 10 min) to give 8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]-2-[1-(tetrahydrothiopyran-4-ylmethyl)pyrazol-4-yl]quinoxaline (18.04 mg, 0.037 mmol, 37%) as a ^white solid. 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 . 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 a solution of (3S,4S)-4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxaline-2-yl]pyrazol-1-yl]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 282 μmol) in tetrahydrofuran (5 mL) was added pyridine hydrofluoride (1.10 g, 11.1 mmol, 1 mL). The mixture was stirred at 80 ° C 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*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 1%-30%, 10 min) to give 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 (67.1 mg, 127 μmol, 45%, formate) as an ^off -white solid. HNMR (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. Synthesis of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-((4-(methylthio)cyclohexyl)methyl)-1H-pyrazol-4-yl)quinoxaline

Step 1. 8-Chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-((4-(methylthio)cyclohexyl)methyl)-1H-pyrazol-4-yl)quinoxaline

A solution of 2-[[6-[5-chloro-3-[1-[(4-methylsulfanylcyclohexyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (20 mg, 30.8 μmol) in trifluoroacetic acid (2 mL) was stirred for 10 min at 25° C. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 22%-52%, 10 min) to give 8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]-2-[1-[(4-methylsulfanylcyclohexyl)methyl]pyrazol-4-yl]quinoxaline (9.6 mg, 18.5 μmol, 60%) as a white solid. ¹ H NMR (400 MHz, 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),7.0 1(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. Synthesis of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)quinoxaline

Step 1. tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

At 0 ° C, to a mixture of tert-butyl 3-hydroxypiperidine-1-carboxylate (5g, 24.84mmol) and triethylamine (5.03g, 49.7mmol, 6.92mL) in dichloromethane (30mL), methanesulfonyl chloride (3.13g, 27.3mmol, 2.12mL) was added. The mixture was then stirred at 25 ° C for 2 hours. After completion, the reaction mixture was quenched by adding water (50mL) at 0 ° C, and then diluted with water (50mL), and extracted with dichloromethane (100mL×3). The combined organic layer was washed with brine (300mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.9g, crude product) as a yellow solid.

Step 2. tert-Butyl 3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of 8-chloro-2-(1H-pyrazol-4-yl)-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (500 mg, 0.99 mmol) and tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (551 mg, 1.97 mmol) in dimethyl sulfoxide (10 mL) was added cesium carbonate (964 mg, 2.96 mmol) and potassium iodide (164 mg, 0.99 mmol). The mixture was stirred at 80 °C for 12 hours. Upon 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 afford tert-butyl 3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (430 mg, 0.56 mmol, 57%) as a yellow solid. m/z ES+[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 μmol) in trifluoroacetic acid (1 mL) was stirred at 30 °C for 1 hour. Upon 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 a solution of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)quinoxaline (67.0 mg, 146 μmol) in N,N-dimethylformamide (1 mL) was added formic acid (140 mg, 2.91 mmol) and paraformaldehyde (87.5 mg, 2.91 mmol). The mixture was stirred at 60 °C for 12 hours. Upon 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*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 10 min) to give 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)quinoxaline (46.4 mg, 0.098 mmol, 67%) as a yellow solid. ¹ H NMR (400 MHz, 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. Synthesis of 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-((2-methyl-2-azabicyclo[2.2.1]heptane-5-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-((2-methyl-2-azabicyclo[2.2.1]heptan-5-yl)methyl)-1H-pyrazol-4-yl)quinoxaline

To a solution of 2-(1-(2-azabicyclo[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 (70.0 mg, 114 μmol) in N,N-dimethylformamide (1 mL) was added formic acid (109 mg, 2.27 mmol) and paraformaldehyde (68.2 mg, 2.27 mmol). The mixture was stirred at 60° C. for 2 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to afford 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 (70.0 mg, crude) as a yellow oil. m/z ES+[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]heptane-5-yl)methyl)-1H-pyrazol-4-yl)quinoxaline

A solution of 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 (70.0 mg, 111 μmol) in trifluoroacetic acid (1 mL) was stirred at 20° C. for 2 hours. Upon completion, 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]; (B%: 3%-33%, 10 min) to give 8-chloro-7-((2-methyl-1H-benzo[d]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, 0.088 mmol, 79%) as a yellow solid. ¹ H NMR (400 MHz, 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),2–1.8 5(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. tert-Butyl 3,3-difluoro-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

To a solution of 3,3-difluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (500mg, 1.99mmol) in dichloromethane (10mL), triethylamine (604mg, 5.97mmol) and methanesulfonyl chloride (341mg, 2.98mmol) were added. The mixture was stirred at 0°C for 1 hour. After completion, the reaction mixture was diluted with sodium bicarbonate solution (10mL) and extracted with ethyl acetate (25mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 3,3-difluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (1g, crude product) 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,1 H),1.46(s,9H),1.43-1.38(m,1H).

Step 2. tert-Butyl 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-carboxylate

To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 394 μmol) in N,N-dimethylformamide (3 mL), potassium carbonate (163 mg, 1.18 mmol) and tert-butyl 3,3-difluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (155 mg, 473 μmol) were added. The mixture was stirred at 80 ° C 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 layer was 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (80.0 mg, 0.11 mmol, 20%) as a yellow solid. m/z ES+[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

A solution of 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (70.0 mg, 94.5 μmol) in trifluoroacetic acid (4 mL) was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 7 min) to give 8-chloro-2-[1-[(3,3-difluoro-4-piperidinyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (22.2 mg, 0.044 mmol, 42%, formate) as an ^off -white solid. 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,1 H),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 a solution of 8-chloro-2-[1-[(3,3-difluoro-4-piperidinyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (80.0 mg, 156 μmol) in N,N-dimethylformamide (1 mL) was added formic acid (75.3 mg, 1.57 mmol) and paraformaldehyde (47.11 mg, 1.57 mmol). The mixture was stirred at 60° C. for 12 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NXC1875*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 7 min) to give 8-chloro-2-[1-[(3,3-difluoro-1-methyl-4-piperidinyl)methyl]pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (28.5 mg, 0.054 mmol, 34%) as an ^off -white solid. 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. Synthesis of 8-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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (170 mg, 335 umol) in N,N-dimethylformamide (2 mL) 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 ° C 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)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (300 mg, crude) as a yellow oil. 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

A solution of 2-[[6-[5-chloro-3-[1-(2-pyrrolidin-1-ylethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 165 umol) in trifluoroacetic acid (2 mL) was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 2%-32%, 7 min) to give 8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)quinoxaline (30 mg, 0.063 mmol, 38%) as a yellow solid. ¹ H NMR (400 MHz, 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. Synthesis of 6-((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. tert-Butyl 4-[[4-(7-bromoquinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate

To a mixture of 7-bromo-2-chloro-quinoxaline (0.250 g, 1.03 mmol) and tert-butyl 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (430 mg, 1.10 mmol) in dioxane (10 mL) and water (2 mL) was added potassium acetate (302 mg, 3.08 mmol) and cyclopenta-2,4-diene-1-yl(diphenyl)phosphane; dichloropalladium; iRoN(II) (75.1 mg, 103 umol). The mixture was stirred at 60°C under nitrogen for 12 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL×3). The combined organic phase was 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 tert-butyl 4-[[4-(7-bromoquinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (220 mg, 470 μmol, 43%) as a yellow solid. 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. tert-Butyl 4-((4-(7-hydroxyquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-[[4-(7-bromoquinoxaline-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (27.0 g, 58.0 mmol) in dioxane (280 mL) and water (140 mL), 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) were added. The mixture was degassed and purged with nitrogen 3 times, and then stirred at 100 ° C for 3 hours under nitrogen. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (300 mL × 3). The combined organic layer was 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, 48.9 mmol, 84%) as a yellow solid. m/z ES ⁺ [M+H] ⁺ 410.0.

Step 3. tert-Butyl 4-((4-(8-bromo-7-hydroxyquinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

At 0 ° C, to a solution of tert-butyl 4-[[4-(7-hydroxyquinoxaline-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (500 mg, 1.22 mmol) in acetonitrile (10 mL) was added portionwise N-bromosuccinimide (196 mg, 1.10 mmol). The mixture was stirred at 80 ° C for 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-hydroxyquinoxaline-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (490 mg, 0.97 mmol, 79%) as a yellow solid. m/zES+[M+H] ⁺ 488.0.

Step 4. tert-Butyl 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-carboxylate

To a solution of tert-butyl 4-[[4-(8-bromo-7-hydroxy-quinoxalin-2-yl)pyrazol-1-yl]methyl]piperidine-1-carboxylate (245 mg, 502 μmol) and [2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]boronic acid (307 mg, 1 mmol) in 1,2-dichloroethane (6 mL) were added copper acetate (109 mg, 602 μmol), Molecular sieves (500mg) and cesium carbonate (409mg, 1.25mmol). The mixture was stirred at 60 ° C under nitrogen at 15psi 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 obtain 4-((4-(8-bromo-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (230mg, 285μmol, 28%) as a yellow solid. m/zES+[M+H] ^+750.1 .

Step 5. tert-Butyl 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-carboxylate

To a solution of tert-butyl 4-[[4-[8-bromo-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (100 mg, 134 μmol) and malononitrile (17.64 mg, 267 μmol, 16.8 μL) in N,N-dimethylformamide (5 mL) were added copper iodide (12.7 mg, 66.8 μmol), 4-di-tert-butylphosphino-N,N-dimethyl-aniline; dichloropalladium (1.89 mg, 2.67 μmol), 1,10-phenanthroline (6.02 mg, 33.39 μmol), sodium tert-butoxide (25.7 mg, 267 μmol) and potassium fluoride (15.5 mg, 267 μmol). The mixture was stirred at 130 ° C for 12 hours under nitrogen. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was 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/z ES+[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

A solution of tert-butyl 4-[[4-[8-cyano-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (50 mg, 60.3 μmol) in trifluoroacetic acid (1 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 6-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)quinoxaline-5-carbonitrile (40 mg, crude, trifluoroacetic acid) as a yellow oil. m/z ES+[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 a solution of 6-[(2-methyl-3H-benzimidazol-5-yl)oxy]-3-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxaline-5-carbonitrile (40 mg, 69.14 μmol, trifluoroacetic acid) in N,N-dimethylformamide (1 mL) was added aqueous formaldehyde solution (56.1 mg, 691 μmol, 51 μL, 37%). The mixture was stirred at 25 ° C for 0.5 hours. Sodium triacetoxyborohydride (73.3 mg, 346 μmol) was then added. The mixture was stirred at 25 ° C 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 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]; (B%: 1%-30%, 10 min) to give 6-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-3-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)quinoxaline-5-carbonitrile (9.0 mg, 18.8 μmol, 27%) as a ^yellow solid. 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,1 H),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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 295 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (122 mg, 887 μmol) and 2-chloro-1-pyrrolidin-1-yl-ethanone (50.0 mg, 338 μmol). The mixture was stirred at 80 ° C 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]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone (200 mg, crude) as a yellow oil. m/z ES+[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

A solution of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone (200 mg, 323 μmol) in trifluoroacetic acid (5.5 mL) was stirred for 0.5 hours at 25° C. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 12%-42%, 7 min) to give 2-[4-[8-chloro-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanone (39.3 mg, 0.081 mmol, 24%) as an ^off- white solid. 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. Synthesis of 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

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 a solution of 2-[[6-[5-chloro-3-[1-(4-piperidinylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (50 mg, 82.8 μmol) in dichloromethane (1 mL) was added diisopropylethylamine (53.48 mg, 414 μmol, 72 μL). Then, 2-chloroethanesulfonyl chloride (13.49 mg, 82.8 μmol, 9 μL) was added at 0°C. The mixture was stirred at 25°C 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]imidazol-6-yl)oxy)-2-(1-((1-(vinylsulfonyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)quinoxaline (60 mg, crude) as a yellow solid. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-[(1-vinylsulfonyl-4-piperidinyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (60 mg, 86.42 μmol) in trifluoroacetic acid (1 mL) was stirred for 1 hour at 25° C. 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]; (B%: 17%-47%, 10 min) to give 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 (6.4 mg, 11.3 μmol, 13%) as an off-white solid. 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＝1 1.2Hz,2H),1.38-1.24(m,2H); m/z ES+[M+H] ⁺ 564.1.

Example 196. Synthesis of 8-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 a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 295 μmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (122 mg, 887 μmol) and 3-(bromomethyl)-1,1-difluoro-cyclobutane (60.0 mg, 324 μmol). The mixture was stirred at 80 ° C 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]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (180 mg, crude) as a yellow solid. m/z ES+[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

A solution of 2-[[6-[5-chloro-3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (140 mg, 229 μmol) in trifluoroacetic acid (2 mL) was stirred at 25° C. for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 20%-50%, 7 min) to give 8-chloro-2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]-7-[( ² -methyl-3H-benzoimidazol-5-yl)oxy]quinoxaline (71.3 mg, 0.15 mmol, 64%) as an off-white solid. 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. 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

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

At 20 ° C, cesium carbonate (3864 mg, 1.18 mmol) was added once to a mixture of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxaline-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 394 μmol) and 2-bromo-1,1-diethoxy-ethane (155 mg, 789 μmol, 119 μL) in N,N-dimethylformamide (3 mL). The mixture was then heated to 100 ° C and stirred for 4 hours. After completion, the reaction mixture was quenched by adding water (20 mL) at 20 ° C 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]quinoxalin-6-yl]oxy-2-methyl-benzoimidazol-1-yl]methoxy]ethyl-trimethyl-silane (0.25 g, 0.40 mmol, 97%) as a yellow oil. m/z ES+[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

At 20 ° C, to a mixture of 2-[[6-[5-chloro-3-[1-(2,2-diethoxyethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-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) in one portion. The mixture was then heated to 120 ° C 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 150*25mm*10um; mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 15%-45%, 10min) and by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 20%-50%, 8min). The impure product was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; (B%: 28%-58%, 8min) was further purified to give 8-chloro-2-[1-(2,2-diethoxyethyl)pyrazol-4-yl]-7-[(2-methyl-3H-benzoimidazol-5-yl)oxy](quinoxaline (8.2mg, 0.017mmol, 4.1%) as a yellow gum and 2-(1-((1,3-dioxane-2-yl)methyl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (10.0mg, 0.021mmol, 5.0%) as a 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＝8.4 Hz,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＝8.8 Hz,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

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 = 9.2 Hz,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＝2.4,8.8 Hz,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 = 6.8 Hz, 1H), 8.67 (d, J = 8.4 Hz, 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)-1λ ⁶ -thiopyran-1-one

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-λ ⁶ -thione

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-benzodiazol-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. tert-Butyl 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-carboxylate

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-1λ ⁶ -thiopyran-1-one

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 = 9.2 Hz,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＝2.4,8.4 Hz,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-λ ⁶ -sulfanyl}(methyl)amine

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-(oxan-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-(2,2,5,5-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 = 9.2 Hz,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-benzodiazol-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-(2,2,5,5-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 = 9.2 Hz,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-benzodiazol-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 = 9.2 Hz,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]cyclopropane-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 = 8.8 Hz,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-(oxan-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 1-1-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 226. N-{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 227. N-{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 = 9.2 Hz,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-benzodiazol-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]heptane-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 = 9.2 Hz,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＝2.4,8.8 Hz, 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 1-1-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 = 9.6 Hz,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＝8.0 Hz,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 = 9.2 Hz,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 = 9.2 Hz,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＝2.0,8.4 Hz,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-benzodiazol-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. Methyl 2-(4-{8-chloro-7-[(7-fluoro-2-methyl-1H-1,3-benzodiazol-6-yl)oxy]quinoxalin-2-yl}-1H-pyrazol-1-yl)-2-methylpropanoate

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),5.3 1(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 = 9.3 Hz,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 -thiazane-1,1-dione

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-benzodiazol-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-(2,2,2-trifluoroethyl)-4-azaspiro[2.5]octan-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)-1,1,1-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＝8.4 Hz, 1H), 6.55 (s, 1H), 4.86 (q, J = 14.0Hz, 1H), 2.53 (s, 3H), 1.26 (s, 3H).

Example 251. (4r)-6-(4-{8-chloro-7-[(2-methyl-1H-1,3-benzodiazol-6-yl)oxy]quinoxalin-2-yl}-1H-pyrazol-1-yl)spiro[3.3]heptan-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. (4s)-6-(4-{8-chloro-7-[(2-methyl-1H-1,3-benzodiazol-6-yl)oxy]quinoxalin-2-yl}-1H-pyrazol-1-yl)spiro[3.3]heptan-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. (4r)-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]heptan-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＝8.4 Hz, 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. (4s)-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]heptan-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-benzodiazol-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]octan-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

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＝6.4 Hz, 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,3r)-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)-1,1,1-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 is a non-limiting example describing a cell proliferation assay used to determine 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 (FGFR2-amplified) cells were resuspended at 18,520 c/ml mL in RPMI containing 10% heat-inactivated FBS, 1% L-glutamine and dispensed in duplicate (463 c/well) into 384-well plates. UM-UC-14 (FGFR3-S249C) cells were resuspended at 40,000 c/ml mL in RPMI containing 10% heat-inactivated FBS, 1% L-glutamine and dispensed in duplicate (1000 c/well) into 384-well plates. DMS-114 (FGFR1 overexpressing) cells were resuspended at 40,000 c/ml mL in RPMI containing 10% heat-inactivated FBS, 1% L-glutamine and dispensed in duplicate (1000 c/well) into 384-well plates. RT-112 (FGFR3-Tacc3 fusion) cells were resuspended in RPMI containing 10% heat-inactivated FBS, 1% L-glutamine at 40,000 c/ml mL and distributed in duplicate (1000 c/well) to 384-well plates. In order to determine the effect of the compounds of the present invention 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 invention. Subsequently, according to the protocol provided by the manufacturer, the inhibition of cell growth was determined by using CellTiterGlo (Promega) to quantify the intracellular ATP content by luminescence (Envision by Perkin Elmer). In order to determine the IC50 value, the cells treated with the vehicle were normalized to viable cells and analyzed using CDD Vault software (Collaborative DrugDiscovery, Burlingame, CA).

Tables A1 and A2 assign various compound potency codes: A, B, C, or D. According to the code, A represents an _IC50 value <20 nM; B represents an _IC50 value ≥20 nM and <100 nM; C represents an _IC50 value ≥100 nM and <400 nM; and D represents an _IC50 value ≥400 nM.

Table A1

Table A2

Equivalent form

The details of one or more embodiments of the present disclosure are set forth in the above attached description. Although any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the present disclosure, preferred methods and materials are now described. Other features, objects and advantages of the present disclosure will be apparent from this specification and claims. In the specification and the appended claims, unless the context clearly specifies otherwise, singular forms also include plural references. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present disclosure belongs. All patents and disclosures 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 present disclosure to the precise form disclosed except as limited by the appended claims.

Claims (31)

1. A compound of formula (I'): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each independently represents a single bond or a double bond; n is 0 or 1; ^W1 is C( ^RW1 ) when attached to one double bond and one single bond, N( ^RW1 ) when attached to two single bonds, or N when attached to one double bond and one single bond; R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl); ^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) or O when attached to two single bonds, or N when attached to one double bond and one single bond; R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl); W ³ is C or N; ^W4 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 alkyl); ^W5 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 alkyl); ^W6 is C ( ^RW6 ) when attached to one double bond and one single bond, N ( ^RW6 ) when attached to two single bonds, or N when attached to one double bond and one 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 alkyl); ^X1 is C or N; ^X2 is N, O or C (R ^X2 ); ^RX2 is H or _C1 - _C6 alkyl; ^X3 is N, O or C (R ^X3 ); ^RX3 is H or _C1 - _C6 alkyl; ^R3 is H, halogen, cyano, _NH2 , -NH( _C1 - _C6 alkyl), -NHC(=O)( _C1 - _C6 haloalkyl), -NHC(=O)O( _C1 - _C6 alkyl), N(C1- _C6 alkyl) ₂ , -S(=O) _2- (C1-C6 alkyl), -C(=O)H, -C(=O)( _C1 - _C6 alkyl), -C(=O)O( _C1 - _C6 alkyl), _C1 -C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, C1- _{C6 alkoxy, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein -NH(C1-C6 alkyl ) is C3 - C12 cycloalkyl} , _C3 - _C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, _C6 - _C10 aryl, or 5- to 10-membered heteroaryl. _R 3a substituted with one or more R 3a ; -NHC(═O)(C ₁ -C ₆ haloalkyl), -NHC(═O)O(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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), 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 is optionally substituted with one or more R ^3a ; each R ^3a is 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) ₂ , -S(═O) _2- (C ₁ -C ₆ alkyl), -C(═O)(C ₁ -C ₆ alkyl), -C(═O)O(C ₁ -C ₆ alkyl), 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) is optionally substituted with one or more halogens; R ⁵ is H, halogen, cyano or C ₁ -C ₆ alkyl; R ⁶ is H, halogen, cyano or C ₁ -C ₆ alkyl; Y is absent and is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy is optionally substituted by 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 optionally substituted by -(C ₁ -C ₆ alkyl)(C ₆ -C ₁₀ aryl), or C ₃ -C ₁₂ cycloalkyl; Z is absent and is 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 is optionally substituted with one or more RZ; each RZ is independently oxo, halogen, cyano, -OH, = ^NRZa , NH2, _NHRZa ^, NH( _C1 - _C6 alkyl), N( _C1 - _C6 alkyl) ₂ , -S( _C1 - _C6 alkyl), -S(=O)(= ^NRZa )-(C1- _C6 alkyl), -S(=O) _2- ( _C1 - _C6 alkyl), -S(=O) _2- ( _C1 - _C6 alkenyl), -C(=O)(3- to 12-membered heterocycloalkyl), -C(=O)NH( _{C1 - C6} alkyl), -C(=O) ^NRZa , -C(=O)-( _C1 - _C6 alkyl), -C(=O)-( _C2 - _C6 alkenyl), -C(=O)-( _C1 - _C6 alkoxy), _C1 - _C6 alkyl, _C2 -C 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} alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) _2- (C _{1 -C} alkyl), -C(═O)-(C ₁ -C alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 is optionally substituted with one or more RZa; Each RZa is independently H, oxo, halogen, cyano, -OH, _NH2 , NH( _C1 - _C6 alkyl), N( _C1 - _C6 alkyl) ₂ , -S(=O) _2- (C1- _C6 alkyl), -C(=O)-( _C1 - _C6 alkyl), -C(=O)-(C2-C6 alkenyl), _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 alkoxy, _C3 - _C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein NH( _{C1 - C6} alkyl), N( _C1 - _C6 alkyl) ₂ , -S(=O) _2- ( _C1 - _C6 alkyl), -C(=O)-( _{C1 - C6} alkyl), -C(=O)-( _{C2-C6 alkenyl} ), _{R Zb} is _{optionally substituted with one} ^or _{more R Zb ; and} Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy. 2. The compound according to claim 1, wherein: Each independently represents a single bond or a double bond; n is 0; ^W1 is C( ^RW1 ) when attached to one double bond and one single bond, N( ^RW1 ) when attached to two single bonds, or N when attached to one double bond and one single bond; R ^W1 is H; ^W2 is C( ^RW2 ) when attached to one double bond and one single bond, N( ^RW2 ) or O when attached to two single bonds, or N when attached to one double bond and one single bond; R ^W2 is H; W ³ is N; W ⁴ is C(R ^W4 ); R ^W4 is H or halogen; ^W5 is C(R ^W5 ); R ^W5 is H or halogen; ^W6 is C ( ^RW6 ) when attached to one double bond and one single bond, N ( ^RW6 ) when attached to two single bonds, or N when attached to one double bond and one single bond; R ^W6 is H or C ₁ -C ₆ alkyl; X ¹ is N; ^X2 is C(R ^X2 ); ^RX2 is H or _C1 - _C6 alkyl; ^X3 is C(R ^X3 ); ^RX3 is H or _C1 - _C6 alkyl; ^R3 is H, halogen, cyano, _NH2 , NHC(=O)O( _C1 - _C6 alkyl), -S ₍ =O) _2- (C1- _C6 alkyl), -C(=O)( _C1 - _C6 alkyl), -C(=O)O( _C1 - _C6 alkyl), _C1 -C6 alkyl, _C2 - _C6 alkenyl, _C3 - _C12 cycloalkyl, 3- to ₁₂ -membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, or 5- to 10-membered heteroaryl, wherein NHC(=O)O( _C1 - _C6 alkyl), -S(=O) _2- ( _C1 - _C6 alkyl), -C(=O)( _C1 - _C6 alkyl), -C(=O)O( _C1 - _C6 alkyl), _C1 -C _6- membered alkyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^3a ; each R ^3a is 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), 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), C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl is optionally substituted with one or more halogen; R ⁵ is H or C ₁ -C ₆ alkyl; ^R6 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, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy is optionally substituted by one or more halogen, oxo, cyano, -OH, NH ₂ , C ₁ -C ₆ alkyl, C ₂ -C 6 alkenyl, C ₁ -C ₆ alkoxy optionally substituted by -(C ₁ -C ₆ alkyl)( _{C 6} -C ₁₀ aryl), or C ₃ -C ₁₂ cycloalkyl; 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 is optionally substituted with one or more RZ; each R ^Z is independently oxo, halogen, -OH, =NR ^Za , NH ₂ , NHR ^Za , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) 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 ₁ -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), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, C ₃ -C 6 the _alkyl ), -S(═O)(═NR Za )-(C ₁ -C ₆ alkyl), -S(═O) ₂ -(C ₁ -C ₆ alkyl), -S(═O) ₂ -(C ₁ -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), _{C 1} -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, C _{3 -C 6 12} -membered cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R ^Za ; each R ^Za is independently H, oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C 6 alkyl), 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 ₁₂ -membered cycloalkyl or 3 to 12-membered heterocycloalkyl is optionally substituted with one or more R ^Zb ; and Each R ^Zb is independently oxo, halogen, -OH. 3. A compound of formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Each independently represents a single bond or a double bond; n is 0 or 1; ^W1 is C ( ^RW1 ) or N ( ^RW1 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond; R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl); ^W2 is C ( ^RW2 ) or N ( ^RW2 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond; R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl); W ³ is C or N; ^X1 is C or N; ^X2 is N, O or C (R ^X2 ); ^RX2 is H or _C1 - _C6 alkyl; ^X3 is N, O or C (R ^X3 ); ^RX3 is H or _C1 - _C6 alkyl; R ¹ is H, halogen, cyano or C ₁ -C ₆ alkyl; R ² is H, halogen, cyano or C ₁ -C ₆ alkyl; R ³ is H, halogen, cyano or C ₁ -C ₆ alkyl; R ⁴ is H, halogen, cyano or C ₁ -C ₆ alkyl; Y is absent or is C ₁ -C ₆ alkyl optionally substituted with one or more oxo or -OH; 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 is optionally substituted by one or more R ^Z ; Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ; each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy. 4. The compound according to claim 3, wherein: Each independently represents a single bond or a double bond; n is 0 or 1; ^W1 is C ( ^RW1 ) or N ( ^RW1 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond; R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl); ^W2 is C ( ^RW2 ) or N ( ^RW2 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond; R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl); W ³ is C or N; ^X1 is C or N; ^X2 is N, O or C (R ^X2 ); ^RX2 is H or _C1 - _C6 alkyl; ^X3 is N, O or C (R ^X3 ); ^RX3 is H or _C1 - _C6 alkyl; R ¹ is H, halogen, cyano or C ₁ -C ₆ alkyl; R ² is H, halogen, cyano or C ₁ -C ₆ alkyl; R ³ is H, halogen, cyano or C ₁ -C ₆ alkyl; R ⁴ is H, halogen, cyano or C ₁ -C ₆ alkyl; Y is absent or is C ₁ -C ₆ alkyl optionally substituted with one or more oxo or -OH; 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 optionally substituted by one or more R ^Z ; Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Za ; each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy. 5. The compound according to claim 3, wherein: Each independently represents a single bond or a double bond; n is 0 or 1; ^W1 is C ( ^RW1 ) or N ( ^RW1 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond; R ^W1 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl); ^W2 is C ( ^RW2 ) or N ( ^RW2 ) when attached to two single bonds, or C or N when attached to one double bond and one single bond; R ^W2 is H, C ₁ -C ₆ alkyl or -S(═O) ₂ -(C ₁ -C ₆ alkyl); W ³ is C or N; ^X1 is C or N; ^X2 is N, O or C (R ^X2 ); ^RX2 is H or _C1 - _C6 alkyl; ^X3 is N, O or C (R ^X3 ); ^RX3 is H or _C1 - _C6 alkyl; R ¹ is H, halogen, cyano or C ₁ -C ₆ alkyl; R ² is H, halogen, cyano or C ₁ -C ₆ alkyl; R ³ is H, halogen, cyano or C ₁ -C ₆ alkyl; R ⁴ is H, halogen, cyano or C ₁ -C ₆ alkyl; Y is C ₁ -C ₆ alkyl optionally substituted by one or more oxo or -OH; 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 optionally substituted by one or more R ^Z ; Each R ^Z is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more RZa; each R ^Za is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), 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 _{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 is optionally substituted with one or more R ^Zb ; and Each R ^Zb is independently oxo, halogen, cyano, -OH, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -S(═O) ₂ -(C ₁ -C ₆ alkyl), -C(═O)-(C ₁ -C ₆ alkyl), -C(═O)-(C ₂ -C ₆ alkenyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy. 6. A compound according to any one of the preceding claims, wherein for 7. A compound according to any one of the preceding claims, wherein for 8. A compound according to any one of the preceding claims, wherein ^R1 is H. 9. The compound according to any one of the preceding claims, wherein ^R1 is halogen, cyano or _C1 - _C6 alkyl. 10. A compound according to any one of the preceding claims, wherein ^R2 is H. 11. The compound according to any one of the preceding claims, wherein ^R2 is halogen, cyano or _C1 - _C6 alkyl. 12. A compound according to any one of the preceding claims, wherein ^R3 is H. 13. A compound according to any one of the preceding claims, wherein ^R3 is halogen, cyano or _C1 - _C6 alkyl. 14. A compound according to any one of the preceding claims, wherein ^R4 is H. 15. A compound according to any one of the preceding claims, wherein ^R4 is halogen, cyano or _C1 - _C6 alkyl. 16. A compound according to any one of the preceding claims, wherein Y is absent. 17. A compound according to any one of the preceding claims, wherein Y is _C1 - _C6 alkyl optionally substituted with one or more oxo or -OH. 18. A compound according to any one of the preceding claims, wherein Z is absent. 19. A compound according to any one of the preceding claims, wherein Z is _C3 - _C12 cycloalkyl, _C3 - _C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, _C6 - _C10 aryl or 5- to 10-membered heteroaryl, wherein _C3 - _C12 cycloalkyl, _C3 - _C12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, _C6 - _C10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more ^RZ . 20. A compound according to any one of the preceding claims, having formula (I-a), (I-b), (I-c), (I-d), (II), (II-a), (II-b), (II-c) or (II-d): 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 pharmaceutically acceptable salts or stereoisomers 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 treating or preventing cancer in a subject. 25. Use of a compound according to any one of the preceding claims in the preparation 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 to 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 to 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 to 27, wherein the cancer is characterized by at least one oncogenic variant of FGFR2 or FGFR3. 31. The method, compound or use of any one of claims 23 to 30, wherein the cancer is 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, renal 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, vulvar cancer, joint cancer, oral cancer, pharyngeal cancer or colorectal cancer.