CN117917405A

CN117917405A - KIF18A protein inhibitors

Info

Publication number: CN117917405A
Application number: CN202311366149.7A
Authority: CN
Inventors: 温俏冬; 杨欣; 江珊玲; 诸葛定娟; 郑鹛; 殷建明; 吕裕斌
Original assignee: Hangzhou Bangshun Pharmaceutical Co ltd
Current assignee: Hangzhou Bangshun Pharmaceutical Co ltd
Priority date: 2022-10-21
Filing date: 2023-10-20
Publication date: 2024-04-23
Also published as: WO2024083208A1

Abstract

The invention provides a compound with a structure shown in a general formula (I), deuterated compound, stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and application of the compound. The compound provided by the invention has good KIF18A protein inhibition effect, and can be used for treating and/or preventing advanced or metastatic colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, peritoneal cancer, fallopian tube cancer, ovarian cancer or endometrial cancer.

Description

KIF18A protein inhibitors

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a KIF18A protein inhibitor, a pharmaceutical composition, a preparation method and application thereof in preparing, preventing and/or treating medicines related to indication diseases of a KIF18A signal path.

Background

The member 18A of the KIF18A kinesin family is a member of the Kinesin-8 family, and is a molecular motor protein which can release energy by hydrolyzing ATP in cells and move in the positive direction by taking microtubules as rails. In the mitosis process, the KIF18A can regulate the dynamic instability of microtubules, regulate the dynamics of spindle microtubules and the amplitude of chromosomes, and has a key effect on timely completing the whole row of the chromosomes in the mitosis period, maintaining the stability of the genome and smoothly completing the mitosis. KIF18A is under-expressed in most human normal tissues, is abnormally high in various malignant tumor tissues, and KIF18A high expression is associated with malignant pathological features and poor prognosis in tumor patients.

Chromosome Instability (CIN) is a marker of tumor cells and is caused by disruption of microtubule dynamics and control changes in the mitotic spindle of tumor cells. The literature indicates that KIF18A gene knockout, or inhibition of KIF18A, can further deregulate CIN tumor cell microtubule dynamics, resulting in a force imbalance that maintains spindle integrity, causing mitotic arrest and centrosome disruption, and thus tumor cell death. Suggesting a targeted inhibitory effect of KIF18A inhibitors in CIN tumors.

KIF18A inhibitors are expected to be anti-tumor drugs with good prospects in the field of treatment of various malignant tumors, but at present, no KIF18A inhibitors are marketed, and KIF18A inhibitors (namely AMG650, compound 4 disclosed in CN113226473 a) developed by the ann company (Amgen) are the only drugs in clinical stages worldwide. AMG650 is currently undergoing phase I clinical studies, and its safety and efficacy are not currently demonstrated. There is therefore an urgent need to develop more safe and effective KIF18A inhibitors to meet the clinical demands of drug administration.

Disclosure of Invention

In a first aspect the present invention provides a compound having the structure of formula (I), a deuterated, a stereoisomer, or a pharmaceutically acceptable salt thereof:

Wherein,

X ₁ and X ₂ are each independently CH or an N atom;

Ring a is a 5-10 membered monocyclic or bicyclic heterocyclic group containing 1-6 heteroatoms selected from N, O, S and substituted with 0, 1,2 or 3R ₃;

Preferably ring a is a 5-10 membered monocyclic or bicyclic heterocyclic group, said ring a containing 1,2 or 3 heteroatoms selected from N, O, S and being substituted by 0, 1,2 or 3R ₃;

the ring a is optionally oxo with 1 to 2C atoms;

Ring B is a 5-, 6-, 7-or 8-membered cycloalkyl or heterocycloalkyl group containing 1,2 or 3 heteroatoms selected from N, O, S, said ring B being optionally substituted with 1,2 or 3R ₄;

R ₁ is-L ₁-R₅, wherein L ₁ is selected from -NR₆-、-NR₆SO₂-、-NR₆SO₂NR₆-、-NR₆CO-、-NR₆CONR₆- or-n=s (=o) (-R ₆) -;

R ₂ is-L ₂-R₇, wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₃ is selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, or cyano;

R ₄ is selected from H, R _4a or R _4b;

The R _4a or R _4b is independently selected from halogen, hydroxy, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, or

R _4a、R_4b forms a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl group with the atom to which it is attached;

The R ₅ is selected from H, R _5a or R _5b;

The R _5a is a 5-6 membered heteroaryl, and is optionally substituted with 1,2, or 3 groups selected from: c _1-3 alkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 haloalkyl or C _1-3 haloalkoxy;

The R _5b is selected from C _1-3 alkyl, C _1-3 alkoxy, which may be optionally substituted with hydroxy or halogen;

The R ₆ is selected from H, C _1-3 alkyl or C _3-6 cycloalkyl;

R ₇ is selected from H, R _7a or R _7b;

R _7a is selected from-C _0-3 alkyl- (3-7) membered cycloalkyl, -C _0-3 alkyl- (3-7) membered heterocycloalkyl optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylene, C _1-6 haloalkyl, C _1-6 haloalkoxy or C _1-6 haloalkylene;

R _7b is selected from C _1-6 alkyl optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-6 alkoxy or C _1-6 haloalkoxy.

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (I), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be:

X ₁ and X ₂ are each CH;

The ring B is Optionally substituted with 1 or 2R ₄; the R ₄ is selected from R ₄ a or R _4b;

The R _4a or R _4b is independently selected from halogen, hydroxy, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, or

Further preferably, the ring B and R _4a、R_4b form the following structure The R _4a or R _4b is independently selected from halogen, C _1-3 alkyl, C _1-3 haloalkyl, or

R _4a、R_4b forms a 3-6 membered cycloalkyl group with the atom to which it is attached;

further preferably, the ring B and R _4a、R_4b form the following structure:

R ₁ is-L ₁-R₅, wherein L ₁ is selected from -NR₆-、-NR₆SO₂-、-NR₆SO₂NR₆-、-NR₆CONR₆- or-n=s (=o) (-R ₆) -;

The R ₅ is selected from H, R _5a or R _5b;

The R ₆ is selected from H, C _1-3 alkyl or C _3-6 cycloalkyl;

Said R _5a is selected from the group consisting of 5 membered heteroaryl groups, preferably And optionally substituted with 1 group selected from: c _1-3 hydroxyalkyl, C _1-3 hydroxyalkyl or C _1-3 haloalkyl, of which-CH ₂ OH is preferred;

Further preferably, R _5a is selected from

The R _5b is hydroxy-substituted C _1-3 alkyl, preferably-CH ₂-CH₂ OH;

further preferred, R ₁ is a group selected from the following structures:

in certain embodiments according to the present invention, the compounds having the structure represented by general formula (I), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (II):

Wherein,

Ring a is selected from 5-6 membered monocyclic heteroaryl, 6 membered monocyclic unsaturated heterocyclyl or 9-10 membered fused ring heteroaryl containing 1-6 heteroatoms selected from N, O, S, said ring a being substituted with 0, 1,2 or 3R ₃;

Preferably ring a is selected from 5-6 membered monocyclic heteroaryl, 6 membered monocyclic unsaturated heterocyclyl or 9-10 membered fused ring heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, said ring a being substituted with 0, 1, 2 or 3R ₃;

When ring a is a 6 membered monocyclic unsaturated heterocyclyl, optionally 1-2C atoms are oxo;

The R ₃ is selected from halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy or 3-6 membered cycloalkyl;

R ₇ is selected from H, R _7a or R _7b;

R _7a is selected from-C _0-3 alkyl- (3-7) membered cycloalkyl, -C _0-3 alkyl- (3-7) membered heterocycloalkyl optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylene, C _1-3 haloalkyl, C _1-3 haloalkoxy or C _1-3 haloalkylene;

Further preferred, R _7a is selected from the group consisting of-CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (3-7) membered heterocycloalkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylene, C _1-3 haloalkyl, C _1-3 haloalkoxy or C _1-3 haloalkylene;

More preferably R _7a is selected from 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylene, C _1-3 haloalkyl, C _1-3 haloalkoxy or C _1-3 haloalkylene;

R _7b is selected from C _1-3 alkyl optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-3 alkoxy or C _1-3 haloalkoxy.

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be:

Ring a is selected from:

And ring a is substituted with 0, 1,2 or 3R ₃;

Ring a is preferably:

And ring a is substituted with 0, 1,2 or 3R ₃;

Further preferably, ring a is selected from:

And ring a is substituted with 0, 1,2 or 3R ₃;

Ring a further preferably:

And ring a is substituted with 0, 1,2 or 3R ₃;

The R ₃ is selected from F, cl, methyl, ethyl, propyl, cyclopropyl, cyclopentyl, cyclohexyl, -OCH ₃、-CF₃, or-OCF ₃, preferably F, methyl, ethyl, cyclopropyl, -OCH ₃、-CF₃, or-OCF ₃.

R ₂ is L ₂-R₇, wherein,

L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from H, R _7a or R _7b;

R _7a is selected from C _0-3 alkyl- (3-7) membered cycloalkyl, -C _0-3 alkyl- (3-7) membered heterocycloalkyl optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylene, C _1-3 haloalkyl, C _1-3 haloalkoxy or C _1-3 haloalkylene;

Preferably R _7a is selected from the group consisting of-CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (3-7) membered heterocycloalkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyls, And optionally substituted with 1,2 or 3 groups selected from: F. cl, C _1-3 alkylene, C _1-3 haloalkylene, preferably F, =cf ₂、＝CH₂、＝C(CH₃)₂;

Further preferably, R _7a is selected from

More preferably, R _7a is selected from

R _7b is selected from methyl, ethyl, n-propyl, optionally substituted with 1,2 or 3 groups selected from: F. -OCH ₃ or-OCF ₃;

further preferably, the R _7b is selected from the group consisting of-CHF ₂、-CF₃、-CH₂-CHF₂、-(CH₂)₂-CF₃, or- (CH ₂)₂-OCF₃);

Further preferred, R ₂ is a group selected from the following structures:

Ring a is a 5 membered heteroaryl containing 1,2 or 3 heteroatoms selected from N, O or S, said ring a being substituted with 0, 1,2 or 3R ₃;

further preferably, said ring A is selected from And substituted with 0, 1 or 2R ₃;

The R ₃ is selected from F, methyl, ethyl, cyclopropyl, -OCH ₃、-CF₃ or-OCF ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

Preferably R _7a is selected from the group consisting of-CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (3-7) membered heterocycloalkyl, And optionally substituted with 1,2 or 3 groups selected from: F. cl, C _1-3 alkylene, C _1-3 haloalkylene, preferably F;

Further preferably, R _7a is selected from

More preferably, R _7a is selected from

R _7b is selected from-CHF ₂、-CF₃、-CH₂-CHF₂、-(CH₂)₂-CF₃ or- (CH ₂)₂-OCF₃).

Further preferably, R ₂ is selected from:

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (III):

R ₃ is selected from F, methyl, ethyl, cyclopropyl, -OCH ₃、-CF₃ or-OCF ₃;

n is selected from 0, 1 or 2;

R ₇ is selected from R _7a;

Preferably R _7a is selected from the group consisting of-CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (3-7) membered heterocycloalkyl, And optionally substituted with 1,2 or 3F;

Further preferably, R _7a is selected from

Further preferably, R ₂ is selected from:

n is selected from 0, 1 or 2;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a;

R _7a is selected from And optionally substituted with 1,2 or 3F;

further preferably, said R _7a is selected from the group consisting of:

Ring a is a 6 membered heteroaryl containing 1,2 or 3 heteroatoms selected from N, O or S, said ring a being substituted with 0, 1,2 or 3R ₃;

Further preferably, the ring A is And substituted with 0, 1 or 2R ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a;

R _7a is selected from And optionally substituted with 1,2 or 3 groups selected from: =ch ₂、＝CF₂、＝C(CH₃)₂;

Further preferably, R _7a is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (IV):

Wherein,

n is selected from 0, 1 or 2;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from the group consisting of-O-, -CO-, covalent bonds;

R ₇ is selected from R _7a;

Further preferably, R _7a is selected from

ring a is a 6 membered unsaturated heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and 1-2C atoms of ring a are oxo; the ring a is substituted with 0, 1, 2 or 3R ₃;

further preferably, the ring a is selected from: And substituted with 0, 1, 2 or 3R ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a;

R _7a is selected from And optionally substituted with 1,2 or 3 groups selected from: F. cl, C _1-3 alkylene, C _1-3 haloalkylene, preferably F;

Further preferably, R _7a is selected from

Further preferably, R ₂ is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (V):

z ₁ is selected from N, CH or C-R ₃;

Z ₂ is selected from NH or N-R ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a;

R _7a is selected from And optionally substituted with 1,2 or 3F;

Further preferably, R _7a is selected from />

Further preferably, R ₂ is selected from

Ring a is a 9-10 membered fused ring heteroaryl containing 1-6 heteroatoms selected from N, O, S, said ring a being substituted with 0, 1, 2 or 3R ₃;

In certain embodiments according to the present invention, the compounds provided herein, deuterated, stereoisomers, or pharmaceutically acceptable salts thereof, may further be: has a structure shown in a general formula (I):

X ₁ and X ₂ are independently CH or an N atom, preferably CH;

Ring a is a 5-10 membered bicyclic heterocyclyl, preferably an 8-, 9-or 10-membered bicyclic heterocyclyl; the ring A contains 1 to 6 heteroatoms selected from N, O, S, preferably 2 to 4, and is substituted by 0, 1,2 or 3R ₃;

the ring a is optionally oxo with 1 to 2C atoms;

R ₇ is selected from H, R _7a or R _7b;

R _7a is selected from-C _0-3 alkyl- (3-7) membered cycloalkyl, -C _0-3 alkyl- (3-7) membered heterocycloalkyl, preferably 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, -CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (4-7) membered heterocycloalkyl, optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylene, C _1-6 haloalkyl, C _1-6 haloalkoxy or C _1-6 haloalkylene;

Ring B is a 5-, 6-, 7-or 8-membered cycloalkyl or heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S, said ring B being optionally substituted with 1, 2,3 or 4R ₄;

R ₄ is selected from H, R _4a or R _4b;

The R ₅ is selected from H, R _5a or R _5b;

The R _5b is selected from C _1-3 alkyl, C _1-3 alkoxy, which may be optionally substituted by hydroxy, halogen;

The R ₆ is selected from H, C _1-3 alkyl or C _3-6 cycloalkyl.

As preferable:

The ring A is selected from 8-membered, 9-membered or 10-membered bicyclic heterocyclyl, 8-membered, 9-membered or 10-membered bicyclic heteroaryl, contains 2-4 heteroatoms selected from N, O, S, and is substituted with 0, 1,2 or 3R ₃; r ₃ is selected from halogen, C _1-3 alkyl, C _1-3 alkoxy, 3-6 membered cycloalkyl, C _1-3 haloalkyl, C _1-3 haloalkoxy or cyano; when ring a is an 8-, 9-or 10-membered bicyclic heterocyclyl, optionally 1-2C atoms are oxo;

Further preferred, the ring a is an 8-, 9-or 10-membered bicyclic heteroaryl group containing 2-4N atoms and substituted with 0, 1,2 or 3R ₃; r ₃ is selected from halogen, 3-5 membered cycloalkyl, C _1-3 alkyl, C _1-3 haloalkyl or cyano.

As preferable:

Ring A is selected from />

Ring A is preferably

Ring A is more preferred

Ring A is further preferred/>

Wherein the terminal is connected with R ₂, and the terminal # is connected with an amido;

ring a is optionally substituted with 0, 1 or 2R ₃;

R ₃ is selected from halogen, 3-5 membered cycloalkyl, C _1-3 alkyl, C _1-3 haloalkyl or cyano, preferably F, methyl, trifluoromethyl or cyano.

As preferable:

R ₇ is selected from H, R _7a or R _7b;

r _7a is selected from 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, -CH ₂ - (3-6) membered cycloalkyl, -CH ₂ - (4-7) membered heterocycloalkyl, more preferably 3-6 membered cycloalkyl, 4-7 membered azetidinyl, -CH ₂ - (3-6) membered cycloalkyl, -CH ₂ - (4-7) membered azetidinyl;

R _7a is preferably More preferably/>

R _7a is further preferred More preferably/>

R _7a is optionally substituted with 1 or 2 groups selected from: halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylene, C _1-3 haloalkyl, C _1-3 haloalkoxy or C _1-3 haloalkylene, more preferably halogen, C _1-3 alkyl, C _1-3 alkylene, C _1-3 haloalkyl or C _1-3 haloalkylene, further preferably F, methyl, =ch ₂、＝C(CH₃)₂, trifluoromethyl, =cf ₂;

R _7b is selected from C _1-6 alkyl, more preferably C _1-3 alkyl, further preferably methyl, ethyl, n-propyl, isopropyl;

R _7b is optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-6 alkoxy or C _1-6 haloalkoxy, more preferably halogen, C _1-3 alkoxy or C _1-3 haloalkoxy, further preferably F, methoxy, trifluoromethoxy, still further preferably F.

As preferable:

Ring B is Optionally substituted with 1,2, 3 or 4R ₄;

R ₄ is selected from H, R _4a or R _4b;

The R _4a or R _4b is independently selected from halogen, hydroxy, cyano, C _1-3 alkyl, C _1-3 alkoxy, or

Further preferably, ring B is Optionally substituted with 1 or 2R ₄, R ₄ is selected from H or R _4a,R_4a is independently selected from halogen, hydroxy, cyano, C _1-3 alkyl, C _1-3 alkoxy, preferably F, hydroxy, cyano, methyl, methoxy;

Still more preferably, ring B is PreferablyMore preferably/>

R ₁ is-L ₁-R₅, wherein L ₁ is selected from-NR ₆SO₂-、-NR₆SO₂NR₆-、-NR₆ CO-or-NR ₆CONR₆ -;

The R ₅ is selected from R _5b;

The R _5b is selected from C _1-3 alkyl, which may be optionally substituted by hydroxy, halogen;

the R ₆ is selected from H, C _1-3 alkyl;

Preferably, R ₁ is-L ₁-R₅, wherein L ₁ is selected from-NHSO ₂ -; the R ₅ is selected from R _5b; said R _5b is selected from methyl, ethyl, n-propyl, which may be optionally substituted with hydroxy, halogen;

further preferably, R ₁ is

In certain embodiments according to the present invention, the compounds provided herein, deuterated, stereoisomers, or pharmaceutically acceptable salts thereof, may further be: has a structure shown in a general formula (X):

the ring A is selected from 8-membered, 9-membered or 10-membered bicyclic heterocyclyl, 8-membered, 9-membered or 10-membered bicyclic heteroaryl, contains 2-4 heteroatoms selected from N, O, S, and is substituted with 0,1, 2 or 3R ₃; when ring a is an 8-, 9-or 10-membered bicyclic heterocyclyl, optionally 1-2C atoms are oxo;

Ring A is preferably

Wherein the terminal is connected with R ₂, and the terminal # is connected with an amido; ring A is more preferred/>/>

Further preferred, ring a is an 8-, 9-or 10-membered bicyclic heteroaryl group containing 2-4N atoms and substituted with 0, 1,2 or 3R ₃;

Ring A is more preferred

Wherein the terminal is connected with R ₂, and the terminal # is connected with an amido; /(I)

R ₃ is selected from halogen, C _1-3 alkyl, 3-5 membered cycloalkyl, C _1-3 haloalkyl or cyano, preferably F, methyl, trifluoromethyl or cyano;

R ₇ is selected from H, R _7a or R _7b;

R _7a is selected from 3-6 membered cycloalkyl, 4-7 membered azacycloalkyl, -CH ₂ - (3-6) membered cycloalkyl, -CH ₂ - (4-7) membered azacycloalkyl, optionally substituted with 1 or 2 groups selected from: halogen, C _1-3 alkyl, C _1-3 alkylene, C _1-3 haloalkyl or C _1-3 haloalkylene;

R _7a is preferably Optionally substituted with 1 or 2 groups selected from: halogen, C _1-3 alkyl, C _1-3 alkylene, C _1-3 haloalkyl or C _1-3 haloalkylene, preferably F, methyl, =ch ₂、＝C(CH₃)₂, trifluoromethyl, =cf ₂;

R _7b is selected from C _1-3 alkyl optionally substituted with 1, 2 or 3 groups selected from: halogen, C _1-3 alkoxy or C _1-3 haloalkoxy;

R _7b is preferably methyl, n-propyl, isopropyl, optionally substituted with 1, 2 or 3 groups selected from: halogen, C _1-3 alkoxy or C _1-3 haloalkoxy, more preferably F, methoxy, trifluoromethoxy, still more preferably F.

R ₄ is selected from halogen, hydroxy, cyano, C _1-3 alkyl, C _1-3 alkoxy, preferably F, hydroxy, cyano, methyl, methoxy;

m is selected from 0, 1 or 2.

Further preferably, the ring A has a structure represented by the general formula (VI-1) and is substituted with 0, 1,2 or 3R ₃:

Wherein,

Z ₃ is selected from N or CH;

Z ₄ is selected from N or C;

Ring A1 is a parallel 5-6 membered heteroaryl group containing 1,2 or 3 heteroatoms selected from N, O, S;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

Preferably R _7a is selected from the group consisting of-CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (3-7) membered heterocycloalkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyls, And optionally substituted with 1,2 or 3 groups selected from: F. cl, C _1-3 alkylene, C _1-3 haloalkylene, preferably F;

Further preferably, R _7a is selected from

R _7b is selected from-CHF ₂、-CF₃、-CH₂-CHF₂、-(CH₂)₂-CF₃ or- (CH ₂)₂-OCF₃);

Further preferably, R ₂ is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: the ring a is selected from: And substituted with 0, 1, 2 or 3R ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

Further preferably, R _7a is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (VI-1 a):

Wherein,

Z ₃ is N or CH;

x and y are independently selected from 0, 1 or 2;

R ₇ is selected from R _7a;

Preferably R _7a is selected from the group consisting of-CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (3-7) membered heterocycloalkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyls, Optionally substituted with 1,2 or 3F;

Further preferably, R _7a is selected from />

Further preferably, R ₂ is selected from

Wherein,

Z ₃ is N or CH;

x and y are independently selected from 0, 1 or 2;

R ₇ is selected from R _7a;

R _7a is selected from Optionally substituted with 1,2 or 3F;

Further preferably, R _7a is selected from

Wherein,

Z ₃ is N or CH;

x and y are independently selected from 0, 1 or 2;

R ₇ is selected from R _7a;

R _7a is selected from Optionally substituted with 1,2 or 3F;

Further preferably, R _7a is selected from

Ring a is a 9-10 membered fused ring heteroaryl, said ring a containing 1-6 heteroatoms selected from N, O, S and being substituted with 0, 1,2 or 3R ₃;

Further preferably, the ring A has a structure represented by the general formula (VI-2) and is substituted with 0, 1,2 or 3R ₃:

z ₅ is selected from N or CH;

Ring a ₂ is a parallel 5-6 membered heteroaryl containing 1,2 or 3 heteroatoms selected from N, O, S;

Further preferably, ring a is selected from: And is substituted with 0, 1, 2 or 3R ₃,/>

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

Further preferably, R _7a is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: ring a is selected from: And substituted with 0, 1, 2 or 3R ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

Further preferably, R _7a is selected from />

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (VI-2 a):

Wherein,

R ₃ is selected from F, methyl, ethyl, cyclopropyl, -OCH ₃、-CF₃ or-OCF;

x is selected from 0 or 1;

y is selected from 0,1,2 or 3;

R ₇ is selected from R _7a or R _7b;

Further preferably, R _7a is selected from

Further preferably, R ₂ is selected from-CF ₃、-CHF₂.

In certain embodiments according to the present invention, the compounds having the structure of formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further have the structure of formula (VI-2 a):

Wherein,

R ₃ is selected from F, methyl, ethyl, cyclopropyl, -OCH ₃、-CF₃ or-OCF;

x is selected from 0 or 1;

y is selected from 0,1,2 or 3;

R ₇ is selected from R _7b;

Further preferably, R ₂ is selected from-CF ₃、-CHF₂.

Ring a is a 9-10 membered fused ring heteroaryl, said ring a containing 1,2 or 3 heteroatoms selected from N, O, S and substituted with 0, 1,2 or 3R ₃;

Further preferably, the ring A has a structure represented by the general formula (VI-3) and is substituted with 0, 1,2 or 3R ₃:

Wherein,

Ring a ₃ is a parallel 5-6 membered heteroaryl containing 1,2 or 3 heteroatoms selected from N, O, S;

Said ring a is substituted with 0, 1, 2 or 3R ₃;

Further preferred, ring A is of the structure or a group thereof substituted with 0, 1,2 or 3R ₃:

And a group substituted with 0, 1,2 or 3R ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

R _7a is selected from And optionally substituted with 1,2 or 3 groups selected from: F. cl, C _1-3 alkylene, C _1-3 haloalkylene, preferably F; /(I)

Further preferably, R _7a is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (VI-3 a):

x and y are independently selected from 0, 1 or 2;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

Further preferably, R _7a is selected from

Further preferably, the ring A has a structure represented by the general formula (VI-4) and is substituted with 0, 1,2 or 3R ₃:

Z ₆ and Z ₇ are independently selected from N or CH;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

Further preferably, R _7a is selected from

In certain embodiments according to the present invention, the compounds having the structure of formula (II), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further have the structure of formula (VI-4 a):

Z ₆ is selected from N or CH;

n is selected from 0, 1 or 2;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

R _7a is selected from-CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (3-7) membered heterocycloalkyl, And optionally substituted with 1,2 or 3 groups selected from: F. cl, C _1-3 alkylene, C _1-3 haloalkylene, preferably F;

Further preferably, R _7a is selected from

More preferably, R _7a is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (I), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (IX):

x and y are independently selected from 0, 1 or 2;

R ₇ is selected from R _7a or R _7b;

Further preferably, R _7a is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (I), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (VII):

n is selected from 0, 1 or 2;

R ₁ is-L ₁-R₅, wherein L ₁ is selected from-NR ₆-、-NR₆SO₂NR₆ -or-NR ₆CONR₆ -;

R ₆ is selected from H, C _1-3 alkyl or C _3-6 cycloalkyl;

Said R ₅ is selected from R _5a or R _5b,

Said R _5a is selected fromAnd optionally substituted with C _1-3 hydroxyalkyl, preferably with-CH ₂ OH; further preferably, R _5a is selected from/>

The R _5b is hydroxy-substituted C _1-3 alkyl, preferably-CH ₂-CH₂ OH;

further preferred, R ₁ is a group selected from the following structures:

R ₂ is L ₂-R₇, wherein,

L ₂ is selected from the group consisting of-O-, -CO-, covalent bonds;

R ₇ is selected from R _7a;

R _7a is selected from Optionally substituted with 1,2 or 3 groups selected from: F. cl, C _1-3 alkylene, C _1-3 haloalkylene, preferably F;

Further preferably, R _7a is selected from

Further preferably, R ₂ is selected from

In certain embodiments according to the present invention, the compounds having the structure represented by general formula (I), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further be: has a structure shown in a general formula (VIII):

n is selected from 0, 1 or 2;

R ₁ is-L ₁-R₅, wherein said L ₁ is selected from-NR ₆SO₂ -;

R ₆ is selected from H, C _1-3 alkyl or C _3-6 cycloalkyl;

the R ₅ is selected from R _5b.

The R _5b is hydroxy-substituted C _1-3 alkyl, preferably-CH ₂-CH₂ OH;

Further preferably, R ₁ is

R ₂ is L ₂-R₇, wherein,

L ₂ is selected from the group consisting of-O-, -CO-, covalent bonds;

R ₇ is selected from R _7a;

further preferably, R ₂ is

In certain embodiments according to the present invention, the compounds having the structure of formula (I), deuterated, stereoisomers, or pharmaceutically acceptable salts thereof provided herein may further comprise any one of the following:

/>

In a second aspect, the invention provides a pharmaceutical composition comprising a compound according to any one of the preceding claims, a deuterated, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.

In a third aspect, the invention provides the use of a compound as described in any one of the preceding claims, a deuterated, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with KIF 18A.

In some preferred embodiments of the invention, the KIF 18A-associated disease is selected from advanced or metastatic solid tumors associated with a p53 gene mutation, or with abnormal expression of one or more other genes selected from RB deletion, BRCA1 mutation/inactivation, CCNE amplification.

In some preferred embodiments of the invention, the KIF 18A-associated disease is selected from colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, peritoneal cancer, fallopian tube, endometrial cancer, ovarian cancer, and the like; preferably Triple Negative Breast Cancer (TNBC), platinum-based resistant advanced serous ovarian cancer (HGSOC), primary peritoneal cancer, fallopian tube cancer or serous endometrial cancer.

The compound provided by the invention has good inhibitory activity on KIF18A, has stronger cell inhibitory activity and lower toxic and side effects compared with an AMG650 inhibitor of KIF18A, has strong animal drug effect, good drug substitution property and high bioavailability, and is an ideal KIF18A inhibitor; the substitution of methyl or halogen (e.g., F) on the bicyclic ring can significantly improve the pharmacokinetic properties of the compound, especially reduce clearance, increase C _max (maximum plasma concentration), increase exposure, etc. The compound is an ideal high-activity KIF18A inhibitor, and can be used for treating and/or preventing clinical diseases such as colon cancer, breast cancer, lung cancer, pancreatic cancer, prostatic cancer, bladder cancer, head cancer, neck cancer, cervical cancer, peritoneal cancer, fallopian tube, endometrial cancer, ovarian cancer and other solid tumors.

Detailed Description

Definition:

"substituted" or "substituted" as used herein refers to any one or more hydrogen atoms on any atom of a group or fragment being substituted with a substituent, and may include heavy hydrogen and hydrogen variants, provided that the valence of the particular atom is normal and the substituted compound is stable.

As used herein, "oxo" refers to an oxygen substitution on a carbon atom, the oxygen substitution of two hydrogen atoms to form a carbonyl group with the carbon atom in the form of a double bond (c=o). "oxo" does not occur on aromatic groups. The term "optionally substituted" means that the substituents may or may not be substituted, and the type and number of substituents may be any on the basis of what is chemically achievable, if in the present application "ring A is a 6-membered monocyclic unsaturated heterocyclic group, ring A contains 0, 1,2 or 3 heteroatoms selected from N, O, S, optionally 1 to 2C atoms are oxo", ring A contains at least the following structure:

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.

When the number of one linking group is 0, for example- (CR ^aR^b)₀ -indicates that the linking group is a single bond/chemical bond).

When one of the variables is selected from covalent/chemical/single bonds, it means that the two groups to which it is attached are directly linked, e.g., L ₂ in A-L ₂-R₇ represents a covalent bond, it means that the structure is actually A-R ₇.

When a substituent is absent, it means that the substituent is absent, e.g., X in A-X is absent, it means that the structure is actually A; for example, the number of the cells to be processed,When n is 0, it means that the hydrogen atom on the ring is not substituted by R ₃.

When none of the listed substituents indicates through which atom it is attached to a substituted group, such substituents may be bonded through any atom thereof, for example,Wherein n is 0-2, then the group comprises at least the following structure: /(I)For another example,/>At least comprises the following structures: /(I)

When the exemplified linking group does not indicate its linking direction, the linking direction is arbitrary, for example, in the case where the linking group L ₁ in the ring A-L ₁-R₁ is-M-W-, the ring A and R ₁ may be linked in the same direction as the reading order from left to right to form the ring A-M-W-R ₁, or the ring A and R ₁ may be linked in the opposite direction to the reading order from left to right to form the ring A-W-M-R ₁. Combinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Where a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds, unless specifically indicated. When the connection mode of the chemical bond is not positioned and the H atoms exist in the connectable site, the number of the H atoms of the site is correspondingly reduced to become a group with a corresponding valence along with the increase of the number of the connected chemical bond when the chemical bond is connected. The chemical bond of the site and other groups can be a straight solid line bondOr a dotted bond/>And (3) representing. For example, a straight solid bond in-OCH ₃ indicates that it is attached to other groups through an oxygen atom in that group; /(I)The straight dashed bonds in (a) represent the attachment to other groups through both ends of a carbon atom in the group; /(I)The dashed lines in (a) represent the attachment to other groups through carbon atoms in the 1 and 4 positions of the phenyl group; /(I)It means that any of the ligatable sites on the piperidinyl group may be attached to other groups by 1 chemical bond, including at leastThese 4 connection schemes, even though H atom is drawn on-N-, are/>Still include/>The group of this linkage is only when 1 chemical bond is linked, the H at this site will be correspondingly reduced by 1 to the corresponding monovalent piperidinyl group.

If not specified, in spiro or fused ring groups, the attachment site of the group or fragment is located on the ring to which the dotted line is attached. For example, the number of the cells to be processed,Any attachment site on the nitrogen-containing spiro ring representing the group may be attached to other groups by 1 chemical bond, including at least/>These 3 connection modes; /(I)Indicating that the group at least includes/>These 6 connection modes; /(I)The group at least comprises: /(I)

These 8 connection modes.

In general, the double bond and the single bond in the aromatic ring or the heteroaromatic ring are not limited. For example, the number of the cells to be processed, All refer to benzene rings or phenyl groups, in which the double bond or/>In particular to a large pi bond of delocalization on the benzene ring plane;

For example, in Wherein, when Z ₃ is defined to be selected from N or CH; z ₄ is selected from N or C;

Where ring A1 is a 5-6 membered heteroaryl group in parallel, non-limiting examples of such structures include: Wherein, even if the six-membered ring in parallel contains only two double bonds, or the five-membered ring in parallel contains only one double bond, these groups are still included, and the double bond represents a large pi bond delocalized on the parallel aromatic ring.

As used herein, numerical intervals include endpoints and any numerical values between the endpoints. For example, "0-3" may include 0, 1, 2, or 3, and "1-3" may include 1, 2, or 3.

As used herein, "C _1-n" includes C _1-2、C_1-3、……C_1-n. For example, a "C _1-6" group refers to a moiety having 1-6 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Thus, for example, a "C _1-4 alkyl" refers to an alkyl group containing 1 to 4 carbon atoms, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Numerical ranges, such as "1-6" herein refer to individual integers in the given range.

Ring member atoms refer to non-hydrogen atoms in the ring group that are used to form a ring. For exampleThe ring atom in (a) is 3 carbon atoms; the middle ring atoms are three carbon atoms and 1 oxygen atom; /(I) The intermediate ring atoms are 1N atom and 5 carbon atoms; The ring segment atoms are 8 carbon atoms and 1 nitrogen atom. /(I)

As used herein, "n-m-membered" refers to the number of ring segment atoms in the ring radical. For example, a "5-10 membered" group means that there are 5-10 ring atoms in the moiety, i.e., the group contains 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, or 10 ring atoms.

The term "hydrocarbyl" as used herein, alone or in combination, refers to an atomic group consisting of only carbon and hydrogen elements, including saturated, unsaturated, or aromatic hydrocarbon groups, such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl. Unless specifically stated, the "hydrocarbyl" may be straight-chain, branched, or cyclic.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. Where the number of carbon atoms is not specified, the "alkyl" herein may preferably have 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like. Where a numerical range occurs for a group, such as "alkyl" as defined herein, for example, "C _1-6 alkyl" refers to an alkyl group that may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and the alkyl group herein also includes cases where a numerical range is not specified. The alkyl group may be optionally substituted or unsubstituted.

"Alkyl" as used herein in combination refers to an alkyl group attached to other groups, e.g., an alkyl group in an alkoxy group, as defined above when used alone.

The term "alkylene" as used herein, alone or in combination, refers to a saturated aliphatic divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a straight or branched saturated aliphatic hydrocarbon group, wherein the two removed hydrogen atoms may be attached to the same carbon atom and the resulting divalent hydrocarbon group may be attached to the same other atom, non-limiting examples of alkylene include-CH ₂ - (i.e., methylene), -CH ₂-CH₂ - (i.e., ethylene )、-CH₂-CH₂-CH₂-、-CH(CH₃)CH₂-、-C(CH₃)₂-、-CH₂-C(CH₃)-CH₂-、-CH₂-CH₂-CH₂-CH₂-、-CH₂-C(CH₃)-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-, etc., also including =cf ₂、＝CH₂、＝C(CH₃)₂, e.g., in the present application, =cf ₂ substitutedCan be/>The alkylene group may be optionally substituted or unsubstituted.

The term "alkoxy" or "-O-alkyl" as used herein, alone or in combination, means "alkyl-O-". Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. C _1-6 alkoxy means that the alkyl group in "alkyl-O-" is an alkyl group having 1 to 6 carbon atoms. Alkoxy groups may be optionally substituted or unsubstituted.

The term "hydroxyalkyl" as used herein, alone or in combination, is alkyl substituted with hydroxy. For example, "C _1-3 hydroxyalkyl" refers to hydroxy-substituted alkyl groups containing 1 to 3 carbon atoms, including hydroxymethyl, hydroxyethyl, hydroxypropyl. In general, the hydroxyl group may be substituted on any carbon atom of the hydroxyalkyl group, with substitution on the terminal carbon atom being preferred in the present application. Hydroxyalkyl groups may be optionally substituted or unsubstituted.

The term "cyclic group" or "ring" as used herein, alone or in combination, refers to any organic compound having a cyclic structure, wherein the cyclic group may be saturated or unsaturated and may include one or more heteroatoms such as N, O or S in its carbon skeleton. Examples of cyclic groups include carbocyclyl and heterocyclyl groups as discussed below, and in particular may be cycloalkyl, cycloalkenyl, heterocycloalkyl, unsaturated heterocyclyl, aryl, and heteroaryl. When the cyclic group is bicyclic or polycyclic, any of the rings is optionally selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, unsaturated heterocyclyl, aryl, or heteroaryl; when one or more of the rings is an aryl group, the remaining rings may be aryl groups, or cycloalkyl groups, heterocycloalkyl groups, or unsaturated heterocyclic groups having no aromaticity. The number of rings in the cyclic group may be monocyclic, bicyclic or polycyclic. Generally, bicyclic or polycyclic ring groups may be classified as spiro, bridged (including fused or fused) rings, depending on the manner of attachment. Unless otherwise specified, a cyclic group is a 3-15 membered cyclic group, meaning that it contains 3 to 12 ring members, preferably a 5-10 membered cyclic group.

In the definition of "cyclic group", the term "spiro" refers to a cyclic group having two or more cyclic structures and single rings sharing one atom (called spiro atom) with each other. Preferably 5-8 membered, more preferably 7-8 membered. Spiro rings are classified as mono-, bi-or multi-spiro groups according to the number of common spiro atoms between rings, with mono-spiro groups being preferred herein, and 3/5 or 3/6 membered spiro groups being preferred. Non-limiting examples thereof include, but are not limited to, 6-azaspiro [2.5] oct-6-yl.

In the definition of "cyclic group," bridged ring "refers to a polycyclic cyclic group containing two or more cyclic structures and sharing two or more atoms. Wherein "fused ring" or "condensed ring" is a special bridged ring, and refers to a bicyclic or polycyclic ring group containing two or more cyclic structures and sharing a pair of atoms with each other. Preferably 9-10 membered, more preferably 9 membered, is used herein. Depending on the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged ring radicals, preference being given here to bicyclic, more preferably 5-membered/6-membered bicyclic, parallel ring radicals.

Unless otherwise indicated, spiro and bridged rings may also be used in cycloalkyl, heterocycloalkyl, unsaturated heterocyclyl groups discussed below, including spirocycloalkyl, spirocycloalkenyl, spiroheterocycloalkyl, spiroheterocycloalkenyl, bridged cycloalkyl, bridged cycloalkenyl, bridged heterocycloalkyl, and bridged heterocycloalkenyl. Condensed rings include condensed ring alkyl, condensed ring alkenyl, condensed ring aryl, and condensed ring heteroaryl. The above terms are defined similarly to spiro, bridged, parallel or fused rings.

The term "heterocyclyl" as used herein, alone or in combination, includes alicyclic and heteroaryl groups wherein one or more (such as one, two, three or four) ring members are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, including monocyclic, fused, bridged and spiro rings. Examples of heterocyclyl groups include heterocycloalkyl, unsaturated heterocyclyl, and heteroaryl groups as discussed below. Preferred herein are 5-10 membered monocyclic or bicyclic heterocyclic groups which may contain 1,2 or 3 ring member atoms selected from nitrogen, oxygen and/or sulphur. Non-limiting examples of "heterocyclyl" include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thialkyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl and thiomorpholinyl, 1-dioxo-thiomorpholinyl, and the like. The heterocyclyl group may be optionally substituted or unsubstituted.

The term "cycloalkyl" as used herein, alone or in combination, refers to a saturated monocyclic, bicyclic or polycyclic carbocycle, which may be a spiro or bridged ring. Preferred herein are 5-8 membered cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like cycloalkyl groups, which may be optionally substituted or unsubstituted.

In the definition of "cycloalkyl", a "spiro" refers to an all-carbon polycyclic group having two or more cyclic structures and single rings sharing one carbon atom (referred to as a spiro atom) with each other. Preferably 5 to 8 membered, more preferably 8 membered. Spiro rings are classified as mono-, bi-or multi-spiro alkyls based on the number of common spiro atoms between rings, with mono-, bi-or multi-spiro alkyls being preferred herein, and 3/6 membered spiroalkyls being preferred.

In the definition of "cycloalkyl", a "fused ring" refers to an all-carbon polycyclic group containing two or more cyclic structures and having a pair of carbon atoms common to each other. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group.

The term "heterocycloalkyl" as used herein, alone or in combination, refers to a saturated monocyclic, bicyclic or polycyclic ring radical in which one or more (such as one, two, three or four) ring members are heteroatoms, which may be spiro or bridged. Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, propylene oxide, thiirane, aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.

The term "aryl" as used herein, alone or in combination, refers to an aromatic hydrocarbyl ring. The term "aryl" includes mono-, and cyclic or polycyclic fused ring aromatic hydrocarbons in which all fused ring systems (excluding any ring systems that are part of or formed by optional substituents) are aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthryl and phenanthryl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl".

The term "heteroaryl", as used herein alone or in combination, refers to a 5-10 membered (preferably 5-6 membered) monocyclic, bicyclic or tricyclic ring system wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and wherein said heteroaryl further has one or more attachment points attached to the remainder of the molecule. "heteroaryl" groups of a bicyclic or tricyclic ring system, if any, contain saturated or unsaturated heterocycloalkyl groups. Non-limiting examples of "heteroaryl" include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, and the like; also included are the following bicyclic rings, but not limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazole, 1, 8-naphthyridine, benzo [ d ] isoxazole, benzo [ d ] thiazole, pyrrolo [3,2-b ] pyridine, furan [3,2-b ] pyridine, pyrrolo [1,2-b ] pyridazine, imidazo [1,2-b ] pyridazine, pyrazolo [1,5-a ] pyrimidine, thiazolo [4,5-c ] pyridine, thieno [3,2-b ] pyridine, pyrrolo [1,2-b ] pyridazine, 2, 3-dihydrobenzofuran, benzo [ c ] [1,2,5] oxadiazole, 1, 3-dihydro-2H-benzo [ d ] imidazol-2-one, benzo [ d ] oxazol-2 (3H) -one, and the like. Heteroaryl groups may be optionally substituted or unsubstituted.

The term "unsaturated heterocyclyl", as used herein alone or in combination, refers to a monocyclic, bicyclic or polycyclic, non-aromatic, unsaturated heterocyclic group having 1 or more unsaturated double bonds, wherein one or more (such as one, two, three or four) ring members atoms are heteroatoms, which may be spiro or bridged. Preferred herein are monocyclic 6-membered unsaturated heterocyclyl groups, where the unsaturated heterocyclyl groups may optionally have 1-2C atoms oxo-ed, non-limiting examples of heterocyclenyl groups include, but are not limited to, the following structures:

the term halogen as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy", as used herein, alone or in combination, refers to-OH.

The term "cyano", as used herein, alone or in combination, refers to-CN.

The term "(substituted) or" substituted with … … "as used herein means that one or more hydrogens on a particular atom are replaced with a specific group (e.g., halogen, alkyl, etc.), where the normal valence of the specified atom is not exceeded under the present circumstances, then the result is a stable compound.

The term "pharmaceutically acceptable salt" as used herein is well known to those skilled in the art.

The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally admixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents and/or excipients.

The term "carrier" as used herein refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of the compound into a cell or tissue.

The term "stereoisomers" as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.

The term "enantiomer" as used herein refers to a compound having the same formula, in which two compounds which are enantiomers are mirror images of each other and cannot coincide, due to isomerism caused by differences in the spatial configuration of atoms or groups of atoms (groups). The term "cis-trans isomer" as used herein generally refers to a stereoisomerism of diastereomers in a compound molecule that occurs due to the restriction factor of free rotation, which varies the spatial arrangement of the individual groups. Organic molecules containing such isomers, such as olefins, azo compounds, alicyclic hydrocarbons, etc., are considered cis-trans isomerism. In the present application, cis-trans isomerism is mainly embodied in the form of alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism occurs when cyclohexane is substituted with two substituents, the two substituents being the "cis" isomer on the same side of the ring and the "trans" isomer on the different side.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, sterically hindered isomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, structures described herein also include all isomers of such structures (e.g., diastereomers, enantiomers, cis-trans isomers, sterically hindered isomers, geometric (conformational) isomeric forms), e.g., R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, aliphatics cis-trans isomers, sterically hindered isomers of biphenyls structures (see "basic organic chemistry" (second edition) upper book, xing Jiyi et al ,p104-105);PAC,1996,68,2193.(Basic terminology of stereochemistry(IUPAC Recommendations 1996,on page 2201))、(Z) and (E) conformational isomers.

The present invention will be described in further detail with reference to the following examples, but the present invention is not limited to the following examples.

Preparation example:

The partial preparation conditions used in the examples are as follows:

Preparation of Pre-HPLC conditions: instrument: GILSON-GX281; wavelength: 220nm &254nm; column model: waters X-bridge (30X 100mm,10 μm) or Luna C18 (30X 75mm,3 μm); mobile phase: a:10mM ammonium bicarbonate or H ₂ O (0.1% formic acid) or H ₂ O (0.1% trifluoroacetic acid), B: acetonitrile; run time: 15min; flow rate: 25mL/min.

Reverse phase column purification Using a C18 reverse phase silica gel column (SPHERICAL C, 40-60 μm,40g-120 g) with water/acetonitrile (95/5-30/70) as mobile phase.

Some intermediates of the present invention are synthesized as follows:

Intermediate 1: 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid

2-Fluoro-4-iodobenzoic acid (2 g,7.50 mmol) was dissolved in dimethyl sulfoxide (10 mL) and 6-azaspiro [2.5] octane hydrochloride (1.3 g,9.00 mmol) and potassium carbonate (3.1 g,22.5 mmol) were added. The reaction mixture was warmed to 140 ℃ under nitrogen and stirred overnight. Water (30 mL) was added to the reaction system, the mixture was extracted with ethyl acetate (20 mL. Times.2) in portions, the aqueous phase was adjusted to pH 6 with 1M dilute hydrochloric acid, filtered, and dried to give intermediate 1 (1.8 g, yellow solid), yield: 67%. MS (ESI) m/z 358.0[ M+H ] ⁺.

Example 1

N- (5- (4, 4-difluoropiperidin-1-yl) -1,3, 4-thiadiazol-2-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5- (4, 4-Difluoropiperidin-1-yl) -1,3, 4-thiadiazol-2-amine

5-Bromo-1, 3, 4-thiadiazol-2-amine (1 g,5.6 mmol) was dissolved in N-methylpyrrolidone (20 mL), 4-difluoropiperidine hydrochloride (1.06 g,6.7 mmol) and N, N-diisopropylethylamine (2.17 g,16.8 mmol) were added and the mixture heated to 180℃under nitrogen and stirred for 2 hours. The reaction was cooled to room temperature, water (100 mL) was added and the aqueous phase was extracted with ethyl acetate (50 mL. Times.5). The organic phase was washed with saturated sodium chloride solution (100 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (100% ethyl acetate) to give the title compound (1.1 g, brown solid), yield: 90%. MS (ESI) M/z221.1[ M+H ] ⁺.

(2) N- (5- (4, 4-difluoropiperidin-1-yl) -1,3, 4-thiadiazol-2-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

5- (4, 4-Dihalopiperidin-1-yl) -1,3, 4-thiadiazol-2-amine (900 mg,4.1 mmol) was dissolved in N, N-dimethylformamide (20 mL), and intermediate 1 (730 mg,2.05 mmol), N, N-diisopropylethylamine (543 mg,4.20 mmol) and HATU (2.3 g,6.15 mmol) were added. The mixture was heated to 50 ℃ under nitrogen for 18 hours. The reaction solution was cooled to room temperature, water (80 mL) was added, the aqueous phase was extracted with ethyl acetate (80 mL. Times.4), the organic phase was washed with saturated sodium chloride solution (100 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (360 mg, white solid), yield: 31%. MS (ESI) m/z 560.0[ M+H ] ⁺.

(3) N- (5- (4, 4-difluoropiperidin-1-yl) -1,3, 4-thiadiazol-2-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (5- (4, 4-difluoropiperidin-1-yl) -1,3, 4-thiadiazol-2-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (70 mg,0.13 mmol) was dissolved in 1, 4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (33 mg,0.26 mmol), xphos (25 mg,0.05 mmol), tris (dibenzylideneacetone) dipalladium (27 mg,0.03 mmol) and cesium carbonate (85 mg,0.26 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate=2/3) to give a crude product. Purification of the crude product by Prep-HPLC gave the title compound (14.6 mg, white solid), yield ：20％.MS(ESI):m/z 557.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ14.34(s,1H),10.28(s,1H),8.01(d,J＝8.0Hz,1H),7.30(d,J＝2.0Hz,1H),7.15(dd,J＝8.4,2.0Hz,1H),4.94(s,1H),3.77(t,J＝6.4Hz,2H),3.60(t,J＝5.6Hz,4H),3.37(t,J＝6.4Hz,2H),2.99(t,J＝5.2Hz,4H),2.17-2.07(m,4H),1.70-1.60(m,4H),0.42(s,4H).

Example 2

N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 4, 4-Difluorocyclohexyl methane sulfonate

4, 4-Difluorocyclohexanol (2 g,15 mmol) was dissolved in dichloromethane (20 mL), triethylamine (4.46 g,45 mmol) was added, and methanesulfonyl chloride (2.06 g,18 mmol) was added dropwise at 0℃and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, then water (40 mL) was added, the aqueous phase was extracted with ethyl acetate (40 ml×2), the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.9 g, yellow oil), yield: 90%. ¹H NMR(400MHz,DMSO-d₆ ) Delta 4.95-4.86 (m, 1H), 3.25 (s, 3H), 2.10-1.89 (m, 8H).

(2) 1- (4, 4-Difluorocyclohexyl) -3-nitro-1H-pyrazole

4, 4-Difluorocyclohexyl methanesulfonate (678 mg,6.0 mmol) and 3-nitro-1H-pyrazole (1.28 g,6.0 mmol) were dissolved in N, N-dimethylformamide (20 mL), sodium hydride (480 mg,12.0 mmol) was added at 0deg.C, and the mixture was stirred at 140deg.C overnight. Water (80 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (80 mL. Times.4), the organic phase was washed with saturated sodium chloride solution (100 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (600 mg, yellow solid), yield ：43％.MS(ESI):m/z 232.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.15(d,J＝2.8Hz,1H),7.08(d,J＝2.8Hz,1H),4.61-4.56(m,1H),2.52-2.02(m,8H).

(3) 1- (4, 4-Difluorocyclohexyl) -1H-pyrazol-3-amine

1- (4, 4-Difluorocyclohexyl) -3-nitro-1H-pyrazole (500 mg,2.2 mmol) was dissolved in methanol (20 mL), palladium on charcoal (100 mg) was added thereto, hydrogen was replaced three times, and the reaction was stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure to give the title compound (480 mg, white solid), yield: 99%. MS (ESI) m/z 202.1[ M+H ] ⁺.

(4) N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1- (4, 4-Difluorocyclohexyl) -1H-pyrazol-3-amine (201 mg,1 mmol) was dissolved in N, N-dimethylformamide (10 mL), and intermediate 1 (178.5 mg,0.5 mmol), N, N-diisopropylethylamine (322.5 mg,2.5 mmol) and HATU (578 mg,1.5 mmol) were added. The mixture was heated to 50 ℃ under nitrogen and stirred for 4 hours. The reaction was cooled to room temperature, saturated sodium bicarbonate solution (50 mL) was added and the aqueous phase was extracted with ethyl acetate (50 mL. Times.2). The organic phase was washed with saturated sodium chloride solution (60 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography (petroleum ether/ethyl acetate=5/1) gave the title compound (275 mg, white solid), yield: 93%. MS (ESI) m/z 541.0[ M+H ] ⁺.

(5) N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (100 mg,0.19 mmol) was dissolved in 1, 4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (48 mg,0.38 mmol), xphos (40 mg,0.08 mmol), tris (dibenzylideneacetone) dipalladium (37 mg,0.04 mmol), and cesium carbonate (124 mg,0.32 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/2) to give a crude product. Purification of the crude product by Prep-HPLC gave the title compound (16.7 mg, white solid) in yield ：16％.MS(ESI):m/z 538.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.74(s,1H),10.12(s,1H),7.99(d,J＝8.4Hz,1H),7.72(d,J＝2.0Hz,1H),7.23(d,J＝2.0Hz,1H),7.09(dd,J＝8.8Hz,2.0Hz,1H),6.60(d,J＝2.0Hz,1H),4.94(s,1H),4.38-4.34(m,1H),3.76(t,J＝6.8Hz,2H),3.35-3.34(m,2H),2.95(t,J＝5.2Hz,4H),2.18-1.99(m,8H),1.68-1.63(m,4H),0.38(s,4H).

Example 3

N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1- (4, 4-Difluorocyclohexyl) -4-nitro-1H-pyrazole

4, 4-Difluorocyclohexyl methanesulfonate (678 mg,6.0 mmol) was dissolved in N, N-dimethylformamide (20 mL), 4-nitro-1H-pyrazole (1.28 g,6.0 mmol) and cesium carbonate (5.83 g,18.0 mmol) were added, and the mixture was stirred at 100℃for 3 hours. The reaction was cooled to room temperature, water (80 mL) was added and the aqueous phase was extracted with ethyl acetate (80 mL. Times.4). The organic phase was washed with saturated sodium chloride solution (100 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (600 mg, yellow solid), yield: 43%. MS (ESI) m/z 232.1[ M+H ] ⁺.

(2) 1- (4, 4-Difluorocyclohexyl) -1H-pyrazol-4-amine

1- (4, 4-Difluorocyclohexyl) -4-nitro-1H-pyrazole (500 mg,2.2 mmol) was dissolved in methanol (20 mL), palladium on charcoal (100 mg) was added, hydrogen was replaced three times, and stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure to give the title compound (480 mg, white solid), yield: 99%. MS (ESI) m/z 202.1[ M+H ] ⁺.

(3) N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1- (4, 4-Difluorocyclohexyl) -1H-pyrazol-4-amine (201 mg,1 mmol) was dissolved in N, N-dimethylformamide (10 mL), and intermediate 1 (178.5 mg,0.5 mmol), N, N-diisopropylethylamine (322.5 mg,2.5 mmol) and HATU (578 mg,1.5 mmol) were added. The mixture was heated to 50 ℃ under nitrogen and stirred for 4 hours. The reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (50 mL) was added, the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), washed with saturated sodium chloride solution (60 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (275 mg, white solid), yield: 93%. MS (ESI) m/z 541.0[ M+H ] ⁺.

(4) N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazol-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (100 mg,0.19 mmol) was dissolved in 1, 4-dioxane solution (5 mL), 2-hydroxyethanesulfonamide (48 mg,0.38 mmol), xphos (40 mg,0.08 mmol), tris (dibenzylideneacetone) dipalladium (37 mg,0.04 mmol) and cesium carbonate (124 mg,0.32 mmol) were added. The mixture was heated to 100 ℃ under nitrogen and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate=1/2) to give a crude product. Purification of the crude product by Prep-HPLC gave the title compound (10.0 mg, white solid), yield ：12％.MS(ESI):m/z 538.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.51(s,1H),10.03(s,1H),8.09(s,1H),7.79(d,J＝8.4Hz,1H),7.61(s,1H),7.13(d,J＝1.6Hz,1H),7.01-6.98(m,1H),4.94(s,1H),4.43-4.36(m,1H),3.76-3.73(m,2H),3.26-3.24(m,2H),2.94-2.92(m,4H),2.12-1.99(m,8H),1.54-1.52(m,4H),0.36(m,4H).

Example 4

N- (5- ((4, 4-difluorocyclohexyl) oxy) -1,3, 4-thiadiazol-2-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5- ((4, 4-Difluorocyclohexyl) oxy) -1,3, 4-thiadiazol-2-amine

5-Bromo-1, 3, 4-thiadiazol-2-amine (1 g,5.62 mmol) and 4, 4-difluorocyclohexane-1-ol (1.15 g,8.43 mmol) were dissolved in N, N-dimethylformamide (25 mL), sodium hydride (0.41 g,16.86 mmol) was added and the mixture stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water, extracted with ethyl acetate (20 mL. Times.3), and the organic phase was washed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (methanol/dichloromethane=1/9) to give the title compound (150 mg, brown oil), yield: 11.36%. MS (ESI) m/z 236.1[ M+H ] ⁺.

(2) N- (5- ((4, 4-difluorocyclohexyl) oxy) -1,3, 4-thiadiazol-2-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (234 mg,0.66 mmol) was dissolved in N, N-dimethylformamide (10 mL) and HATU (684 mg,1.80 mmol) and N, N-diisopropylethylamine (387 mg,3.00 mmol) were added sequentially. After stirring at room temperature for 0.5 hours, 5- ((4, 4-difluorocyclohexyl) oxy) -1,3, 4-thiadiazol-2-amine (140 mg,0.6 mmol) was added, and the mixture was heated to 50℃and stirred for 12 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (20 ml×3). The organic phase was washed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=7/3) to give the title compound (80 mg, pale yellow solid), yield: 23.26%. MS (ESI) m/z 574.9[ M+H ] ⁺.

(3) N- (5- ((4, 4-difluorocyclohexyl) oxy) -1,3, 4-thiadiazol-2-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (5- ((4, 4-difluorocyclohexyl) oxy) -1,3, 4-thiadiazol-2-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (80 mg,0.14 mmol) and 2-hydroxyethanesulfonamide (34.8 mg,0.28 mmol) were dissolved in 1, 4-dioxane (3 mL), and tris (dibenzylideneacetone) dipalladium (26 mg,0.03 mmol), xphos (28 mg,0.06 mmol) and cesium carbonate (92 mg,0.28 mmol) were added. The mixture was heated to 110 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane/methanol=10/1) to give a crude product. Purification of the crude product by Pre-HPLC gave the title compound (12.5 mg, white powder), yield ：14.39％.MS(ESI):m/z 572.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ14.60(s,1H),10.30(s,1H),8.01(d,J＝8.8Hz,1H),7.30(d,J＝1.6Hz,1H),7.16-7.13(m,1H),5.12(s,1H),4.98-4.95(m,1H),3.77(t,J＝6.0Hz,2H),3.24-3.23(m,2H),3.00(t,J＝4.8Hz,4H),2.11-1.93(m,8H),1.65(s,4H),0.42(s,4H).

Example 5

N- (5- (3, 3-difluorocyclobutoxy) -1,3, 4-thiadiazol-2-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5- (3, 3-Difluorocyclobutoxy) -1,3, 4-thiadiazol-2-amine

5-Bromo-1, 3, 4-thiadiazol-2-amine (300 mg,1.67 mmol) and 3, 3-difluorocyclobutanol (319 mg,3.34 mmol) were dissolved in N, N-dimethylformamide (20 mL), and sodium hydride (80 mg,5.01 mmol) was added. The reaction solution was stirred for 2 minutes at room temperature under nitrogen protection. The reaction solution was poured into ice water and extracted with ethyl acetate (20 ml×3). The organic phase was washed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (300 mg, yellow oil), yield: 86%. MS (ESI) m/z 208.0[ M+H ] ⁺.

(2) N- (5- (3, 3-difluorocyclobutoxy) -1,3, 4-thiadiazol-2-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (778 mg,2.17 mmol) and 5- (3, 3-difluorocyclobutoxy) -1,3, 4-thiadiazol-2-amine (300 mg,1.45 mmol) were dissolved in pyridine (20 mL) and phosphorus oxychloride (447 mg,2.90 mmol) was slowly added dropwise. The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (20 ml×3). The organic phase was washed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give the title compound (100 mg, grey solid), yield: 12%. MS (ESI) m/z 546.9[ M+H ] ⁺.

(3) N- (5- (3, 3-difluorocyclobutoxy) -1,3, 4-thiadiazol-2-yl) -4- ((2-hydroxyethyl) sulfonylamino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (5- (3, 3-difluorocyclobutoxy) -1,3, 4-thiadiazol-2-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (100 mg,0.18 mmol) was dissolved in 1, 4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (23 mg,0.18 mmol), xphos (43 mg,0.09 mmol), tris (dibenzylideneacetone) dipalladium (83 mg,0.09 mmol), and cesium carbonate (178 mg,0.54 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred for 3 hours. The reaction solution was concentrated, and the residue was purified by Pre-HPLC to give the title compound (5 mg, white solid) in yield ：5％.MS(ESI):m/z 544.0[M+H]⁺.1HNMR(400MHz,DMSO-d₆)δ14.71(s,1H),10.31(s,1H),8.01(d,J＝8.4Hz,1H),7.30(s,1H),7.15(d,J＝8.8Hz,1H),5.24-5.19(m,1H),4.94(s,1H),3.78-3.74(m,2H),3.24-3.16(m,4H),3.00-2.88(m,6H),1.64-1.63(m,4H),0.41(m,4H).

Example 6

N- (1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the procedure of example 2, steps 3 and 4, starting from intermediate 1 and 1- (2, 2-difluoroethyl) -1H-pyrazol-3-amine, the title compound (25 mg, white solid) was obtained by similar procedures ).MS(ESI):m/z 484.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.5(s,1H),9.97(d,J＝8.0Hz,1H),7.71(d,J＝2.0Hz,1H),7.23(d,J＝2.0Hz,1H),7.08(dd,J＝8.4,2.0Hz,1H),6.71(d,J＝2.4Hz,1H),6.30(tt,J＝55.2,3.6Hz,1H),4.56(dt,J＝15.2,3.6Hz,2H),3.76(t,J＝6.4Hz,2H),3.34-3.27(m,2H),2.97-2.94(m,4H),1.67-1.54(m,4H),0.38(s,4H).

Example 7

N- (1- (4, 4-difluorocyclohexyl) -5-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1- (4, 4-Difluorocyclohexyl) -3-methyl-5-nitropyridin-2 (1H) -one

4, 4-Difluorocyclohexyl methanesulfonate (3.8 g,17.8 mmol) was dissolved in N, N-dimethylformamide (40 mL), and 3-methyl-5-nitropyridin-2 (1H) -one (1.4 g,8.9 mmol) and cesium carbonate (8.7 g,26.7 mmol) were added. The mixture was stirred at 100℃overnight. The reaction was cooled to room temperature, water (150 mL) was added and the aqueous phase was extracted with ethyl acetate (100 mL. Times.2). The organic phase was washed with saturated sodium chloride solution (100 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=7/1) to give the title compound (900 mg, yellow solid), yield ：37％.MS(ESI):m/z 273.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.79(d,J＝3.2Hz,1H),8.08(d,J＝1.6Hz,1H),4.85-4.77(m,1H),2.17-2.13(m,2H),2.10(s,3H),2.07-1.92(m,6H).

(2) 5-Amino-1- (4, 4-difluorocyclohexyl) -3-methylpyridin-2 (1H) -one

1- (4, 4-Difluorocyclohexyl) -3-methyl-5-nitropyridin-2 (1H) -one (400 mg,1.47 mmol) was dissolved in ethyl acetate (20 mL), palladium on charcoal (80 mg) was added, hydrogen was replaced three times, and stirring was performed at room temperature for 4 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure to give the title compound (194 mg, white solid), yield: 54%. MS (ESI) m/z 243.1[ M+H ] ⁺.

(3) N- (1- (4, 4-difluorocyclohexyl) -5-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

5-Amino-1- (4, 4-difluorocyclohexyl) -3-methylpyridin-2 (1H) -one (194 mg,0.8 mmol) was dissolved in N, N-dimethylformamide (5 mL), followed by intermediate 1 (143 mg,0.4 mmol), N, N-diisopropylethylamine (258 mg,2.0 mmol) and HATU (458 mg,1.2 mmol). The mixture was stirred at 50 ℃ overnight. The reaction was purified by reverse phase column to give the title compound (20 mg, yellow solid), yield: 9%. MS (ESI) m/z 582.0[ M+H ] ⁺.

(4) N- (1- (4, 4-difluorocyclohexyl) -5-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- (4, 4-difluorocyclohexyl) -5-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (20 mg,0.034 mmol) was dissolved in 1, 4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (9 mg,0.068 mmol), xphos (7 mg,0.014 mmol), tris (dibenzylideneacetone) dipalladium (6 mg, 0.0070 mmol) and cesium carbonate (22 mg,0.068 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give the title compound (2.1 mg, white solid) in yield ：11％.MS(ESI):m/z 579.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.13(s,1H),9.99(s,1H),8.18(s,1H),7.74(d,J＝8.4Hz,1H),7.50(s,1H),7.11(s,1H),6.98(dd,J＝8.0,1.2Hz,1H),4.98-4.92(m,1H),3.75(t,J＝6.4Hz,2H),3.33-3.29(m,3H),2.95(t,J＝4.4Hz,4H),2.18-2.10(m,4H),2.06(s,3H),1.99-1.79(m,4H),1.53-1.49(m,4H),0.35(s,4H).

Example 8

N- (5- (4, 4-difluoropiperidin-1-yl) -1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 3-Bromo-1-methyl-5-nitropyridin-2 (1H) -one

To a solution of 3-bromo-5-nitropyridin-2 (1H) -one (2.19 g,10 mmol) in N, N-dimethylformamide (30 mL) was added sodium hydride (1.2 g,60% purity), and after the addition was completed, the mixture was warmed to room temperature and stirred for 30 minutes, and methyl iodide (4.26 g,30 mmol) was further added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (3×75 mL), and the organic phases were combined, washed with saturated 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=3/1) to give the title compound (1.0 g, yellow solid), yield: 42.9%. MS (ESI) m/z 232.9[ M+H ] ⁺.

(2) 3- (4, 4-Difluoropiperidin-1-yl) -1-methyl-5-nitropyridin-2 (1H) -one

3-Bromo-1-methyl-5-nitropyridin-2 (1H) -one (1.0 g,4.29 mmol) was dissolved in 1, 4-dioxane (20 mL) and palladium acetate (47 mg,0.21 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (122 mg,0.21 mmol), 4-difluoropiperidine hydrochloride (676 mg,4.29 mmol) and cesium carbonate (2.8 mg,8.6 mmol) were added sequentially. The mixture was heated to 105 ℃ under nitrogen and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give a crude product, which was further purified by reverse phase column (70% acetonitrile in water) to give the title compound (365 mg, yellow solid), yield: 31.2%. MS (ESI) m/z 274.1[ M+H ] ⁺.

(3) 5-Amino-3- (4, 4-difluoropiperidin-1-yl) -1-methylpyridin-2 (1H) -one

3- (4, 4-Dihaloperidin-1-yl) -1-methyl-5-nitropyridin-2 (1H) -one (300 mg,1.1 mmol) was dissolved in ethyl acetate (10 mL), methanol (10 mL) and 10% palladium on charcoal (200 mg) were added, and the hydrogen was replaced three times. The mixture was reacted at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite, and the cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give the title compound (267 mg, brown oil), yield: 100%. MS (ESI) m/z 244.1[ M+H ] ⁺.

(4) N- (5- (4, 4-difluoropiperidin-1-yl) -1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (393 mg,1.1 mmol) was dissolved in N, N-dimethylformamide (10 mL) and HATU (836 mg,2.2 mmol) and N, N-diisopropylethylamine (709 mg,5.5 mmol) were added. After stirring at room temperature for 10 minutes, 5-amino-3- (4, 4-difluoropiperidin-1-yl) -1-methylpyridin-2 (1H) -one (267 mg,1.1 mmol) was added and the mixture was reacted at room temperature for 3 hours. The reaction was poured into saturated sodium bicarbonate (80 mL) and the aqueous phase was extracted with ethyl acetate (2X 40 mL). The organic phase was washed with saturated 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=1/2) to give the title compound (330 mg, white solid), yield: 51.6%. MS (ESI) m/z 583.0[ M+H ] ⁺.

(5) N- (5- (4, 4-difluoropiperidin-1-yl) -1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (5- (4, 4-difluoropiperidin-1-yl) -1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (116 mg,0.2 mmol) was dissolved in 1, 4-dioxane (4 mL), and 2-hydroxyethanesulfonamide (50 mg,0.4 mmol), tris (dibenzylideneacetone) dipalladium (18 mg,0.02 mmol), xphos (19 mg,0.04 mmol) and cesium carbonate (130 mg,0.4 mmol) were added sequentially. The mixture was heated to 90 ℃ under nitrogen for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/methanol=10/1) to give a crude product, which was purified by Prep-HPLC to give the title compound (14.8 mg, white solid), yield ：12.8％.MS(ESI):m/z 580.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.25(s,1H),10.05(s,1H),8.10(d,J＝2.4Hz,1H),7.75(d,J＝8.8Hz,1H),7.12(d,J＝1.6Hz,1H),7.01(dd,J＝8.4,2.0Hz,1H),6.90(d,J＝2.4Hz,1H),4.95(s,1H),3.75(t,J＝6.8Hz,2H),3.47(s,3H),3.32-3.27(m,6H),2.95(t,J＝5.2Hz,4H),2.12-2.05(m,4H),1.58-1.48(m,4H),0.34(s,4H).

Example 9

N- (6- (4, 4-difluoropiperidin-1-yl) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5-Bromo-3- (4, 4-difluoropiperidin-1-yl) -1-methylpyrazin-2 (1H) -one

3, 5-Dibromo-1-methylpyrazin-2 (1H) -one (3.0 g,11.1 mmol) was dissolved in 1, 4-dioxane (20 mL) and 4, 4-difluoropiperidine hydrochloride (1.7 g,11.1 mmol), tris (dibenzylideneacetone) dipalladium (1.1 g,1.1 mmol), xphos (1.2 g,2.2 mmol) and cesium carbonate (11.5 g,33.6 mmol) were added sequentially. The mixture was heated to 110 ℃ under nitrogen for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (1.35 g, yellow solid), yield: 38.8%. MS (ESI) m/z 308.0[ M+H ] ⁺.

(2) 5-Amino-3- (4, 4-difluoropiperidin-1-yl) -1-methylpyrazin-2 (1H) -one

5-Bromo-3- (4, 4-difluoropiperidin-1-yl) -1-methylpyrazin-2 (1H) -one (1.3 g,4.38 mmol) was dissolved in 1, 4-dioxane (20 mL) and tert-butyl carbamate (616 mg,5.26 mmol), tris (dibenzylideneacetone) dipalladium (1.2 g,1.31 mmol), xphos (1.3 g,2.63 mmol) and cesium carbonate (4.3 g,13.14 mmol) were added sequentially. The mixture was heated to 110 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, trifluoroacetic acid (5 mL) was added thereto, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (500 mg, yellow solid), yield: 69.5%. MS (ESI) M/z245.1[ M+H ] ⁺.

(3) N- (6- (4, 4-difluoropiperidin-1-yl) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

5-Amino-3- (4, 4-difluoropiperidin-1-yl) -1-methylpyrazin-2 (1H) -one (500 mg,2.05 mmol) was dissolved in dichloromethane (20 mL) and intermediate 1 (431 mg,2.05 mmol), N, N-diisopropylethylamine (1.3 g,10.24 mmol) and HATU (1.2 g,3.07 mmol) were added sequentially. The mixture was stirred at room temperature overnight. To the reaction solution was added saturated sodium bicarbonate solution (50 mL), and the aqueous phase was extracted with ethyl acetate (50 ml×2). The organic phase was washed with saturated sodium chloride solution (50 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give the title compound (180 mg, pale yellow solid), yield: 15.1%. MS (ESI) m/z 584.0[ M+H ] ⁺.

(4) N- (6- (4, 4-difluoropiperidin-1-yl) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (6- (4, 4-difluoropiperidin-1-yl) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (70.0 mg,0.12 mmol) was dissolved in 1, 4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (18.0 mg,0.14 mmol), tris (dibenzylideneacetone) dipalladium (27.7 mg,0.03 mmol), xphos (28.8 mg,0.06 mmol) and cesium carbonate (117.3 mg,0.36 mmol) were added sequentially. The mixture was heated to 110 ℃ under nitrogen for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give the title compound (5.9 mg, white solid) in yield ：8.4％.MS(ESI):m/z 581.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.69(s,1H),10.04(s,1H),8.03(d,J＝8.8Hz,1H),7.96(s,1H),7.26(d,J＝2.0Hz,1H),7.12(dd,J＝8.8,2.4Hz,1H),4.98-4.88(m,1H),3.99(t,J＝10.8Hz,4H),3.75(t,J＝5.6Hz,2H),3.45(s,3H),3.36-3.34(m,2H),2.95(t,J＝4.4Hz,4H),2.10-2.03(m,4H),1.85-1.57(m,4H),0.39(s,4H).

Example 10

N- (1- (4, 4-difluorocyclohexyl) -5-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

/>

(1) 1- (4, 4-Difluorocyclohexyl) -5-methyl-3-nitropyridin-2 (1H) -one

4, 4-Difluorocyclohexyl methanesulfonate (700 mg,3.27 mmol) was dissolved in N, N-dimethylformamide (20 mL), 5-methyl-3-nitropyridin-2 (1H) -one (504 mg,3.27 mmol) and cesium carbonate (3.2 g,9.81 mmol) were added and the mixture heated to 100deg.C and stirred overnight. The reaction was cooled to room temperature, water (150 mL) was added, and the mixture was extracted with ethyl acetate (100 mL. Times.2). The organic phase was washed with saturated sodium chloride solution (100 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (450 mg, yellow oil), yield ：51％.¹H NMR(400MHz,DMSO-d₆)δ8.34-8.31(m,2H),5.43-5.42(m,1H),2.32(s,3H),2.13-1.95(m,8H).

(2) 3-Amino-1- (4, 4-difluorocyclohexyl) -5-methylpyridin-2 (1H) -one

1- (4, 4-Difluorocyclohexyl) -5-methyl-3-nitropyridin-2 (1H) -one (450 mg,1.65 mmol) was dissolved in ethyl acetate (25 mL), palladium on charcoal (90 mg) was added and hydrogen was replaced three times. The mixture was stirred at room temperature for 2 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave the title compound (300 mg, yellow oil), yield: 75%. MS (ESI) m/z 243.1[ M+H ] ⁺.

(3) N- (1- (4, 4-difluorocyclohexyl) -5-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

3-Amino-1- (4, 4-difluorocyclohexyl) -5-methylpyridin-2 (1H) -one (300 mg,1.24 mmol) was dissolved in N, N-dimethylformamide (30 mL), followed by intermediate 1 (447 mg,1.24 mmol), N, N-diisopropylethylamine (800 mg,6.20 mmol) and HATU (942 mg,2.48 mmol). The mixture was stirred at room temperature overnight. To the reaction mixture was added saturated sodium bicarbonate solution (180 mL), and the mixture was extracted with ethyl acetate (80 mL. Times.2). The organic phase was washed with saturated sodium chloride solution (80 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to give the title compound (20 mg, pale yellow oil), yield ：62％.MS(ESI):m/z 582.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.66(s,1H),8.56(d,J＝2.0Hz,1H),7.73(d,J＝1.2Hz,1H),7.59-7.58(m,3H),5.30-5.26(m,1H),3.01-2.99(m,4H),2.24(s,3H),2.06-1.83(m,8H),1.54-1.42(m,4H),0.30(s,4H).

(4) N- (1- (4, 4-difluorocyclohexyl) -5-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- (4, 4-difluorocyclohexyl) -5-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (150 mg,0.26 mmol) was dissolved in 1, 4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (65 mg,0.52 mmol), xphos (50 mg,0.104 mmol), tris (dibenzylideneacetone) dipalladium (48 mg,0.052 mmol) and cesium carbonate (170 mg,0.52 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give the title compound (24.5 mg, white solid) in yield ：16％.MS(ESI):m/z 579.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.78(s,1H),10.13(s,1H),8.59(d,J＝2.0Hz,1H),7.85(d,J＝8.4Hz,1H),7.72(d,J＝1.2Hz,1H),7.16(d,J＝1.6Hz,1H),7.02(dd,J＝8.8,2.4Hz,1H),5.33-5.28(m,1H),4.93(s,1H),3.76(t,J＝6.8Hz,2H),3.35(t,J＝6.4Hz,2H),2.99-2.97(m,4H),2.24(s,3H),2.10-2.01(m,6H),1.89-1.83(m,2H),1.58-1.46(m,4H),0.33(s,4H).

Example 11

N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 8-Bromo-6-nitroimidazo [1,2-a ] pyridine

3-Bromo-5-nitropyridin-2-amine (2.0 g,9.2 mmol) and 2-bromo-1, 1-diethoxyethane (2.7 g,13.8 mmol) were dissolved in N, N-dimethylformamide (20 mL), heated to 150℃and stirred for 3 hours. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound (1.7 g, yellow solid), yield: 77%. MS (ESI) m/z 241.9[ M+H ] ⁺.

(2) 8-Bromoimidazo [1,2-a ] pyridin-6-amine

8-Bromo-6-nitroimidazo [1,2-a ] pyridine (500 mg,2.1 mmol) is dissolved in a tetrahydrofuran/water (10 mL/2 mL) mixture solvent, and iron powder (588 mg,10.5 mmol) and ammonium chloride (1.1 g,21 mmol) are added. The mixture was heated to reflux and stirred for 3 hours. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (437 mg, yellow oil), yield: 100%. MS (ESI) m/z 212.0[ M+H ] ⁺.

(3) (8-Bromoimidazo [1,2-a ] pyridin-6-yl) (tert-Butoxycarbonyl) carbamic acid tert-butyl ester

8-Bromoimidazo [1,2-a ] pyridin-6-amine (433 mg,2.1 mmol), di-tert-butyl dicarbonate (803 mg,4.2 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (404 mg,4.2 mmol) and 4-dimethylaminopyridine (24.4 mg,0.2 mmol) were added, and the reaction was stirred at room temperature overnight. Water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phase 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 give the title compound (400 mg, yellow oil), yield: 47%. MS (ESI) m/z 412.0[ M+H ] ⁺.

(4) (Tert-Butoxycarbonyl) (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) carbamic acid tert-butyl ester

Tert-butyl (8-bromoimidazo [1,2-a ] pyridin-6-yl) (tert-butoxycarbonyl) carbamate (400 mg,0.97 mmol) is dissolved in dioxane (10 mL), 4-difluoropyridine hydrochloride (184 mg,1.17 mmol), xphos (48 mg,0.09 mmol), tris (dibenzylideneacetone) dipalladium (44 mg,0.05 mmol) and cesium carbonate (630 mg,1.94 mmol) are added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phase 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 give the title compound (100 mg, yellow oil), yield: 23%. MS (ESI) m/z 453.1[ M+H ] ⁺.

(5) 8- (4, 4-Difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-amine

Tert-butyl (tert-butoxycarbonyl) (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) carbamate (25 mg,0.06 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added and the reaction stirred at room temperature for 1 hour. The reaction was concentrated to give the title compound (14 mg, yellow oil), yield: 100%. MS (ESI) m/z 253.1[ M+H ] ⁺.

(6) N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8- (4, 4-Difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-amine (14 mg,0.06 mmol) was dissolved in N, N-dimethylformamide (2 mL), followed by addition of intermediate 1 (21 mg,0.06 mmol), HATU (34 mg,0.09 mmol) and N, N-diisopropylethylamine (15 mg,0.12 mmol). The mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phase 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 give the title compound (10 mg, yellow solid), yield: 30%. MS (ESI) M/z592.0[ M+H ] ⁺.

(7) N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (10 mg,0.02 mmol) was dissolved in dioxane (5 mL), and 2-hydroxyethanesulfonamide (5 mg,0.04 mmol), xphos (1 mg,0.002 mmol), tris (dibenzylideneacetone) dipalladium (1 mg,0.001 mmol) and cesium carbonate (13 mg,0.04 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give the title compound (2.5 mg, white solid) in yield ：25％.MS(ESI):m/z 589.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.64(s,1H),10.08(s,1H),9.04(d,J＝1.2Hz,1H),7.98(d,J＝1.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.45(d,J＝0.8Hz,1H),7.15(d,J＝2.0Hz,1H),7.03(dd,J＝8.4,2.0Hz,1H),6.56(s,1H),4.96(s,1H),3.78-3.74(m,6H),3.61-3.55(m,2H),2.99-2.97(m,4H),2.18-2.12(m,4H),1.57-1.56(m,4H),0.35(s,4H).

Example 12

N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5-Amino-6-bromopyrazine-2-carboxylic acid methyl ester

Methyl 5-aminopyrazine-2-carboxylate (1.95 g,12.73 mmol) was dissolved in acetonitrile (40 mL), N-bromosuccinimide (2.72 g,15.28 mmol) was added and the mixture stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give the title compound (2 g, light brown solid), yield: 68%. MS (ESI) M/z232.0[ M+H ] ⁺.

(2) 8-Bromoimidazo [1,2-a ] pyrazine-6-carboxylic acid methyl ester

5-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (2 g,8.6 mmol) and 2-bromo-1, 1-diethoxyethane (2.54 g,12.9 mmol) were dissolved in N, N-dimethylformamide (40 mL), and the mixture was heated to 150℃and stirred for 2 hours. Water (250 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL. Times.2). The organic phase was washed with saturated sodium chloride solution (100 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (800 mg, light brown solid), yield: 36%. MS (ESI) m/z 256.0[ M+H ] ⁺.

(3) 8- (4, 4-Dihalopiperidin-1-yl) imidazo [1,2-a ] pyrazine-6-carboxylic acid methyl ester

Methyl 8-bromoimidazo [1,2-a ] pyrazine-6-carboxylate (750 mg,2.9 mmol) was dissolved in acetonitrile (15 mL), followed by the addition of 4, 4-difluoropyridine hydrochloride (552 mg,3.5 mmol) and cesium carbonate (2.8 g,8.7 mmol). The mixture was heated to 75 ℃ and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound (450 mg, yellow solid), yield: 55%. MS (ESI) m/z 297.1[ M+H ] ⁺.

(4) 8- (4, 4-Difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazine-6-carboxylic acid

Methyl 8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazine-6-carboxylate (400 mg,1.35 mmol) was dissolved in a mixed solution of methanol/water (10 mL/1 mL), lithium hydroxide (170 mg,4.05 mmol) was added and the mixture stirred at room temperature for 1 hour. The reaction mixture was added with water (40 mL), the pH was adjusted to acidity with a 3N diluted hydrochloric acid solution, and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The organic phase was washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (320 mg, green solid), yield: 91%. MS (ESI) m/z 283.1[ M+H ] ⁺.

(5) (8- (4, 4-Dihalopiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) carbamic acid tert-butyl ester

8- (4, 4-Dihalopiperidin-1-yl) imidazo [1,2-a ] pyrazine-6-carboxylic acid (320 mg,1.13 mmol) was dissolved in tert-butanol (20 mL) and diphenyl azide phosphate (292 mg,2.26 mmol) and triethylamine (342 mg,3.39 mmol) were added. The mixture was heated to 90 ℃ under nitrogen and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (100 mg, yellow oil), yield: 25%. MS (ESI) m/z 354.1[ M+H ] ⁺.

(6) 8- (4, 4-Difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-amine

Tert-butyl (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) carbamate (100 mg,0.28 mmol) is dissolved in dichloromethane (8 mL), trifluoroacetic acid (2 mL) is added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (71 mg, brown oil), yield: 100%. MS (ESI) m/z 254.1[ M+H ] ⁺.

(7) N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8- (4, 4-Difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-amine (60 mg,0.24 mmol) was dissolved in N, N-dimethylformamide (5 mL), intermediate 1 (86 mg,0.24 mmol), N, N-diisopropylethylamine (155 mg,1.20 mmol) and HATU (182 mg,0.48 mmol) were added sequentially. The mixture was stirred at room temperature overnight. The reaction was directly purified by reverse phase column to give the title compound (10 mg, white solid), yield: 7%. MS (ESI) m/z 593.0[ M+H ] ⁺.

(8) N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (10 mg,0.017 mmol) was dissolved in 1, 4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (4 mg,0.034 mmol), xphos (3 mg, 0.0070 mmol), tris (dibenzylideneacetone) dipalladium (3 mg, 0.003mmol) and cesium carbonate (11 mg,0.034 mmol) were added sequentially. The mixture was heated to 90℃under nitrogen and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-TLC (petroleum ether/ethyl acetate=2/3) to give a crude product. Purification of the crude product by Prep-HPLC gave the title compound (1.8 mg, white solid) in yield ：18％.MS(ESI):m/z 590.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.89(s,1H),10.18(s,1H),8.84(s,1H),8.09-8.06(m,2H),7.56(s,1H),7.28(d,J＝1.6Hz,1H),7.13(dd,J＝8.4,1.6Hz,1H),4.99(s,1H),4.47-4.39(m,4H),3.76(t,J＝6.4Hz,2H),3.40-3.36(m,2H),3.03-2.94(m,4H),2.15-2.07(m,4H),1.88-1.43(m,4H),0.41(s,4H).

Example 13

4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (3, 3-trifluoropropyl) -1H-indazol-4-yl) benzamide

(1) 4-Nitro-1- (3, 3-trifluoropropyl) -1H-indazole

4-Nitro-1H-indazole (3 g,18.41 mmol) was dissolved in N, N-dimethylformamide (100 mL), 1-trifluoro-3-iodopropane (6.2 g,27.61 mmol) and potassium carbonate (7.62 g,55.22 mmol) were added and heated to 140℃for 16H. The reaction was filtered through celite, and the filtrate was poured into water (200 mL) and extracted with ethyl acetate (100 mL. Times.3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=9/1) to give the title compound (530 mg, pale yellow oil), yield: 11.1%. MS (ESI) m/z 260.0[ M+H ] ⁺.

(2) 1- (3, 3-Trifluoropropyl) -1H-indazol-4-amine

4-Nitro-1- (3, 3-trifluoropropyl) -1H-indazole (530 mg,2.04 mmol) was dissolved in ethyl acetate (20 mL), and 10% palladium on charcoal (53 mg) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 4 hours. The reaction solution was filtered through celite and concentrated. Purification of the residue by Pre-HPLC afforded the title compound (220 mg, yellow-green oil), yield ：46.8％.MS(ESI):m/z230.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.15(d,J＝0.8Hz,1H),7.08-7.04(m,1H),6.70(d,J＝8.4Hz,1H),6.20(t,J＝7.2Hz,1H),5.80(s,2H),4.52(t,J＝6.8Hz,2H),2.91-2.79(m,2H).

(3) 4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (3, 3-trifluoropropyl) -1H-indazol-4-yl) benzamide

Intermediate 1 (311 mg,0.87 mmol) was dissolved in N, N-dimethylformamide (10 mL), HATU (999.5 mg,2.63 mmol) and N, N-diisopropylethylamine (514 mg,4.37 mmol) were added sequentially, and after stirring at room temperature for 0.5H, 1- (3, 3-trifluoropropyl) -1H-indazol-4-amine (200 mg,0.87 mmol) was added. The reaction mixture was stirred for 12 hours at 50 ℃. The reaction was poured into water (20 mL) and extracted with ethyl acetate (20 mL. Times.3). The organic phase was washed with saturated brine (20 ml×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (340 mg, yellow oil), yield: 71.13%. MS (ESI) m/z 568.9[ M+H ] ⁺.

(4) 4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (3, 3-trifluoropropyl) -1H-indazol-4-yl) benzamide

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (3, 3-trifluoropropyl) -1H-indazol-4-yl) benzamide (100 mg,0.18 mmol) was dissolved in 1, 4-dioxane (3 mL), 2-hydroxyethanesulfonamide (43.75 g,0.35 mmol), tris (dibenzylideneacetone) dipalladium (37 mg,0.04 mmol), xphos (40 mg,0.08 mmol), and cesium carbonate (115 mg,0.35 mmol) were added sequentially. The mixture was heated to 110 ℃ under nitrogen atmosphere and reacted overnight. The reaction solution was filtered, concentrated, and the residue was purified by column chromatography (100% ethyl acetate) to give a crude product, which was further purified by Pre-HPLC to give the title compound (7.5 mg, white powder), yield ：7.54％.MS(ESI):m/z 566.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.30(s,1H),8.38(s,1H),7.91(d,J＝6.4Hz,1H),7.78(d,J＝8.4Hz,1H),7.44-7.37(m,2H),7.13(s,1H),7.01-6.98(m,1H),4.68(t,J＝6.4Hz,2H),3.77(t,J＝6.4Hz,2H),3.32-3.30(m,2H),3.01-2.88(m,6H),1.43-1.40(m,4H),0.26(s,4H).

Example 14

4- ((2-Hydroxyethyl) sulphonamido) -N- (1-methyl-3- (trifluoromethyl) -1H-indazol-5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5-Bromo-1-methyl-3- (trifluoromethyl) -1H-indazole

5-Bromo-3- (trifluoromethyl) -1H indazole (470 mg,1.77 mmol) was dissolved in acetonitrile (20 mL), and methyl iodide (303 mg,2.13 mmol) and cesium carbonate (867 mg,2.66 mmol) were added. The mixture was reacted at room temperature under nitrogen protection for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (420 mg, white solid), yield: 84.8%. MS (ESI) m/z 278.9[ M+H ] ⁺.

(2) 1-Methyl-3- (trifluoromethyl) -1H-indazol-5-amine

5-Bromo-1-methyl-3- (trifluoromethyl) -1H indazole (200 mg,0.72 mmol) was dissolved in 1, 4-dioxane (10 mL), and tert-butyl carbamate (135 mg,1.08 mmol), tris (dibenzylideneacetone) dipalladium (33 mg,0.04 mmol), xphos (34 mg,0.07 mmol) and cesium carbonate (467 mg,1.43 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, trifluoroacetic acid (0.8 mL) was added, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give the title compound (150 mg, yellow oil), yield: 91.9%. MS (ESI) M/z216.1[ M+H ] ⁺.

(3) 4-Iodo-N- (1-methyl-3- (trifluoromethyl) -1H-indazol-5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

1-Methyl-3- (trifluoromethyl) -1H-indazol-5-amine (150 mg,0.70 mmol) was dissolved in dichloromethane (20 mL), intermediate 1 (300 mg,0.84 mmol), N, N-diisopropylethylamine (450 mg,3.49 mmol) and HATU (400 mg,1.05 mmol) were added sequentially and stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate (50 mL) and extracted with ethyl acetate (50 mL. Times.2). The organic phase was washed with saturated sodium chloride solution (50 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give the title compound (67 mg, white solid), yield: 17.3%. MS (ESI) m/z 555.0[ M+H ] ⁺.

(4) 4- ((2-Hydroxyethyl) sulphonamido) -N- (1-methyl-3- (trifluoromethyl) -1H-indazol-5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Iodo-N- (1-methyl-3- (trifluoromethyl) -1H-indazol-5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (67 mg,0.12 mmol) was dissolved in 1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (23 mg,0.18 mmol), tris (dibenzylideneacetone) dipalladium (5.6 mg, 0.006mmol), xphos (5.8 mg,0.012 mmol) and cesium carbonate (79 mg,0.24 mmol) were added sequentially. The mixture was heated to 95℃under nitrogen for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to give the title compound (23.1 mg, white solid) in yield ：34.6％.MS(ESI):m/z 552.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.62(s,1H),10.05(s,1H),8.55(s,1H),7.88(d,J＝9.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.67(dd,J＝8.8,2.0Hz,1H),7.15(d,J＝2.0Hz,1H),7.02(dd,J＝8.4,2.0Hz,1H),4.96(s,1H),4.16(s,3H),3.77(t,J＝6.4Hz,2H),3.35-3.33(m,2H),2.99(t,J＝4.8Hz,4H),1.58-1.44(m,4H),0.33(s,4H).

Example 15

N- (1- (difluoromethyl) -1H-indazol-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1- (Difluoromethyl) -6-nitro-1H-indazoles

6-Nitro-1H-indazole (5 g,30.68 mmol) was dissolved in 1-methyl-2-pyrrolidone (200 mL), and sodium 2-chloro-2, 2-difluoroacetate (9.32 g,61.35 mmol) and sodium hydride (2.21 g,92.03 mmol) were added. The mixture was heated to 100 ℃ and reacted for 1 hour. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate (100 mL. Times.3). The organic phase was washed with saturated brine (200 ml×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=9/1) to give the title compound (3.4 g, orange solid), yield: 51.8%. MS (ESI) m/z 214.1[ M+H ] ⁺.

(2) 1- (Difluoromethyl) -1H-indazol-6-amine

1- (Difluoromethyl) -6-nitro-1H-indazole (2.0 g,9.39 mmol) was dissolved in ethyl acetate (50 mL), and palladium on charcoal (200 mg) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. Purification of the residue by Pre-HPLC afforded the title compound (570 mg, tan solid) in yield ：33.14％.MS(ESI):m/z 184.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.05-7.76(m,2H),7.47(d,J＝8.8Hz,1H),6.77(s,1H),6.67-6.63(m,1H),5.71(s,2H).

(3) N- (1- (difluoromethyl) -1H-indazol-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (430 mg,1.20 mmol) was dissolved in N, N-dimethylformamide (20 mL) and 1- (difluoromethyl) -1H-indazol-6-amine (200 mg,1.09 mmol), HATU (1250 mg,3.27 mmol), N, N-diisopropylethylamine (704 mg,5.45 mmol) was added sequentially. The mixture was reacted at room temperature for 12 hours. The reaction was poured into water (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phase was washed with saturated brine (100 ml×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (360 mg, pale yellow solid), yield: 63.27%. MS (ESI) m/z 523.0[ M+H ] ⁺.

(4) N- (1- (difluoromethyl) -1H-indazol-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- (difluoromethyl) -1H-indazol-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (100 mg,0.18 mmol) was dissolved in 1, 4-dioxane (3 mL), and 2-hydroxyethanesulfonamide (43.71 mg,0.35 mmol), tris (dibenzylideneacetone) dipalladium (33 mg,0.04 mmol), xphos (36 mg,0.07 mmol), and cesium carbonate (115 mg,0.35 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen atmosphere and reacted overnight. The reaction solution was concentrated, and the residue was purified by Pre-HPLC to give the title compound (7 mg, white solid) in yield ：7.44％.MS(ESI):m/z 520.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.80(s,1H),10.09(s,1H),8.68(s,1H),8.31(s,1H),8.12(t,J＝58.8Hz,1H),7.94(d,J＝8.8Hz,1H),7.83(d,J＝8.4Hz,1H),7.43-7.40(m,1H),7.17(d,J＝2.0Hz,1H),7.06-7.03(m,1H),4.98(s,1H),3.77(t,J＝6.8Hz,2H),3.36-3.33(m,2H),3.00(t,J＝4.8Hz,4H),1.55-1.51(m,4H),0.34(s,4H).

Example 16

N- (2- (4- (difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 4- (Difluoro (pyridine-2-sulfonyl) methyl) -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4-oxopiperidine-1-carboxylate (1 g,5.00 mmol), 2- ((difluoromethyl) sulfonyl) pyridine (0.97 g,5.00 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to-50℃and potassium tert-butoxide (1.0 g,9.00 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mL. Times.2). The organic phase 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 give the title compound (1.4 g, colorless oil), yield: 71%. MS (ESI) m/z 293.1[ M+H-100] ⁺.

(2) 4- (Difluoro (pyridine-2-sulfonyl) methyl) piperidin-4-ol

4- (Difluoro (pyridine-2-sulfonyl) methyl) -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.2 g,3.10 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was directly dried to give the title compound (890 mg, yellow oil), yield: 96%. MS (ESI) m/z 293.1[ M+H ] ⁺.

(3) 2- (4- (Difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-amine

2-Chloro-6-methylpyrimidin-4-amine (0.53 g,3.60 mmol) and 4- (difluoro (pyridine-2-sulfonyl) methyl) piperidin-4-ol (0.89 g,3.00 mmol) were dissolved in N-methylpyrrolidone (10 mL) and N, N-diisopropylethylamine (1.2 g,9.00 mmol) was added. The mixture was heated to 180 ℃ and stirred for 6 hours. The reaction was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phase 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 give the title compound (300 mg, yellow solid), yield: 41%. MS (ESI) m/z 241.1[ M+H ] ⁺.

(4) N- (2- (4- (difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

2- (4- (Difluoromethylene) piperidin-1-yl) -6-methylpyridin-4-amine (150 mg,0.42 mmol) and intermediate 1 (100 mg,0.42 mmol) were dissolved in pyridine (5 mL) and phosphorus oxychloride (188 mg,1.26 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours. To the reaction solution was added water (20 mL), and the mixture was extracted with ethyl acetate (20 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give the title compound (60 mg, white solid), yield: 25%. MS (ESI) m/z 580.0[ M+H ] ⁺.

(5) N- (2- (4- (difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (2- (4- (difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (90 mg,0.16 mmol) was dissolved in 1, 4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (39 mg,0.32 mmol), xphos (8 mg,0.016 mmol), tris (dibenzylideneacetone) dipalladium (7 mg,0.008 mmol) and cesium carbonate (104 mg,0.32 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phase 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 give crude product, which was further purified by Pre-HPLC to give the title compound (22 mg, white solid), yield ：24％.MS(ESI):m/z 577.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.32(s,1H),10.25(s,1H),8.06(d,J＝8.8Hz,1H),7.36(s,1H),7.28(d,J＝2.0Hz,1H),7.14(dd,J＝8.8,2.0Hz,1H),4.94(s,1H),3.84(t,J＝5.6Hz,4H),3.76(t,J＝6.4Hz,2H),3.37(t,J＝6.4Hz,2H),2.98(t,J＝4.8Hz,4H),2.31(s,3H),2.21-2.15(m,4H),1.81-1.65(m,4H),0.40(s,4H).

Example 17

N- (2- (3- (difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 3- (Difluoromethylene) piperidine-1-carboxylic acid tert-butyl ester

3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (965 mg,5 mmol) and 2- ((difluoromethyl) sulfonyl) pyridine (1.194 g,6 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), cooled to-78℃and then a solution of potassium tert-butoxide (1.0 g,9.0 mmol) in anhydrous tetrahydrofuran (4 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride (50 mL) and the aqueous phase extracted with ethyl acetate (2X 50 mL). The organic phases were combined, washed with saturated brine (75 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1) to give the title compound (376 mg, colorless oil), yield: 32.3%. MS (ESI) m/z 178.1[ M+H-56] ⁺.

(2) 3- (Difluoromethylene) piperidine

3- (Difluoromethylene) piperidine-1-carboxylic acid tert-butyl ester (376 mg,1.61 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (3 mL) was added and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give the title compound (398 mg, pale yellow oil), yield: 100%. MS (ESI) m/z 134.1[ M+H ] ⁺.

(3) 2- (3- (Difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-amine

3- (Difluoromethylene) piperidine (346 mg,1.4 mmol) and 2-chloro-6-methylpyrimidin-4-amine (201 mg,1.4 mmol) were dissolved in N, N-dimethylformamide (6 mL), and N, N-diisopropylethylamine (1.8 g,14 mmol) was added. The mixture was heated to 140 ℃ and stirred for 2 hours. The reaction solution was purified by reverse phase column to give the title compound (200 mg, pale yellow solid), yield: 59.2%. MS (ESI) m/z 241.1[ M+H ] ⁺.

(4) N- (2- (3- (difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

2- (3- (Difluoromethylene) piperidin-1-yl) -6-methylpyridin-4-amine (200 mg,0.83 mmol) and intermediate 1 (294 mg,0.83 mmol) were dissolved in pyridine (5 mL) and phosphorus oxychloride (382 mg,2.5 mmol) was added and reacted at room temperature for 1 hour. The reaction was diluted with water (50 mL) and extracted with dichloromethane (2X 30 mL). The organic phases were combined, washed with 1N diluted hydrochloric acid (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (84 mg, white solid), yield: 17.5%. MS (ESI) m/z 580.0[ M+H ] ⁺.

(5) N- (2- (3- (difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (2- (3- (difluoromethylene) piperidin-1-yl) -6-methylpyrimidin-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (84 mg,0.15 mmol) was dissolved in 1, 4-dioxane (10 mL), 2-hydroxyethanesulfonamide (37 mg,0.3 mmol), tris (dibenzylideneacetone) dipalladium (14 mg,0.015 mmol), xphos (14 mg,0.03 mmol) and cesium carbonate (96 mg,0.3 mmol) were added sequentially. The mixture was heated to 90 ℃ under nitrogen and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give a crude product, which was purified by Prep-HPLC to give the title compound (13.5 mg, white solid), yield ：16％.MS(ESI):m/z 577.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.18(s,1H),10.23(s,1H),8.05(d,J＝8.8Hz,1H),7.38(s,1H),7.28(d,J＝1.6Hz,1H),7.14(dd,J＝8.8,2.0Hz,1H),4.94(s,1H),4.41-4.33(m,2H),3.82(t,J＝5.6Hz,2H),3.76(t,J＝6.4Hz,2H),3.38-3.36(m,2H),2.98-2.97(m,4H),2.35-2.25(m,5H),2.00-1.55(m,6H),0.37(s,4H).

Example 18

N- (2- (3- (difluoromethylene) pyrrolidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

In a similar procedure, as defined in example 16, starting from tert-butyl 3-oxopyrrolidine-1-carboxylate, the title compound (3.8 mg, white solid) was obtained ).MS(ESI):m/z 563.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.48(s,1H),10.26(s,1H),8.06(d,J＝8.8Hz,1H),7.39(s,1H),7.28(d,J＝2.0Hz,1H),7.14(dd,J＝8.8,1.6Hz,1H),4.94(s,1H),4.21-4.14(m,2H),3.76(t,J＝6.4Hz,2H),3.70(t,J＝7.2Hz,2H),3.38-3.36(m,2H),3.02-2.90(m,4H),2.73-2.65(m,2H),2.31(s,3H),2.01-1.60(m,4H),0.38(s,4H).

Example 19

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- (3- (2-hydroxyethyl) ureido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 2- (4, 4-Difluoropiperidin-1-yl) -6-methylpyrimidin-4-amine

2-Chloro-6-methylpyrimidin-4-amine (1.7 g,11.84 mmol) and 4, 4-difluoropyridine hydrochloride (2.2 g,14.21 mmol) were dissolved in N, N-dimethylformamide solution (40 mL), and N, N-diisopropylethylamine (4.6 g,35.52 mmol) was added. The mixture was heated to 180 ℃ and stirred for 2 hours. The reaction was cooled to room temperature, water (80 mL) was added and the aqueous phase was extracted with ethyl acetate (80 mL. Times.2). The organic phase was washed with saturated sodium chloride solution (80 ml x 4), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (2.4 g, white solid), yield: 89%. MS (ESI) M/z229.1[ M+H ] ⁺.

(2) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

2- (4, 4-Difluoropiperidin-1-yl) -6-methylpyridin-4-amine (1.35 g,5.9 mmol) and intermediate 1 (2.1 g,5.9 mmol) were dissolved in pyridine (30 mL), phosphorus oxychloride was slowly added dropwise at room temperature, and the reaction solution was then stirred for 3 hours at 50 ℃. The reaction was cooled to room temperature, water (100 mL) was added and the aqueous phase was extracted with ethyl acetate (80 mL. Times.3). The organic phase was washed with dilute hydrochloric acid (100 mL. Times.2), saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/ethyl acetate=4/1) to give the title compound (1.1 g, pale yellow solid), yield: 33%. MS (ESI) m/z 568.0[ M+H ] ⁺.

(3) (4- ((2- (4, 4-Difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) carbamoyl) -3- (6-azaspiro [2.5] oct-6-yl) phenyl) carbamic acid tert-butyl ester

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (1.1 g,2.0 mmol) and tert-butyl carbamate (4639 mg,4.0 mmol) were dissolved in 1, 4-dioxane (20 mL), and Xphos (191 mg,0.4 mmol), tris (dibenzylideneacetone) dipalladium (183mg, 0.2 mmol) and cesium carbonate (1.3 g,4.0 mmol) were added sequentially. The mixture was heated to 85 ℃ under nitrogen and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (1.0 g, brown solid), yield: 90%. MS (ESI) M/z557.2[ M+H ] ⁺.

(4) 4-Amino-N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Tert-butyl (4- ((2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) carbamoyl) -3- (6-azaspiro [2.5] oct-6-yl) phenyl) carbamate (100 mg,0.18 mmol) was dissolved in dichloromethane (4 mL), and a hydrochloric acid/1, 4-dioxane solution (1 mL) was added to stir the reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the title compound (82 mg, yellow solid), yield: 100%. MS (ESI) m/z 457.2[ M+H ] ⁺.

(5) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- (3- (2-hydroxyethyl) ureido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Amino-N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (82 mg,0.18 mmol) and triethylamine (91 mg,0.90 mmol) were dissolved in tetrahydrofuran (5 mL), triphosgene (39 mg,0.13 mmol) was added and the mixture was heated to 60℃and stirred for half an hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to 2mL under reduced pressure. Ethanolamine (33 mg,0.54 mmol) was dissolved in tetrahydrofuran (5 mL), added dropwise to the above filtrate (2 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to 100% ethyl acetate) to give a crude product. Purification of the crude product by Prep-HPLC gave the title compound (10.5 mg, white solid) in yield ：11％.MS(ESI):m/z 544.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.63(s,1H),9.04(s,1H),7.99(d,J＝8.8Hz,1H),7.81(d,J＝1.2Hz,1H),7.40(s,1H),7.16(dd,J＝8.8Hz,1.6Hz,1H),6.36(t,J＝5.2Hz,1H),4.77(t,J＝5.2Hz,1H),3.99-3.86(m,4H),3.48-3.44(m,2H),3.20-3.16(m,2H),3.04-2.91(m,4H),2.31(s,3H),2.02-1.95(m,4H),1.90-1.36(m,4H),0.39(s,4H). example 20

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((4- (hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) (4-Amino-1, 2, 5-oxadiazol-3-yl) methanol

Ethyl 4-amino-1, 2, 5-oxadiazole-3-carboxylate (6278 mg,4 mmol) was dissolved in tetrahydrofuran (25 mL), followed by slow addition of lithium aluminum hydride (304 mg,8 mmol), and the reaction was stirred at room temperature for 2 hours. To the reaction solution, water (0.3 mL) was slowly added, and after stirring for a while, a 15% aqueous sodium hydroxide solution (0.3 mL) was slowly added, and further, water (0.9 mL) was added, followed by stirring for 15 minutes, and then, anhydrous sodium sulfate was added, followed by stirring for a minute, and filtration. The filtrate was concentrated under reduced pressure to give the title compound (350 mg, brown oil), yield: 76%. MS (ESI) m/z 116.0[ M+H ] ⁺.

(2) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((4- (hydroxymethyl) -1,2, 5-oxadiazol-3-yl) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (28 mg,0.05mmol, example 19, step 2) was dissolved in 1, 4-dioxane (3 mL), and (4-amino-1, 2, 5-oxadiazol-3-yl) methanol (6.5 mg,0.06 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethoxyxanthene (3 mg,5 umol), tris (dibenzylideneacetone) dipalladium (2.5 mg,2.5 umol) and cesium carbonate (48.75 mg,0.15 mmol) were added sequentially. The reaction was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was cooled to room temperature, diluted with methanol, insoluble matter was filtered off, and the filtrate was concentrated. Purification of the residue by Prep-HPLC gave the title compound (6.6 mg, white solid), yield ：27％.MS(ESI):m/z 555.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.55(s,1H),9.45(s,1H),8.13(d,J＝8.8Hz,1H),7.77(d,J＝1.6Hz,1H),7.59-7.56(m,1H),7.42(s,1H),5.73(s,1H),4.79(s,2H),3.92(t,J＝5.6Hz,4H),3.05-3.29(m,4H),2.32(s,3H),2.07-1.96(m,4H),1.87-1.34(m,4H),0.41(s,4H).

Example 21

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((2-hydroxyethyl) sulfamido) -3- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 4-Nitro-3- (6-azaspiro [2.5] oct-6-yl) benzoic acid ethyl ester

Ethyl 3-fluoro-4-nitrobenzoate (1.065 g,5 mmol) was dissolved in N, N-dimethylformamide (30 mL), 6-azaspiro [2.5] octane hydrochloride (1.11 g,7.5 mmol) and potassium carbonate (2.07 g,15 mmol) were added and the mixture was heated to 90℃and stirred for 5 hours. The reaction was poured into water (200 mL) and extracted with ethyl acetate (2X 75 mL). The organic phases were combined and washed with saturated brine (75 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to the title compound (1.52 g, orange oil), yield: 100%. MS (ESI) m/z 305.1[ M+H ] ⁺.

(2) 4-Amino-3- (6-azaspiro [2.5] oct-6-yl) benzoic acid ethyl ester

Ethyl 4-nitro-3- (6-azaspiro [2.5] oct-6-yl) benzoate (1.3 g,4.27 mmol) was dissolved in methanol (50 mL), 10% palladium on charcoal (300 mg) was added, the system was replaced with hydrogen three times, and the mixture was reacted under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the cake was washed with methanol (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1) to give the title compound (850 mg, white solid), yield: 72.6%. MS (ESI) m/z 275.2[ M+H ] ⁺.

(3) 4-Bromo-3- (6-azaspiro [2.5] oct-6-yl) benzoic acid ethyl ester

To an acetonitrile (20 mL) solution of ethyl 4-amino-3- (6-azaspiro [2.5] oct-6-yl) benzoate at 0deg.C were added tert-butyl nitrite (441 mg,3.86 mml) and copper bromide (430 mg,1.93 mmol), and the reaction solution was stirred at room temperature under nitrogen for 16 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (2X 50 mL). The organic phases were combined, washed with saturated 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=20/1) to give the title compound (350 mg, white solid), yield: 35.3%. MS (ESI) m/z 338.0[ M+H ] ⁺.

(4) 4-Bromo-3- (6-azaspiro [2.5] oct-6-yl) benzoic acid

Ethyl 4-bromo-3- (6-azaspiro [2.5] oct-6-yl) benzoate (350 mg,1.04 mmol) was dissolved in methanol (15 mL), and water (5 mL) and lithium hydroxide monohydrate (131 mg,3.12 mmol) were added to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL), adjusted to pH 3 with 2N diluted hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (2X 20 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (280 mg, white solid), yield: 87.5%. MS (ESI) m/z 310.0[ M+H ] ⁺.

(5) 4-Bromo-N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -3- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Bromo-3- (6-azaspiro [2.5] oct-6-yl) benzoic acid (220 mg,0.71 mmol) and 2- (4, 4-difluoropiperidin-1-yl) -6-methylpyridin-4-amine (162 mg,0.71 mmol) were dissolved in pyridine (5 mL), cooled to 0℃and phosphorus oxychloride (435 mg,2.84 mmol) was added dropwise. The mixture was allowed to react for 2 hours at room temperature. Methanol was added to the reaction solution, which was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=40/1) to give the title compound (200 mg, white solid), yield: 54.2%. MS (ESI) m/z 520.0[ M+H ] ⁺.

(6) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((2-hydroxyethyl) sulfamido) -3- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Bromo-N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -3- (6-azaspiro [2.5] oct-6-yl) benzamide (120 mg,0.23 mmol) was dissolved in 1, 4-dioxane (10 mL), and 2-hydroxyethanesulfonamide (57 mg,0.46 mmol), tris (dibenzylideneacetone) dipalladium (21 mg,0.023 mmol), xphos (22 mg,0.046 mmol), and cesium carbonate (150 mg,0.46 mmol) were added sequentially. The mixture was heated to 90 ℃ under nitrogen and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give a crude product, which was purified by Prep-HPLC to give the title compound (12.8 mg, white solid), yield ：10％.MS(ESI):m/z 565.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.49(s,1H),8.61(s,1H),7.92(s,1H),7.78(d,J＝8.4Hz,1H),7.54(d,J＝8.8Hz,1H),7.35(s,1H),5.24(s,1H),3.92(t,J＝5.6Hz,4H),3.83-3.78(m,2H),3.49-3.40(m,2H),2.87(t,J＝4.8Hz,4H),2.30(s,3H),2.04-1.95(m,4H),1.62-1.45(m,4H),0.36(s,4H).

Example 22

N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 3-Bromo-2-hydrazino-5-nitropyridine

3-Bromo-2-chloro-5-nitropyridine (5.0 g,21.1 mmol) was dissolved in 1, 4-dioxane (40 mL), hydrazine hydrate (30 g,0.63 mol) was added at 0deg.C, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated, water (20 mL) was added thereto, and the mixture was stirred for half an hour to precipitate a solid. Direct filtration gave the title compound (4.4 g, yellow solid), yield: 90%. ¹H NMR(400MHz,DMSO-d₆ ) δ8.94 (d, j=2.0 hz,1 h), 8.38 (d, j=2.4 hz,1 h).

(2) 8-Bromo-6-nitro- [1,2,4] triazolo [4,3-a ] pyridine

3-Bromo-2-hydrazino-5-nitropyridine (4.4 g,18.9 mmol) was dissolved in trimethyl orthoformate (20 g,0.19 mol) and the mixture was heated to 100deg.C and stirred for 3 hours. The reaction was cooled to room temperature, and a solid was precipitated, filtered, and the solid was washed with petroleum ether and dried to give the title compound (4.0 g, yellow solid), yield: 87%. MS (ESI) m/z 242.8[ M+H ] ⁺.

(3) 8-Bromo- [1,2,4] triazolo [4,3-a ] pyridin-6-amine

8-Bromo-6-nitro- [1,2,4] triazolo [4,3-a ] pyridine (1.0 g,4.1 mmol) was dissolved in a mixed solvent of tetrahydrofuran/water (10 mL/2 mL), and iron powder (695 mg,12.4 mmol) and ammonium chloride (885.6 mg,16.4 mmol) were added thereto and the mixture was stirred and refluxed for 3 hours. Water (20 mL) was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (876 mg, yellow oil), yield: 100%. MS (ESI) m/z 212.8[ M+H ] ⁺.

(4) (Boc) (8-bromo- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) carbamic acid tert-butyl ester

8-Bromo- [1,2,4] triazolo [4,3-a ] pyridin-6-amine (876 mg,4.1 mmol) and di-tert-butyl dicarbonate (1.8 g,8.2 mmol) were dissolved in tetrahydrofuran (10 mL), triethylamine (1.2 g,12.3 mmol) and 4-dimethylaminopyridine (48.8 mg,0.4 mmol) were added, and stirred overnight at room temperature. To the reaction mixture was added water (30 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (90 mg, yellow oil), yield: 5%. MS (ESI) m/z 412.8[ M+H ] ⁺.

(5) (Boc) (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) carbamic acid tert-butyl ester

Tert-butyl (tert-butoxycarbonyl) (8-bromo- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) carbamate (560 mg,1.4 mmol) and 4, 4-difluoropyridine hydrochloride (439 mg,2.8 mmol) were dissolved in 1, 4-dioxane (10 mL), xphos (48 mg,0.1 mmol), tris (dibenzylideneacetone) dipalladium (46 mg,0.05 mmol) and cesium carbonate (1.3 g,4.2 mmol) were added and the mixture was heated to 100deg.C under nitrogen and stirred overnight. To the reaction solution was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (200 mg, yellow oil), yield: 15%. MS (ESI) m/z 454.0[ M+H ] ⁺.

(6) 8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyridin-6-amine

Tert-butyl (tert-butoxycarbonyl) (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) carbamate (200 mg,0.4 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated directly to give the title compound (112 mg, yellow oil). MS (ESI) m/z 254.0[ M+H ] ⁺.

(7) N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyridin-6-amine (28 mg,0.11 mmol) and intermediate 1 (40 mg,0.11 mmol) were dissolved in N, N-dimethylformamide (2 mL), HATU (50 mg,0.13 mmol) and N, N-diisopropylethylamine (43 mg,0.33 mmol) were added and the mixture stirred at room temperature overnight. To the reaction solution was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (60 mg, white solid), yield: 92%. MS (ESI) M/z592.9[ M+H ] ⁺.

(8) N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (60 mg,0.1 mmol) was dissolved in1, 4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (25 mg,0.2 mmol), xphos (5 mg,0.01 mmol), tris (dibenzylideneacetone) dipalladium (5 mg,0.005 mmol) and cesium carbonate (65 mg,0.2 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (11.1 mg, white solid) in yield ：18％.MS(ESI):m/z 590.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.72(s,1H),10.08(brs,1H),9.21(d,J＝1.6Hz,1H),8.38(s,1H),7.79(d,J＝8.8Hz,1H),7.15(d,J＝2.0Hz,1H),7.03(dd,J＝8.4,1.6Hz,1H),6.98(d,J＝1.2Hz,1H),4.98(brs,1H),3.82-3.75(m,6H),3.35-3.32(m,2H),3.00-2.97(m,4H),2.20-2.13(m,4H),1.58-1.51(m,4H),0.34(s,4H).

Example 23

N- (3- (difluoromethyl) -1-methyl-1H-indazol-5-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1-Methyl-5-nitro-1H-indole-3-carbaldehyde

5-Nitro-1H-indazole-3-carbaldehyde (780 mg,4.1 mmol) was dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (1.68 g,12.2 mmol) and methyl iodide (696 mg,4.9 mmol) were added to react at room temperature for 16 hours. The reaction mixture was poured into water (75 mL), extracted with ethyl acetate (2×50 mL), and the organic phases were combined, washed with saturated brine (75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by beating (petroleum ether/ethyl acetate=10/1) to give the title compound (633 mg, reddish brown solid), yield: 76%. MS (ESI) m/z 206.0[ M+H ] ⁺.

(2) 3- (Difluoromethyl) -1-methyl-5-nitro-1H-indole

1-Methyl-5-nitro-1H-indole-3-carbaldehyde (633 mg,3.1 mmol) was dissolved in dichloromethane (15 mL), DAST (1.24 g,7.7 mmol) was added dropwise, and the mixture was reacted at room temperature for 2 hours. The reaction solution was slowly poured into saturated aqueous sodium bicarbonate (100 mL), a large amount of gas was evolved, the organic phase was separated, the aqueous phase was extracted with dichloromethane (2×50 mL), the organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=100/1) to give the title compound (500 mg, reddish brown solid), yield: 71%. MS (ESI) m/z 228.0[ M+H ] ⁺.

(3) 3- (Difluoromethyl) -1-methyl-1H-indazol-5-amine

3- (Difluoromethyl) -1-methyl-5-nitro-1H-indole (50 mg,0.22 mmol) was dissolved in ethyl acetate (5 mL), methanol (5 mL) and 10% wet palladium on carbon (30 mg) were added, hydrogen was replaced three times, and the reaction was carried out at room temperature for 2 hours. The reaction was filtered through celite, the filter cake was washed with methanol (5 mL), and the filtrate was concentrated under reduced pressure to give the title compound (43 mg, pale yellow oil), yield: 100%. MS (ESI) m/z 198.0[ M+H ] ⁺.

(4) N- (3- (difluoromethyl) -1-methyl-1H-indazol-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (78 mg,0.22 mmol) was dissolved in N, N-dimethylformamide (4 mL), HATU (67 mg,0.44 mmol) and N, N-diisopropylethylamine (142 mg,1.1 mmol) were added, and after stirring at room temperature for 10 min 3- (difluoromethyl) -1-methyl-1H-indazol-5-amine (43 mg,0.22 mmol) was added and reacted at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution (50 mL), the aqueous phase was extracted with ethyl acetate (2×25 mL), and the organic phases were combined, washed with saturated 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=4/1) to give the title compound (76 mg, colorless oil), yield: 64%. MS (ESI) m/z 536.9[ M+H ] ⁺.

(5) N- (3- (difluoromethyl) -1-methyl-1H-indazol-5-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (3- (difluoromethyl) -1-methyl-1H-indazol-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (76 mg,0.14 mmol) was dissolved in 1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (35 mg,0.28 mmol), tris (dibenzylideneacetone) dipalladium (13 mg,0.014 mmol), XPhos (14 mg,0.03 mmol) and cesium carbonate (137 mg,0.42 mmol) were added. The mixture was heated to 90 ℃ under nitrogen for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give a crude product, which was purified by Prep-HPLC to give the title compound (12.2 mg, white solid), yield ：16％.MS(ESI):m/z 534.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.56(s,1H),10.04(s,1H),8.58(s,1H),7.82-7.79(m,2H),7.62(dd,J＝8.8,2.0Hz,1H),7.32(d,J＝54.0Hz,1H),7.16(d,J＝2.4Hz,1H),7.04(dd,J＝8.4,2.0Hz,1H),4.95(s,1H),4.10(s,3H),3.77(t,J＝6.8Hz,2H),3.35-3.32(m,2H),3.01-2.98(m,4H),1.58-1.44(m,4H),0.34(s,4H).

Example 24

N- (3, 3-difluoroazetidin-1-yl) -1-methyl-1H-indazol-5-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 3-Iodo-1-methyl-5-nitro-1H-indazole

3-Iodo-5-nitroindazole (2.32 g,8 mmol) was dissolved in N, N-dimethylformamide (40 mL), sodium hydride (380 mg,16 mmol) was slowly added, stirred at room temperature for 10 minutes, methyl iodide (1.36 g,9.6 mmol) was further added, and the reaction solution was allowed to stand at 30℃overnight. The reaction was quenched with water (200 mL) and the aqueous phase extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (80 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column to give the title compound (790 mg, yellow solid), yield ：65％.MS(ESI):m/z 303.8[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.31-8.29(m,2H),7.91(d,J＝8.0Hz,1H),4.15(s,3H).

(2) 3- (3, 3-Difluoroazetidin-1-yl) -1-methyl-5-nitro-1H-indazole

3-Iodo-1-methyl-5-nitro-1H-indazole (480 mg,1.6 mmol) was dissolved in 1, 4-dioxane (15 mL), 3-difluoroazetidine (250 mg,1.92 mmol), xantPhos (92 mg,0.16 mmol), tris (dibenzylideneacetone) dipalladium (73 mg,0.08 mmol) and cesium carbonate (1.56 g,4.8 mmol) were added. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to give the title compound (300 mg, yellow solid), yield: 70%. MS (ESI) m/z 269.0[ M+H ] ⁺.

(3) 3- (3, 3-Difluoroazetidin-1-yl) -1-methyl-1H-indazol-5-amine

3- (3, 3-Difluoroazetidin-1-yl) -1-methyl-5-nitro-1H-indazole (200 mg,0.74 mmol) was dissolved in a mixed solvent of methanol/water (6 mL/3 mL), iron powder (125 mg,2.24 mmol) and ammonium chloride (120 mg,2.24 mmol) were added, and the reaction solution was heated to 80℃and stirred overnight. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was diluted with dichloromethane, filtered, and the filtrate concentrated to give the title compound (150 mg, reddish brown solid), yield: 85%. MS (ESI) m/z 239.0[ M+H ] ⁺.

(4) N- (3, 3-difluoroazetidin-1-yl) -1-methyl-1H-indazol-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

3- (3, 3-Difluoroazetidin-1-yl) -1-methyl-1H-indazol-5-amine (80 mg,0.34 mmol) and intermediate 1 (134 mg,0.37 mmol) were dissolved in N, N-dimethylformamide (15 mL), N-diisopropylethylamine (132 mg,1.02 mmol) and HATU (258 mg,0.68 mmol) were added and the mixture stirred at room temperature for 3 hours. To the reaction solution was added saturated sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (25 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (120 mg, yellow solid), yield: 61%. MS (ESI) m/z 577.9[ M+H ] ⁺.

(5) N- (3, 3-difluoroazetidin-1-yl) -1-methyl-1H-indazol-5-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (3, 3-difluoroazetidin-1-yl) -1-methyl-1H-indazol-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (50 mg,0.21 mmol) was dissolved in 1, 4-dioxane solution (3 mL), 2-hydroxyethanesulfonamide (78 mg,0.62 mmol), xphos (21 mg,0.04 mmol), tris (dibenzylideneacetone) dipalladium (20 mg,0.02 mmol) and cesium carbonate (200 mg,0.62 mmol) were added. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated under reduced pressure, insoluble matters were filtered off, diluted with methanol, and purified by Prep-HPLC to give the title compound (10.3 mg, pale yellow solid), yield ：20.4％.MS(ESI):m/z 575.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.59(s,1H),10.07(brs,1H),8.10(d,J＝1.6Hz,1H),7.84(d,J＝8.8Hz,1H),7.63(dd,J＝7.6,1.6Hz,1H),7.52(d,J＝9.2Hz,1H),7.16(d,J＝2.0Hz,1H),7.03(dd,J＝6.0,2.4Hz,1H),4.96(s,1H),4.49(t,J＝12.0Hz,4H),3.85(s,3H),3.76(t,J＝6.8Hz,2H),3.33-3.31(m,2H),2.99(t,J＝5.2Hz,4H),1.58-1.49(m,4H),0.34(s,4H).

Example 25

N- (3-cyclopropyl-1-methyl-1H-indazol-5-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 3-Iodo-1-methyl-5-nitro-1H-indazole

3-Iodo-5-nitroindazole (2.32 g,8 mmol) was dissolved in N, N-dimethylformamide (40 mL), sodium hydride (380 mg,16 mmol) was slowly added, stirred at room temperature for 10 minutes, methyl iodide (1.36 g,9.6 mmol) was further added, and the mixture was stirred at 30℃overnight. The reaction was quenched with water (200 mL) and the aqueous phase extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (80 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.08 g, yellow solid), yield ：86％.MS(ESI):m/z 303.8[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.31-8.29(m,2H),7.92-7.90(m,1H),4.15(s,3H).

(2) 3-Cyclopropyl-1-methyl-5-nitro-1H-indazole

3-Iodo-1-methyl-5-nitro-1H-indazole (1.0 g,3.3 mmol) and cyclopropylboronic acid (344 mg,4.0 mmol) were dissolved in a1, 4-dioxane/water (10 mL/1 mL) mixture, and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (270 mg,0.33 mmol) and cesium carbonate (911 mg,6.6 mmol) were added sequentially, and the mixture was heated to 100℃under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (190 mg, yellow solid), yield: 27%. MS (ESI) m/z 218.1[ M+H ] ⁺.

(3) 3-Cyclopropyl-1-methyl-1H-indazol-5-amine

3-Cyclopropyl-1-methyl-5-nitro-1H-indazole (190 mg,0.88 mmol) was dissolved in tetrahydrofuran/water (5 mL/1 mL) mixed solvent, iron powder (148 mg,2.64 mmol) and ammonium chloride (141 mg,2.64 mmol) were added, and the mixture was heated to 78℃and stirred for 3 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, diluted with dichloromethane, filtered, and the filtrate was concentrated to give the title compound (150 mg, reddish brown solid), yield: 91%. MS (ESI) m/z 188.1[ M+H ] ⁺.

(4) N- (3-cyclopropyl-1-methyl-1H-indazol-5-yl) -4-iodo-2- (6-azaspiro [2.5] octyl-6-yl) benzamide

3-Cyclopropyl-1-methyl-1H-indazol-5-amine (150 mg,0.8 mmol) and intermediate 1 (284 mg,0.8 mmol) were dissolved in N, N-dimethylformamide (5 mL), N-diisopropylethylamine (516 mg,4.0 mmol) and HATU (608 mg,1.6 mmol) were added and stirred at room temperature for 2 hours. The reaction was poured into saturated sodium bicarbonate solution (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (100 mg, yellow solid), yield: 24%. MS (ESI) m/z 526.9[ M+H ] ⁺.

(5) N- (3-cyclopropyl-1-methyl-1H-indazol-5-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (3-cyclopropyl-1-methyl-1H-indazol-5-yl) -4-iodo-2- (6-azaspiro [2.5] octyl-6-yl) benzamide (50 mg,0.1 mmol) was dissolved in 1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (25 mg,0.2 mmol), xphos (19 mg,0.04 mmol), tris (dibenzylideneacetone) dipalladium (18 mg,0.02 mmol) and cesium carbonate (65 mg,0.2 mmol) were added sequentially and the mixture was heated to 90℃under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1 to dichloromethane/methanol=20/1) to give a crude product, which was diluted with methanol and purified by Prep-HPLC to give the title compound (14.3 mg, white solid), yield ：28％.MS(ESI):m/z 524.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.52(s,1H),9.98(s,1H),8.38(d,J＝0.8Hz,1H),7.83(d,J＝8.4Hz,1H),7.59-7.51(m,2H),7.16(d,J＝2.4Hz,1H),7.03(dd,J＝8.4,1.6Hz,1H),4.96(s,1H),3.92(s,3H),3.77(t,J＝6.4Hz,2H),3.42-3.35(m,2H),3.01-2.98(m,4H),2.22-2.15(m,1H),1.61-1.48(m,4H),1.02-0.91(m,4H),0.35(s,4H).

Example 26

N- (1- (4, 4-difluorocyclohexyl) -1H-indazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1- (4, 4-Difluorocyclohexyl) -3-nitro-1H-indazole

4, 4-Difluorocyclohexyl mesylate (500 mg,2.33mmol, example 2, step 1) and 3-nitro-1H-indazole (380 mg,2.33 mmol) were dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (2.28 g,6.99 mmol) was added and the mixture heated to 100deg.C and stirred for 3 hours. The reaction solution was purified by column chromatography to give the title compound (500 mg, yellow solid) ).MS(ESI):m/z 282.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.17(d,J＝8.4Hz,1H),8.04(d,J＝8.8Hz,1H),7.67-7.65(m,1H),7.58-7.54(m,1H),5.22-5.14(m,1H),2.25-2.12(m,8H).

(2) 1- (4, 4-Difluorocyclohexyl) -1H-indazol-3-amine

1- (4, 4-Difluorocyclohexyl) -3-nitro-1H-indazole (500 mg,1.77 mmol) was dissolved in methanol/water (8 mL/2 mL), iron powder (294 mg,5.31 mmol) was added, ammonium chloride (284 mg,5.31 mmol), and the mixture was heated to 80℃and stirred for 2 hours. The reaction was filtered, the filter cake was washed with water (30 mL) and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (100 mg, black oil), yield: 78%. MS (ESI) m/z 252.1[ M+H ] ⁺.

(3) N- (1- (4, 4-difluorocyclohexyl) -1H-indazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1- (4, 4-Difluorocyclohexyl) -1H-indazol-3-amine (350 mg,1.39 mmol), intermediate 1 (497 mg,1.39 mmol) was dissolved in N, N-dimethylformamide (10 mL), HATU (760 mg,2 mmol) and N, N-diisopropylethylamine (640 mg,5 mmol) were added and the mixture stirred under nitrogen overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (150 mg, white solid), yield: 18.2%. MS (ESI) M/z591.0[ M+H ] ⁺.

(4) N- (1- (4, 4-difluorocyclohexyl) -1H-indazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- (4, 4-difluorocyclohexyl) -1H-indazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (150 mg,0.25 mmol) was dissolved in1, 4-dioxane (10 mL), 2-hydroxyethanesulfonamide (50 mg,0.8 mmol), tris (dibenzylideneacetone) dipalladium (37 mg,0.04 mmol), xphos (38 mg,0.08 mmol) and cesium carbonate (399mg, 1.2 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen protection and reacted for 3 hours. The reaction solution was purified by Prep-HPLC to give the title compound (35 mg, white solid) in yield ：23.3％.MS(ESI):m/z 588.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.08(s,1H),10.16(s,1H),8.21(d,J＝8.4Hz,1H),8.03(d,J＝8.4Hz,1H),7.65(d,J＝8.4Hz,1H),7.41(t,J＝7.6Hz,1H),7.26(d,J＝2.0Hz,1H),7.13-7.08(m,2H),4.99-4.86(m,2H),3.78-3.75(m,2H),3.37-3.33(m,2H),3.03-3.00(m,4H),2.27-2.01(m,8H),1.72-1.67(m,4H),0.37(s,4H).

Example 27

N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) (3, 3-Difluorocyclobutyl) methanesulfonic acid methyl ester

(3, 3-Difluorocyclobutyl) methanol (0.5 g,4.1 mmol) was dissolved in methylene chloride (10 mL), triethylamine (1.2 g,12.3 mmol) was added thereto, methanesulfonyl chloride (0.9 g,8.2 mmol) was added dropwise at 0℃and stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL) and the aqueous phase extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.0 g, yellow oil), yield: 90%.

(2) 1- ((3, 3-Difluorocyclobutyl) methyl) -3-nitro-1H-pyrazole

Methyl (3, 3-difluorocyclobutyl) methane sulfonate (1.0 g,4.6 mmol) and 3-nitro-1H-pyrazole (520 mg,4.6 mmol) were dissolved in dimethyl sulfoxide (8 mL), cesium carbonate (4.48 g,13.8 mmol) was added and the mixture was heated to 100deg.C under nitrogen and stirred overnight. To the reaction mixture was added water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (40 ml x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/ethyl acetate=10/1) to give the title compound (0.33 g, pale yellow oil), yield: 34%. MS (ESI) m/z 218.0[ M+H ] ⁺.

(3) 1- ((3, 3-Difluorocyclobutyl) methyl) -1H-pyrazol-3-amine

1- ((3, 3-Difluorocyclobutyl) methyl) -3-nitro-1H-pyrazole (0.23 g,1.1 mmol) was dissolved in a mixed solvent of methanol/water (6 mL/3 mL), iron powder (184 mg,3.3 mmol) and ammonium chloride (177 mg,3.3 mmol) were added, and the mixture was heated to 80℃under nitrogen and stirred for 2 hours. The reaction was filtered, the filter cake was washed with water (10 mL) and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (100 mg, gray oil), yield: 51%. MS (ESI) m/z 188.0[ M+H ] ⁺.

(4) N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1- ((3, 3-Difluorocyclobutyl) methyl) -1H-pyrazol-3-amine (100 mg,0.6 mmol) and intermediate 1 (0.32 g,0.9 mmol) were dissolved in pyridine (5 mL), phosphorus oxychloride (0.28 g,1.8 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction was quenched with water (10 mL) and the aqueous phase extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (58 mg, white solid), yield: 18%. MS (ESI) m/z 527.0[ M+H ] ⁺.

(5) N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (58 mg,0.11 mmol) was dissolved in1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (42 mg,0.33 mmol), cesium carbonate (108 mg,0.33 mmol), tris (dibenzylideneacetone) dipalladium (11 mg,0.01 mmol) and Xphos (11 mg,0.022 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give the title compound (21.1 mg, white solid) in yield ：36％.MS(ESI):m/z 524.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.68(s,1H),10.18(s,1H),7.98(d,J＝8.8Hz,1H),7.68(d,J＝2.4Hz,1H),7.22(d,J＝1.6Hz,1H),7.08(dd,J＝8.8,2.4Hz,1H),6.60(d,J＝2.0Hz,1H),4.93(s,1H),4.17(d,J＝6.0Hz,2H),3.75(t,J＝6.8Hz,2H),3.35-3.32(m,2H),2.95(t,J＝5.2Hz,4H),2.68-2.55(m,4H),2.45-2.33(m,1H),1.66-1.62(m,4H),0.38(s,4H).

Example 28

N- (8- (3, 3-difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

/>

(1) (Tert-Butoxycarbonyl) (8- (3, 3-difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) carbamic acid tert-butyl ester

Tert-butyl (8-bromoimidazo [1,2-a ] pyridin-6-yl) (tert-butoxycarbonyl) carbamate (1.0 g,2.4mmol, example 11, step 3) is dissolved in 1, 4-dioxane (20 mL) and 3, 3-difluoroazetidine hydrochloride (373 mg,2.9 mmol), xphos (119 mg,0.24 mmol), tris (dibenzylideneacetone) dipalladium (110 mg,0.12 mmol) and cesium carbonate (1.5 g,4.8 mmol) are added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (260 mg, white solid), yield: 25.5%. MS (ESI) m/z 425.1[ M+H ] ⁺.

(2) 8- (3, 3-Difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-6-amine

Tert-butyl (tert-butoxycarbonyl) (8- (3, 3-difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) carbamate (260 mg,0.5 mmol) is dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) is added and stirred at room temperature for 1 hour. The reaction was concentrated, sodium bicarbonate solution (30 mL) was added and the aqueous phase extracted with dichloromethane (20 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (174 mg, yellow solid), yield: 100%.

(3) N- (8- (3, 3-difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl ] benzamide

8- (3, 3-Difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-6-amine (174 mg,0.8 mmol), intermediate 1 (315 mg,0.88 mmol) is dissolved in N, N-dimethylformamide (8 mL), N-diisopropylethylamine (310 mg,2.4 mmol) and HATU (319 mg,1.6 mmol) are added and the mixture stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (100 mg, colorless oil), yield: 24%. MS (ESI) m/z 563.9[ M+H ] ⁺.

(4) N- (8- (3, 3-difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (3, 3-Difluoroazetidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl ] benzamide (100 mg,0.18 mmol) was dissolved in 1, 4-dioxane (8 mL), 2-hydroxyethanesulfonamide (113 mg,0.9 mmol), xphos (36 mg,0.072 mmol), tris (dibenzylideneacetone) dipalladium (50 mg,0.054 mmol) and cesium carbonate (234 mg,0.72 mmol) were added sequentially, the mixture was heated to 100℃under nitrogen protection overnight, the reaction was concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the crude product, which was purified by Prep-HPLC to give the title compound (1 mg, white solid), yield ：1％.MS(ESI):m/z 561.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.47(s,1H),10.08(s,1H),8.91-8.89(m,1H),7.98(d,J＝0.8Hz,1H),7.77(dd,J＝8.4,3.6Hz,1H),7.45(d,J＝0.8Hz,1H),7.15-7.14(m,1H),7.04-7.01(m,1H),6.20-6.19(m,1H),4.57(t,J＝12.4Hz,4H),3.77-3.74(m,2H),3.38-3.34(m,2H),2.98(t,J＝5.2Hz,4H),1.58-1.55(m,4H),0.35(s,4H).

Example 29

N- (8- (3, 3-difluoropyrrolidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the synthesis of example 28, starting with tert-butyl (8-bromoimidazo [1,2-a ] pyridin-6-yl) (tert-butoxycarbonyl) carbamate (example 11, step 3) and 3, 3-difluoropyrrolidine hydrochloride, the title compound (3.3 mg, white solid) was obtained by similar procedures ).MS(ESI):m/z 575.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.61(s,1H),10.09(s,1H),8.90(d,J＝1.2Hz,1H),7.97(s,1H),7.81(d,J＝8.4Hz,1H),7.44(d,J＝0.8Hz,1H),7.17(d,J＝1.6Hz,1H),7.04(dd,J＝8.4,2.0Hz,1H),6.15(s,1H),4.95(t,J＝5.6Hz,1H),4.27(t,J＝13.6Hz,2H),3.84-3.74(m,4H),3.35-3.21(m,2H),2.99-2.97(m,4H),2.62-2.54(m,2H),1.62-1.55(m,4H),0.35(s,4H).

Example 30

N- (8- (4- (difluoromethylene) piperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the synthesis of example 28, using tert-butyl (8-bromoimidazo [1,2-a ] pyridin-6-yl) (tert-butoxycarbonyl) carbamate (example 11, step 3) and 4- (difluoromethylene) piperidine as starting materials, the title compound (3 mg, white solid) was obtained by similar procedure ).MS(ESI):m/z 601.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.02(s,1H),7.96(s,1H),7.80(d,J＝8.4Hz 1H),7.44(s,1H),7.15(s,1H),7.04-7.01(m,1H),6.51(s,1H),3.77-3.74(m,2H),3.70-3.66(m,4H),3.36-3.35(m,2H),2.98-2.96(m,4H),2.33-2.32(m,4H),1.59-1.55(m,4H),0.34(s,4H).

Example 31

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- (((2-hydroxyethyl) (methyl) (oxo) -lambda ⁶ -sulfinamide) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) Tert-butyldimethyl (2- (methylthio) ethoxy) silane

2- (Methylthio) ethan-1-ol (5.0 g,54 mmol) was dissolved in dichloromethane (50 mL), imidazole (4.4 g,65 mmol) and t-butyldimethylchlorosilane (8.9 g,60 mmol) were added and stirred at room temperature overnight. To the reaction solution was added water (20 mL), and the mixture was extracted with dichloromethane (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (11 g, colorless oil), yield: 98%.

(2) (2- ((Tert-Butyldimethylsilyl) oxy) ethyl) (imino) (methyl) -lambda ⁶ -sulphone

Tert-butyldimethyl (2- (methylthio) ethoxy) silane (2.0 g,9.7 mmol) was dissolved in methanol (30 mL), iodobenzene acetate (3.8 g,11.8 mmol) and 7M methanolic ammonia solution (2.3 mL,16.1 mmol) were added and the mixture stirred overnight at 30 ℃. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/2) to give the title compound (1.1 g, yellow solid), yield: 48%. MS (ESI) m/z 238.0[ M+H ] ⁺.

(3) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (6-azaspiro [2.5] oct-6-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (430 mg,0.76mmol, example 19, step 2) and pinacol diboronate (231 mg,0.91 mmol) were dissolved in dioxane (10 mL), and PdCl ₂ (dppf) (57 mg,0.07 mmol) and potassium acetate (149 mg,1.52 mmol) were added. The reaction was heated to 90 ℃ under nitrogen and stirred overnight. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (200 mg, yellow solid), yield: 47%. MS (ESI) m/z 568.1[ M+H ] ⁺.

(4) (4- ((2- (4, 4-Difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) carbamoyl) -3- (6-azaspiro [2.5] oct-6-yl) phenyl) boronic acid

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (6-azaspiro [2.5] oct-6-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (150 mg,0.26 mmol) was dissolved in a mixed solvent of tetrahydrofuran/water (8 mL/2 mL), sodium periodate (170 mg,0.79 mmol) was added, stirring was continued at room temperature for half an hour, and 1M aqueous hydrochloric acid (0.26 mL) was further added, and stirring was continued at room temperature overnight. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane/methanol=60/1) to give the title compound (120 mg, white solid), yield: 94%. MS (ESI) m/z 486.1[ M+H ] ⁺.

(5) 4- (((2- ((Tert-butyldimethylsilyl) oxy) ethyl) (methyl) (oxo) -lambda ⁶ -sulfinyl) amino) -N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(4- ((2- (4, 4-Difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) carbamoyl) -3- (6-azaspiro [2.5] oct-6-yl) phenyl) boronic acid (70 mg,0.14 mmol) was dissolved in methanol (5 mL), and (2- ((tert-butyldimethylsilyl) oxy) ethyl) (imino) (methyl) -lambda ⁶ -sulphone (34 mg,0.14 mmol) and copper acetate (3 mg,0.014 mmol) were added and the mixture stirred overnight at 35 ℃. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (20 mg, yellow oil), yield: 20%. MS (ESI) m/z 677.2[ M+H ] ⁺.

(6) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- (((2-hydroxyethyl) (methyl) (oxo) -lambda ⁶ -sulfinamide) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

4- (((2- ((Tert-Butyldimethylsilyl) oxy) ethyl) (methyl) (oxo) -lambda ⁶ -sulfinyl) amino) -N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (20 mg,0.03 mmol) was dissolved in tetrahydrofuran (5 mL), and 1M tetrabutylammonium fluoride tetrahydrofuran solution (0.12 mL,0.12 mmol) was added and reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (100% ethyl acetate) to give a crude product, which was further purified by Prep-HPLC to give the title compound (2.9 mg, white solid), yield ：17％.MS(ESI):m/z 563.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.57(s,1H),7.95(d,J＝8.8Hz,1H),7.41(s,1H),6.94-6.89(m,2H),5.20(s,1H),3.92-3.85(m,6H),3.57-3.54(m,2H),3.28(s,3H),2.98-2.96(m,4H),2.30(s,3H),2.02-1.95(m,4H),1.85-1.44(m,4H),0.38(s,4H).

Example 32

N- (1- ((4, 4-difluorocyclohexyl) methyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) (4, 4-Difluorocyclohexyl) methane sulfonic acid methyl ester

(4, 4-Difluorocyclohexyl) methanol (1.5 g,10 mmol) was dissolved in methylene chloride (10 mL), triethylamine (3.0 g,30 mmol) was added, methanesulfonyl chloride (1.3 g,12 mmol) was added dropwise at 0℃and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.3 g, yellow oil).

(2) 1- ((4, 4-Difluorocyclohexyl) methyl) -3-nitro-1H-pyrazole

Methyl (4, 4-difluorocyclohexyl) methanesulfonate (1.5 g,6.7 mmol) and 3-nitro-1H-pyrazole (0.83 g,7.3 mmol) were dissolved in N, N-dimethylformamide (10 mL), cesium carbonate (6.5 g,20 mmol) was added and the mixture was heated to 100deg.C under nitrogen and stirred overnight. To the reaction mixture was added water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (40 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (1.4 g, pale yellow oil), yield ：88％.MS(ESI):m/z 226.0[M+H-HF]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.04(d,J＝2.4Hz,1H),7.06(d,J＝2.8Hz,1H),4.19(d,J＝7.6Hz,2H),2.53-2.51(m,3H),2.02-1.97(m,2H),1.88-1.76(m,2H),1.31-1.20(m,2H).

(3) 1- ((4, 4-Difluorocyclohexyl) methyl) -1H-pyrazol-3-amine

1- ((4, 4-Difluorocyclohexyl) methyl) -3-nitro-1H-pyrazole (600 mg,2.5 mmol) was dissolved in a mixed solvent of methanol/water (6 mL/3 mL), iron powder (410 mg,7.5 mmol) and ammonium chloride (405 mg,7.5 mmol) were added, and the mixture was heated to 80℃under nitrogen and stirred for 2 hours. The reaction was filtered, water (10 mL) was added to the filtrate, and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (500 mg, yellow solid), yield: 93%. MS (ESI) m/z 216.1[ M+H ] ⁺.

(4) N- (1- ((4, 4-difluorocyclohexyl) methyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1- ((4, 4-Difluorocyclohexyl) methyl) -1H-pyrazol-3-amine (108 mg,0.5 mmol), intermediate 1 (180 mg,0.5 mmol), were dissolved in N, N-dimethylformamide (10 mL), HATU (380 mg,1.0 mmol) and N, N-diisopropylethylamine (200 mg,1.5 mmol) were added, and the mixture was stirred at room temperature overnight. To the reaction solution was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (100 mg, white solid), yield: 36%. MS (ESI) m/z 554.9[ M+H ] ⁺.

(5) N- (1- ((4, 4-difluorocyclohexyl) methyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- ((4, 4-difluorocyclohexyl) methyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (100 mg,0.18 mmol) was dissolved in 1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (34 mg,0.27 mmol), cesium carbonate (176 mg,0.54 mmol), tris (dibenzylideneacetone) dipalladium (16 mg,0.018 mmol) and Xphos (18 mg,0.036 mmol) were added. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by Prep-HPLC to give the title compound (32.9 mg, white solid) in yield ：33％.MS(ESI):m/z 552.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.47(s,1H),10.15(s,1H),7.97(d,J＝8.8Hz,1H),7.63(d,J＝2.0Hz,1H),7.22(d,J＝2.0Hz,1H),7.08(dd,J＝8.4,2.0Hz,1H),6.60(d,J＝2.0Hz,1H),4.95(s,1H),3.98(d,J＝6.8Hz,2H),3.76(t,J＝6.8Hz,2H),3.36-3.34(m,2H),2.95(t,J＝5.2Hz,4H),2.01-1.62(m,11H),1.27-1.24(m,2H),0.37(s,4H).

Example 33

N- (1- (cyclopropylmethyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1- (Cyclopropylmethyl) -3-nitro-1H-pyrazole

3-Nitro-1H-pyrazole (1.0 g,8.8 mmol) and (bromomethyl) cyclopropane (2.4 g,17.7 mmol) were dissolved in N, N-dimethylformamide (15 mL), potassium carbonate (2.4 g,17.7 mmol) was added, and the mixture was heated to 120deg.C and stirred overnight. To the reaction solution was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (1.1 g, colorless oil), yield ：74％.MS(ESI):m/z 168.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.70(d,J＝2.8Hz,1H),7.06(d,J＝2.4Hz,1H),4.10(d,J＝7.2Hz,2H),1.32-1.27(m,1H),0.59-0.55(m,2H),0.44-0.40(m,2H).

(2) 1- (Cyclopropylmethyl) -1H-pyrazol-3-amine

1- (Cyclopropylmethyl) -3-nitro-1H-pyrazole (500 mg,3.0 mmol) was dissolved in methanol (10 mL), 10% wet palladium on charcoal (50 mg) was added, and the mixture was stirred at room temperature under hydrogen for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (410 mg, yellow oil). MS (ESI) m/z 138.1[ M+H ] ⁺.

(3) N- (1- (cyclopropylmethyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1- (Cyclopropylmethyl) -1H-pyrazol-3-amine (200 mg,1.5 mmol) and intermediate 1 (430 mg,1.2 mmol) were dissolved in N, N-dimethylformamide (5 mL), HATU (874 mg,2.3 mmol) and N, N-diisopropylethylamine (580 mg,4.5 mmol) were added, and stirred at room temperature overnight. To the reaction solution was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (260 mg, yellow oil), yield: 37%. MS (ESI) m/z 477.0[ M+H ] ⁺.

(4) N- (1- (cyclopropylmethyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- (cyclopropylmethyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (100 mg,0.2 mmol) and 2-hydroxyethanesulfonamide (53 mg,0.2 mmol) were dissolved in 1, 4-dioxane (5 mL), xphos (10 mg,0.02 mmol), tris (dibenzylideneacetone) dipalladium (10 mg,0.01 mmol), and cesium carbonate (136 mg,0.4 mmol) were added and the mixture was heated to 100℃under nitrogen and stirred overnight. The reaction was concentrated and the residue was purified by column chromatography (100% ethyl acetate) to give the crude product, which was further purified by Prep-HPLC to give the title compound (11.9 mg, white solid) in yield ：12％.MS(ESI):m/z 474.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.56(s,1H),10.09(s,1H),7.98(d,J＝8.8Hz,1H),7.67(d,J＝2.0Hz,1H),7.23(d,J＝1.6Hz,1H),7.08(dd,J＝8.8,1.6Hz,1H),6.60(d,J＝2.0Hz,1H),4.96(s,1H),3.90(d,J＝7.2Hz,2H),3.76(t,J＝6.8Hz,2H),3.32-3.29(m,2H),2.97-2.94(m,4H),1.70-1.60(m,4H),1.21-1.17(m,1H),0.54-0.50(m,2H),0.39-0.35(m,6H). example 34

N- (1-cyclopropyl-2-methyl-1H-benzo [ d ] imidazol-5-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1-Cyclopropyl-2-methyl-6-nitro-1H-benzo [ d ] imidazole

2-Methyl-6-nitro-1H-benzo [ d ] imidazole (1.0 g,5.64 mmol), cyclopropylboronic acid (960 mg,11.28 mmol) and 2, 2-bipyridine (260 mg,1.69 mmol) were dissolved in N, N-dimethylformamide (30 mL), and copper acetate (210 mg,1.69 mmol) and sodium carbonate (1.780 g,11.28 mmol) were added. The mixture was stirred at 100℃overnight. To the reaction solution was added water (70 mL), and the aqueous phase was extracted with ethyl acetate (80 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (100 ml x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound and its isomer mixture (650 mg, yellow solid), yield: 53%. MS (ESI) m/z 218.0[ M+H ] ⁺.

(2) 1-Cyclopropyl-2-methyl-1H-benzo [ d ] imidazol-6-amine

1-Cyclopropyl-2-methyl-6-nitro-1H-benzo [ d ] imidazole (650 mg,2.99 mmol) was dissolved in methanol/water (20 mL), iron powder (502 mg,8.97 mmol) and ammonium chloride (500 mg,9.00 mmol) were added and the mixture was heated to 80℃under nitrogen and stirred for 2 hours. The reaction solution was filtered through celite, water (100 mL) was added to the filtrate, and the aqueous phase was extracted with ethyl acetate (100 ml×2). The organic phases were combined, washed with saturated sodium chloride solution (100 ml x 3), dried over anhydrous sodium sulfate, and concentrated to give the title compound and its isomer mixture (500 mg, black oil), yield: 89%. MS (ESI) m/z 188.1[ M+H ] ⁺.

(3) N- (1-cyclopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1-Cyclopropyl-2-methyl-1H-benzo [ d ] imidazol-6-amine (500 mg,2.67 mmol) and intermediate 1 (964 mg,2.7 mmol) were dissolved in N, N-dimethylformamide (20 mL), HATU (2.05 g,5.4 mmol) and N, N-diisopropylethylamine (1.74 g,13.5 mmol) were added and stirred at room temperature for 2 hours. To the reaction solution was added water (70 mL), and the aqueous phase was extracted with ethyl acetate (80 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (70 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound and an isomer mixture thereof (400 mg, yellow oil), yield: 56%. MS (ESI) m/z 527.0[ M+H ] ⁺.

(4) N- (1-cyclopropyl-2-methyl-1H-benzo [ d ] imidazol-5-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1-cyclopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (150 mg,0.28 mmol) and 2-hydroxyethanesulfonamide (85 mg,0.68 mmol) were dissolved in1, 4-dioxane solution (5 mL), and Xphos (67 mg,0.14 mmol), tris (dibenzylideneacetone) dipalladium (64 mg,0.07 mmol) and cesium carbonate (222 mg,0.68 mmol) were added. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was purified by Prep-HPLC to give the title compound (3.0 mg, white solid) ).MS(ESI):m/z 524.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.82(s,1H),8.22(s,1H),7.87(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),7.38-7.35(m,1H),7.16(d,J＝2.0Hz,1H),7.04-7.01(m,1H),3.77-3.74(m,2H),3.30-3.29(m,3H),3.00-2.98(m,4H),2.56(s,3H),1.58-1.56(m,4H),1.21-1.17(m,2H),1.03-1.00(m,2H),0.36(s,4H).

Example 35

N- (1-cyclopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Reference to example 36, step 4, gives another isomer, the title compound N- (1-cyclopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (1.2 mg, white solid ).MS(ESI):m/z 524.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.51(s,1H),10.06(s,1H),8.01(s,1H),7.84(d,J＝8.4Hz,1H),7.54-7.51(m,2H),7.16(s,1H),7.03-7.01(m,1H),4.96(s,1H),3.77-3.74(m,2H),3.39-3.35(m,3H),2.99-2.97(m,4H),2.58(s,3H),1.54-1.50(m,4H),1.20-1.15(m,2H),1.03-0.99(m,2H),0.34(s,4H).

Example 36

N- (3- (4, 4-difluorocyclohexyl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1-Methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one

N ¹ -methyl-4-nitrobenzene-1, 2-diamine (1 g,6 mmol) was dissolved in tetrahydrofuran (20 mL), N' -carbonyldiimidazole (973 mg,6 mmol) was added and the mixture stirred overnight at 65 ℃. The reaction was filtered and the filter cake dried to give the title compound (1.16 g, dark grey solid), yield: 100%. MS (ESI) m/z 194.0[ M+H ] ⁺.

(2) 3- (4, 4-Difluorocyclohexyl) -1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one

1-Methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (1.1 g,5.7 mmol) was dissolved in N, N-dimethylformamide (30 mL), 4-difluorocyclohexyl methanesulfonate (2.4 g,11.4mmol, example 2, step 1) and cesium carbonate (5.57 g,17.1 mmol) were added and the mixture stirred overnight at 100deg.C. To the reaction solution was added water (80 mL), and the aqueous phase was extracted with ethyl acetate (80 ml×2). The organic phases were combined, washed with saturated sodium chloride solution (100 ml x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (550 mg, yellow solid), yield ：31％.MS(ESI):m/z 312.0[M+H-20]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.17(d,J＝2.0Hz,1H),8.07(dd,J＝8.8Hz,2.0Hz,1H),7.36(d,J＝8.4Hz,1H),4.61-4.55(m,1H),3.39(s,3H),2.47-1.83(m,8H).

(3) 5-Amino-3- (4, 4-difluorocyclohexyl) -1-methyl-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one

3- (4, 4-Difluorocyclohexyl) -1-methyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (300 mg,0.96 mmol) was dissolved in methanol (20 mL), 10% wet palladium on charcoal (80 mg) was added to replace hydrogen three times, and stirring was performed at room temperature for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated to give the title compound (250 mg, beige oil), yield: 92%. MS (ESI) m/z 282.1[ M+H ] ⁺.

(4) N- (3- (4, 4-difluorocyclohexyl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

5-Amino-3- (4, 4-difluorocyclohexyl) -1-methyl-1, 3-dihydro-2H-benzo [ d ] imidazol-2-one (250 mg,0.89 mmol) and intermediate 1 (318 mg,0.89 mmol) were dissolved in N, N-dimethylformamide (5 mL), HATU (676 mg,1.78 mmol) and N, N-diisopropylethylamine (514 mg,4.45 mmol) were added and stirred at room temperature overnight. The reaction was purified by reverse phase column to give the title compound (250 mg, yellow solid), yield: 45%. MS (ESI) m/z 620.9[ M+H ] ⁺.

(5) N- (3- (4, 4-difluorocyclohexyl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (3- (4, 4-difluorocyclohexyl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (100 mg,0.16 mmol) was dissolved in 1, 4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (40 mg,0.32 mmol), xphos (31 mg,0.064 mmol), tris (dibenzylideneacetone) dipalladium (29 mg,0.032 mmol), and cesium carbonate (104 mg,0.32 mmol) were added sequentially. The mixture was heated to 90 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1 to methylene chloride/methanol=20/1) to give a crude product, which was further purified by Prep-HPLC to give the title compound (4.4 mg, white solid), yield ：4.4％.MS(ESI):m/z 618.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.57(s,1H),9.97(brs,1H),7.84-7.82(m,2H),7.43(dd,J＝8.4,1.6Hz,1H),7.18-7.15(m,2H),7.02(dd,J＝8.4,1.6Hz,1H),4.96(brs,1H),4.49-4.41(m,1H),3.76(t,J＝6.4Hz,2H),3.38-3.32(m,2H),3.31(s,3H),2.98(t,J＝4.8Hz,4H),2.46-2.38(m,2H),2.19-2.09(m,4H),1.84-1.81(m,2H),1.58-1.50(m,4H),0.34(s,4H).

Example 37

N- (1- (cyclopropylmethyl) -1H-indazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

According to the method of example 33, starting with 3-nitro-1H-indazole and (bromomethyl) cyclopropane, the title compound (23.0 mg, white solid) was obtained by a similar procedure ).MS(ESI):m/z 524.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.72(s,1H),10.17(s,1H),8.11(d,J＝8.0Hz,1H),8.03(d,J＝8.0Hz,1H),7.65(d,J＝9.6Hz,1H),7.38(t,J＝8.0Hz,1H),7.26(d,J＝2.0Hz,1H),7.13-7.07(m,2H),4.96(s,1H),4.24(d,J＝7.2Hz,2H),3.77(t,J＝6.4Hz,2H),3.38-3.36(m,2H),3.03(t,J＝4.8Hz,4H),1.76-1.60(m,4H),1.28-1.24(m,1H),0.51-0.50(m,2H),0.44-0.43(m,2H),0.38(s,4H).

Example 38

N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-indazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 1- ((3, 3-Difluorocyclobutyl) methyl) -3-nitro-1H-indazole

Methyl (3, 3-difluorocyclobutyl) methanesulfonate (300 mg,1.5mmol, example 27, step 1) and 3-nitro-1H-indazole (270 mg,1.6 mmol) were dissolved in N, N-dimethylformamide (10 mL), cesium carbonate (1.5 g,4.5 mmol) was added and the mixture was heated to 100deg.C under nitrogen and stirred overnight. To the reaction solution was added water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (40 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to give the title compound (200 mg, pale yellow solid), yield ：50％.MS(ESI):m/z 268.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.16(d,J＝8.0Hz,1H),8.05(d,J＝8.8Hz,1H),7.69-7.65(m,1H),7.58-7.54(m,1H),4.77(d,J＝7.2Hz,2H),2.80-2.51(m,5H).

(2) 1- ((3, 3-Difluorocyclobutyl) methyl) -1H-indazol-3-amine

1- ((3, 3-Difluorocyclobutyl) methyl) -3-nitro-1H-indazole (110 mg,0.4 mmol) was dissolved in methanol (5 mL), 10% wet palladium on charcoal (11 mg) was added, and the mixture was reacted at room temperature under hydrogen protection for 2 hours. The reaction solution was filtered and concentrated to give the title compound (90 mg, yellow solid), yield: 92%. MS (ESI) m/z 238.1[ M+H ] ⁺.

(3) N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-indazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1- ((3, 3-Difluorocyclobutyl) methyl) -1H-indazol-3-amine (90 mg,0.4 mmol) and intermediate 1 (143 mg,0.4 mmol) were dissolved in N, N-dimethylformamide (10 mL), HATU (304 mg,0.8 mmol) and N, N-diisopropylethylamine (155 mg,1.2 mmol) were added and stirred overnight at room temperature. To the reaction solution was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=15/1) to give the title compound (160 mg, yellow solid), yield: 73%. MS (ESI) m/z 577.0[ M+H ] ⁺.

(4) N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-indazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-indazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (160 mg,0.28 mmol) was dissolved in1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (35 mg,0.28 mmol), cesium carbonate (2793 mg,0.84 mmol), tris (dibenzylideneacetone) dipalladium (13 mg,0.014 mmol) and Xphos (14 mg,0.028 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by Prep-HPLC to give the title compound (8.7 mg, white solid) in yield ：5％.MS(ESI):m/z574.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.97(s,1H),10.14(s,1H),8.20(d,J＝8.0Hz,1H),8.06(d,J＝8.4Hz,1H),7.64(d,J＝8.4Hz,1H),7.43-7.39(m,1H),7.27(d,J＝2.4Hz,1H),7.14-7.09(m,2H),4.92(s,1H),4.48(d,J＝5.2Hz,2H),3.78(t,J＝6.4Hz,2H),3.42-3.38(m,2H),3.02(t,J＝5.2Hz,4H),2.69-2.54(m,5H),1.69-1.65(m,4H),0.38(s,4H).

Example 39

N- (1- ((3, 3-difluorocyclobutyl) methyl) -5-methyl-1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] octane-6-yl) benzamide

(1) 1- ((3, 3-Difluorocyclobutyl) methyl) -5-methyl-3-nitro-1H-pyrazole

Methyl (3, 3-difluorocyclobutyl) methanesulfonate (1.2 g,5.5mmol, example 27, step 1) and 5-methyl-3-nitro-1H-pyrazole (700 mg,5.5 mmol) were dissolved in N, N-dimethylformamide (12 mL), cesium carbonate (5.4 g,16.5 mmol) was added and the mixture was heated to 100deg.C under nitrogen and stirred overnight. To the reaction mixture was added water (50 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (560 mg, pale yellow solid), yield ：44％.MS(ESI):m/z 232.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ6.86(s,1H),4.30(d,J＝5.2Hz,2H),2.70-2.65(m,3H),2.48-2.41(m,2H),2.36(s,3H).

(3) 1- ((3, 3-Difluorocyclobutyl) methyl) -5-methyl-1H-pyrazol-3-amine

1- ((3, 3-Difluorocyclobutyl) methyl) -5-methyl-3-nitro-1H-pyrazole (300 mg,1.3 mmol) was dissolved in a mixed solvent of methanol/water (8 mL/4 mL), iron powder (218 mg,3.9 mmol) and ammonium chloride (209 mg,3.9 mmol) were added, and the mixture was heated to 80℃under nitrogen protection and stirred for 2 hours. To the reaction mixture was added saturated brine (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (217 mg, red-brown oil), yield: 83%. MS (ESI) m/z 202.0[ M+H ] ⁺.

(4) N- (1- ((3, 3-difluorocyclobutyl) methyl) -5-methyl-1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1- ((3, 3-Difluorocyclobutyl) methyl) -5-methyl-1H-pyrazol-3-amine (217 mg,1.1 mmol) and intermediate 1 (308 mg,0.87 mmol) were dissolved in N, N-dimethylformamide (8 mL), HATU (837 mg,2.2 mmol) and N, N-diisopropylethylamine (426 mg,3.3 mmol) were added and the mixture stirred at room temperature overnight. To the reaction solution was added water (30 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (10 ml×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (400 mg, white solid), yield: 67%. MS (ESI) m/z 541.1[ M+H ] ⁺.

(5) N- (1- ((3, 3-difluorocyclobutyl) methyl) -5-methyl-1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] octane-6-yl) benzamide

N- (1- ((3, 3-difluorocyclobutyl) methyl) -5-methyl-1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (200 mg,0.37 mmol) was dissolved in 1, 4-dioxane (8 mL), and 2-hydroxyethanesulfonamide (139 mg,1.11 mmol), xphos (37 mg,0.075 mmol), tris (dibenzylideneacetone) dipalladium (34 mg,0.037 mmol) and cesium carbonate (361 mg,1.11 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (100% ethyl acetate) to give a crude product, which was further purified by Prep-HPLC to give the title compound (21 mg, white solid), yield ：10.6％.MS(ESI):m/z 538.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.57(s,1H),10.15(s,1H),7.97(d,J＝8.8Hz,1H),7.20(d,J＝2.0Hz,1H),7.07(dd,J＝8.8,2.0Hz,1H),6.44(s,1H),4.96(s,1H),4.07(d,J＝5.6Hz,2H),3.75(t,J＝6.4Hz,2H),3.32-3.27(m,2H),2.94(t,J＝4.8Hz,4H),2.67-2.55(m,4H),2.46-2.41(m,1H),2.26(s,3H),1.67-1.60(m,4H),0.37(s,4H).

Example 40

N- (1- (4, 4-difluorocyclohexyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the synthesis of example 26, starting with 4, 4-difluorocyclohexyl methanesulfonate (step 1 of example 2) and 3-nitro-1H-pyrazolo [3,4-b ] pyridine, the title compound (59.2 mg, white solid) was obtained by similar procedures ).MS(ESI):m/z 589.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.56(s,1H),10.22(brs,1H),8.78(dd,J＝8.0,1.2Hz,1H),8.55(dd,J＝4.8,2.0Hz,1H),8.08(d,J＝8.4Hz,1H),7.28(d,J＝1.2Hz,1H),7.24-7.20(m,1H),7.15(dd,J＝8.4,2.0Hz,1H),5.12(s,1H),4.96(brs,1H),3.77(t,J＝6.0Hz,2H),3.44-3.38(m,2H),3.02(t,J＝4.8Hz,4H),2.28-2.05(m,8H),1.78-1.66(m,4H),0.39(s,4H).

Example 41

N- (8-Cyclopropylimidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 8-Cyclopropyl-6-nitroimidazo [1,2-a ] pyridine

8-Bromo-6-nitroimidazo [1,2-a ] pyridine (500 mg,2.07mmol, example 11, step 1) is dissolved in toluene (10 mL), and cyclopropylboronic acid (266 mg,3.10 mmol), triphenylphosphine (54 mg,0.21 mmol), tris (dibenzylideneacetone) dipalladium (95 mg,0.10 mmol) and potassium carbonate (857 mg,6.20 mmol) are added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred for 12 hours. The reaction mixture was filtered through celite, and water (20 mL) was added to the filtrate, followed by extraction with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (170 mg, yellow solid), yield: 40%. MS (ESI) m/z 204.0[ M+H ] ⁺.

(2) 8-Cyclopropylimidazo [1,2-a ] pyridin-6-amine

8-Cyclopropyl-6-nitroimidazo [1,2-a ] pyridine (170 mg,0.84 mmol) was dissolved in absolute ethanol (5 mL), 20% wet palladium on carbon (34 mg) was added, the reaction solution was replaced with hydrogen 3 times, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through celite and concentrated to give the title compound (80 mg, pale yellow solid), yield: 55%. MS (ESI) m/z 174.0[ M+H ] ⁺.

(3) N- (8-Cyclopropylimidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8-Cyclopropylimidazo [1,2-a ] pyridin-6-amine (80 mg,0.46 mmol) and intermediate 1 (214 mg,0.66 mmol) were dissolved in dichloromethane (10 mL), HATU (264 mg,0.69 mmol) and N, N-diisopropylethylamine (180 mg,1.39 mmol) were added and the reaction stirred at room temperature for 12 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate (30 mL) and the aqueous phase was extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (30 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (211 mg, white solid), yield: 89%. MS (ESI) m/z 512.9[ M+H ] ⁺.

(4) N- (8-Cyclopropylimidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8-Cyclopropylimidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (200 mg,0.39 mmol) was dissolved in 1, 4-dioxane (10 mL), and 2-hydroxyethanesulfonamide (59 mg,0.47 mmol), xphos (9 mg,0.02 mmol), tris (dibenzylideneacetone) dipalladium (36 mg,0.04 mmol) and cesium carbonate (382 mg,1.17 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (6.8 mg, white solid) in yield ：3.4％.MS(ESI):m/z 510.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.66(s,1H),9.23(d,J＝5.6Hz,1H),8.02(d,J＝3.6Hz,1H),7.76(d,J＝8.4Hz,1H),7.51(d,J＝2.0Hz,1H),7.10(d,J＝2.0Hz,1H),6.97(dd,J＝8.0,1.6Hz,1H),6.76(d,J＝1.6Hz,1H),3.75(t,J＝6.8Hz,2H),3.25-3.20(m,2H),2.96(t,J＝5.2Hz,4H),2.34-2.31(m,1H),1.57-1.50(m,4H),1.12-1.08(m,2H),0.97-0.92(m,2H),0.36(s,4H).

Example 42

N- (8- (6, 6-difluoro-3-azabicyclo [3.1.0] hexane-3-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the synthesis of example 28, starting with tert-butyl (8-bromoimidazo [1,2-a ] pyridin-6-yl) (tert-butoxycarbonyl) carbamate (example 11, step 3) and 6, 6-difluoro-3-azabicyclo [3.1.0] hexane hydrochloride, the title compound (2 mg, pale yellow solid) is obtained by similar procedures ).MS(ESI):m/z 587.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.79(s,1H),8.83(d,J＝1.2Hz,1H),7.93(d,J＝1.2Hz,1H),7.78(d,J＝8.4Hz,1H),7.40(d,J＝1.2Hz,1H),7.10(s,1H),6.97(d,J＝6.8Hz,1H),6.00(s,1H),4.27(d,J＝10.0Hz,2H),3.91(d,J＝10.4Hz,2H),3.75(t,J＝6.4Hz,2H),3.26-3.24(m,2H),2.97(t,J＝5.2Hz,4H),2.75-2.69(m,2H),1.62-1.57(m,4H),0.37(s,4H).

Example 43

N- (1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl) -4- ((2-hydroxyethyl) sulfamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the synthesis of example 38, using methyl (3, 3-difluorocyclobutyl) methanesulfonate (example 27, step 1) and 3-nitro-1H-pyrazolo [3,4-b ] pyridine as starting materials, the title compound (14.0 mg, white solid) was obtained by similar procedures ).MS(ESI):m/z 575.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.38(s,1H),10.20(brs,1H),8.77(dd,J＝8.4,1.2Hz,1H),8.55(dd,J＝4.4,1.2Hz,1H),8.07(d,J＝8.4Hz,1H),7.27(d,J＝1.6Hz,1H),7.21(dd,J＝8.4Hz,4.4Hz,1H),7.12(dd,J＝8.8Hz,1.6Hz,1H),4.97(brs,1H),4.55(d,J＝6.0Hz,2H),3.77(t,J＝6.0Hz,2H),3.35(t,J＝6.4Hz,2H),3.02(t,J＝5.2Hz,4H),2.77-2.60(m,4H),2.59-2.54(m,1H),1.75-1.62(m,4H),0.39(s,4H).

Example 44

N- (3-cyclopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5-Bromo-1-methyl-1H-pyrazolo [3,4-b ] pyridine

5-Bromo-1H-pyrazolo [3,4-b ] pyridine (1.50 g,7.5 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (7.41 g,22.5 mmol) and methyl iodide (3.17 g,22.5 mmol) were added and the mixture was stirred at 30℃for 1 hour. To the reaction solution was added water (200 mL), and the aqueous phase was extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (80 ml x 3), dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.50 g, grey solid), yield: 94%. MS (ESI) m/z 211.9[ M+H ] ⁺.

(2) (1-Methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) carbamic acid tert-butyl ester

5-Bromo-1-methyl-1H-pyrazolo [3,4-b ] pyridine (1.00 g,4.7 mmol) and tert-butyl carbamate (1.65 g,14.1 mmol) were dissolved in 1, 4-dioxane (10 mL), xphos (4475 mg,0.93 mmol), tris (dibenzylideneacetone) dipalladium (430 mg,0.47 mmol) and cesium carbonate (4.61 g,14.1 mmol) were added sequentially and the mixture was heated to 100deg.C under nitrogen and stirred overnight. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (700 mg, yellow solid), yield: 60%. MS (ESI) m/z 249.1[ M+H ] ⁺.

(3) (3-Iodo-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) carbamic acid tert-butyl ester

Tert-butyl (1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) carbamate (700 mg,2.82 mmol) was dissolved in N, N-dimethylformamide (10 mL), elemental iodine (1.07 g,4.23 mmol) and potassium hydroxide (284 mg,7.05 mmol) were added and the mixture stirred at 100deg.C overnight. To the reaction mixture was added water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (50 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (700 mg, grey solid), yield: 66%. MS (ESI) m/z 375.1[ M+H ] ⁺.

(4) (3-Cyclopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) carbamic acid tert-butyl ester

Tert-butyl (3-iodo-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) carbamate (700 mg,1.87 mmol) and cyclopropylboronic acid (480 mg,5.61 mmol) were dissolved in a mixed solvent of 1, 4-dioxane/water (10 mL/1 mL), and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (163 mg,0.2 mmol) and potassium carbonate (178 mg,5.6 mmol) were added. The mixture was heated to 70 ℃ under nitrogen and stirred overnight. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound (165 mg, black oil), yield: 30%. MS (ESI) m/z 289.0[ M+H ] ⁺.

(5) 3-Cyclopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-amine

Tert-butyl (3-cyclopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) carbamate (165 mg,0.57 mmol) was added to a 30% solution of trifluoroacetic acid in dichloromethane (5 mL) and stirred at room temperature for 1 hour. To the reaction mixture was added saturated sodium bicarbonate (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (100 mg, black oil), yield: 91%. MS (ESI) m/z 189.0[ M+H ] ⁺.

(6) N- (3-cyclopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

3-Cyclopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-amine (165 mg,0.87 mmol) and intermediate 1 (284 mg,0.8 mmol) are dissolved in N, N-dimethylformamide (5 mL), N-diisopropylethylamine (516 mg,4.0 mmol) and HATU (608 mg,1.6 mmol) are added and stirred at room temperature for 2 hours. To the reaction mixture was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (50 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound (70 mg, yellow solid), yield: 15%. MS (ESI) m/z 527.9[ M+H ] ⁺.

(7) N- (3-cyclopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (3-cyclopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (70 mg,0.13 mmol) was dissolved in 1, 4-dioxane solution (5 mL), followed by 2-hydroxyethanesulfonamide (25 mg,0.2 mmol), xphos (19 mg,0.04 mmol), tris (dibenzylideneacetone) dipalladium (18 mg,0.02 mmol) and cesium carbonate (65 mg,0.2 mmol). The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction was concentrated and the residue was purified by Prep-HPLC to give the title compound (14.3 mg, white solid) in yield ：31％.MS(ESI):m/z 525.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.04(s,1H),8.79(d,J＝2.4Hz,1H),8.63(d,J＝2.4Hz,1H),7.77(d,J＝8.8Hz,1H),7.03(s,1H),6.88(d,J＝8.8Hz,1H),6.03(brs,1H),3.94(s,3H),3.75-3.72(m,2H),3.18-3.12(m,2H),2.99-2.95(m,4H),2.30-2.22(m,1H),1.58-1.51(m,4H),1.05-1.93(m,4H),0.36(s,4H).

Example 45

N- (1- ((3, 3-difluorocyclobutyl) methyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (5- (trifluoromethyl) -1H-pyrazol-3-yl) benzamide

5- (Trifluoromethyl) -1H-pyrazol-3-amine (100 mg,0.66 mmol) and intermediate 1 (284 mg,0.79 mmol) were dissolved in dichloromethane (10 mL), HATU (377 mg,0.99 mmol) and N, N-diisopropylethylamine (257 mg,1.99 mmol) were added, and stirred at room temperature for 12 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate (30 mL) and the aqueous phase was extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (30 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give the title compound (190 mg, white solid), yield: 58%. MS (ESI) m/z 490.8[ M+H ] ⁺.

(2) N- (1- ((3, 3-difluorocyclobutyl) methyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (5- (trifluoromethyl) -1H-pyrazol-3-yl) benzamide (190 mg,0.39 mmol) was dissolved in N, N-dimethylformamide (10 mL), methyl (3, 3-difluorocyclobutyl) methanesulfonate (116 mg,0.58mmol, example 27, step 1) and cesium carbonate (379 mg,1.16 mmol) were added and the mixture was heated to 100℃under nitrogen protection and stirred overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=9/1) to give the title compound (55 mg, white solid), yield ：24％.MS(ESI):m/z 594.8[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.12(s,1H),7.78(d,J＝1.2Hz,1H),7.73(d,J＝8.0Hz,1H),7.69(dd,J＝8.4Hz,1.6Hz,1H),7.13(s,1H),4.32(d,J＝5.4Hz,2H),3.01(t,J＝5.6Hz,4H),2.75-2.54(m,5H),1.67-1.54(m,4H),0.37(s,4H).

(3) N- (1- ((3, 3-difluorocyclobutyl) methyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- ((3, 3-difluorocyclobutyl) methyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (50 mg,0.08 mmol) was dissolved in 1, 4-dioxane (10 mL), and 2-hydroxyethanesulfonamide (16 mg,0.13 mmol), xphos (8.0 mg,0.02 mmol), tris (dibenzylideneacetone) dipalladium (7.7 mg,0.01 mmol) and cesium carbonate (82 mg,0.25 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (7.7 mg, white solid) in yield ：16％.MS(ESI):m/z 592.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.21(s,1H),7.98(d,J＝8.4Hz,1H),7.23(d,J＝2.0Hz,1H),7.13(s,1H),7.09(dd,J＝8.8,2.0Hz,1H),4.31(d,J＝6.0Hz,2H),3.75(t,J＝6.8Hz,2H),3.34-3.32(m,2H),2.96(t,J＝5.2Hz,4H),2.72-2.56(m,5H),1.70-1.60(m,4H),0.39(s,4H).

Example 46

N- (5-cyclopropyl-1- ((3, 3-difluorocyclobutyl) methyl) -1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] octane-6-yl) benzamide

With reference to the synthetic method of example 45, starting from 5-cyclopropyl-1H-pyrazol-3-amine and intermediate 1, a similar procedure was followed to give the title compound (10.9 mg, white solid ).MS(ESI):m/z 564.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.62(s,1H),7.95(d,J＝8.4Hz,1H),7.20(d,J＝2.0Hz,1H),7.06(dd,J＝8.8Hz,2.0Hz,1H),6.25(s,1H),4.22(d,J＝5.6Hz,2H),3.75(t,J＝6.8Hz,2H),3.38-3.33(m,2H),2.93(t,J＝4.8Hz,4H),2.69-2.55(m,5H),1.94-1.86(m,1H),1.74-1.54(m,4H),0.99-0.94(m,2H),0.67-0.64(m,2H),0.37(s,4H).

Example 47

N- (1- ((3, 3-difluorocyclobutyl) methyl) -4-fluoro-5-methyl-1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 4-Fluoro-5-methyl-3-nitro-1H-pyrazole

5-Methyl-3-nitro-1H-pyrazole (2 g,15.75 mmol) and SelectFluor reagent (13.9 g,39.38 mmol) were dissolved in acetonitrile (60 mL) and reacted under stirring at 80℃under reflux for 5 days. The reaction was concentrated, then water (100 mL) was added and the aqueous phase was extracted with ethyl acetate (70 mL. Times.3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by Prep-HPLC gave the title compound (250 mg, yellow solid), yield: 11%. MS (ESI) m/z 145.8[ M+H ] ⁺.

(2) 1- ((3, 3-Difluorocyclobutyl) methyl) -4-fluoro-5-methyl-3-nitro-1H-pyrazole

4-Fluoro-5-methyl-3-nitro-1H-pyrazole (200 mg,1.4 mmol), (3, 3-difluorocyclobutyl) methanesulfonate (560 mg,2.8mmol, example 27, step 1) and cesium carbonate (1.37 g,4.2 mmol) were dissolved in N, N-dimethylformamide (10 mL) and the mixture was stirred at 100deg.C overnight. The reaction was concentrated, water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (230 mg, yellow solid), yield ：67％.MS(ESI):m/z 249.8[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ4.32-4.30(m,2H),2.70-2.60(m,3H),2.48-2.38(m,2H),2.33(s,3H).

(3) 1- ((3, 3-Difluorocyclobutyl) methyl) -4-fluoro-5-methyl-1H-pyrazol-3-amine

1- ((3, 3-Difluorocyclobutyl) methyl) -4-fluoro-5-methyl-3-nitro-1H-pyrazole (230 mg,0.92 mmol) was dissolved in absolute ethanol (15 mL), 20% palladium on charcoal (46 mg) was added, the system was replaced with hydrogen gas 3 times, and the reaction was stirred at room temperature for 1 hour. The reaction solution was filtered through celite and concentrated to give the title compound (200 mg, yellow oil), yield: 99%. MS (ESI) m/z 219.9[ M+H ] ⁺.

(4) N- (1- ((3, 3-difluorocyclobutyl) methyl) -4-fluoro-5-methyl-1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (196 mg,0.55 mmol) was dissolved in N, N-dimethylformamide (5 mL), HATU (518 mg,1.36 mmol) and N, N-diisopropylethylamine (439 mg,3.4 mmol) were added and stirred at room temperature for 10 min, then 1- ((3, 3-difluorocyclobutyl) methyl) -4-fluoro-5-methyl-1H-pyrazol-3-amine (150 mg,0.68 mmol) was added and the reaction continued at room temperature with stirring overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate (40 mL) and the aqueous phase was extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (225 mg, yellow solid), yield: 59%. MS (ESI) m/z 559.0[ M+H ] ⁺.

(5) N- (1- ((3, 3-difluorocyclobutyl) methyl) -4-fluoro-5-methyl-1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (1- ((3, 3-difluorocyclobutyl) methyl) -4-fluoro-5-methyl-1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (100 mg,0.18 mmol) was dissolved in 1, 4-dioxane (3 mL), 2-hydroxyethanesulfonamide (27.5 mg,0.22 mmol), xphos (33 mg,0.07 mmol), tris (dibenzylideneacetone) dipalladium (33 mg,0.04 mmol) and cesium carbonate (117 mg,0.36 mmol) were added in sequence, and the mixture was heated to 90℃under nitrogen protection overnight with stirring. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give a crude product. The crude product was further purified by Prep-HPLC to give the title compound (30 mg, white solid) in yield ：30％.MS(ESI):m/z 556.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.86(s,1H),7.85(d,J＝8.4Hz,1H),7.16(d,J＝2.0Hz,1H),7.02(dd,J＝8.8Hz,2.0Hz,1H),4.08(d,J＝6.4Hz,2H),3.75(t,J＝6.8Hz,2H),3.31-3.29(m,2H),2.95(t,J＝5.2Hz,4H),2.68-2.55(m,4H),2.45-2.42(m,1H),2.24(s,3H),1.64-1.53(m,4H),0.35(s,4H).

Example 48

N- (8- (3, 3-difluorocyclobutoxy) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5-Bromo-3- (3, 3-difluorocyclobutoxy) -2-nitropyridine

5-Bromo-3-fluoro-2-nitropyridine (2 g,9.05 mmol) and 3, 3-difluorocyclobutan-1-ol (1.03 g,9.51 mmol) were dissolved in N, N-dimethylformamide (55 mL), sodium hydride (1.9 g,27.15mmol, 60%) was added in portions under ice-salt bath conditions, and the reaction was stirred under these conditions for 10 minutes. The reaction was poured into ice water (50 mL) and quenched, and the aqueous phase was extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (100 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=9/1) to give the title compound (2.2 g, pale yellow solid), yield: 78.6%. MS (ESI) m/z 308.8[ M+H ] ⁺.

(2) 5-Bromo-3- (3, 3-difluorocyclobutoxy) pyridin-2-amine

5-Bromo-3- (3, 3-difluorocyclobutoxy) -2-nitropyridine (2.2 g,7.2 mmol) was dissolved in tetrahydrofuran/water (80 mL/20 mL), reduced iron powder (2.0 g,35.6 mmol) and ammonium chloride (2.0 g,35.6 mmol) were added and the mixture was heated to 80℃and stirred for 12 hours. The reaction was filtered hot through celite, the filter cake was rinsed with ethyl acetate (100 mL) and the filtrate was concentrated to give the title compound (2.0 g, brown solid). MS (ESI) m/z 278.8[ M+H ] ⁺.

(3) 6-Bromo-8- (3, 3-difluorocyclobutoxy) imidazo [1,2-a ] pyridine

5-Bromo-3- (3, 3-difluorocyclobutoxy) pyridin-2-amine (2.0 g,7.17 mmol) and 2-bromo-1, 1-diethoxyethane (4.22 g,21.5 mmol) were dissolved in ethanol/water (50 mL/50 mL), the pH was adjusted to about 4 with 1N HCl, and the reaction mixture was heated to 80℃and stirred for 72 hours before it became clear. The reaction was neutralized with saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (200 ml x 3), dried over anhydrous sodium sulfate and concentrated to give the title compound (2.7 g, brown oil). MS (ESI) m/z 302.6[ M+H ] ⁺.

(4) (8- (3, 3-Difluorocyclobutoxy) imidazo [1,2-a ] pyridin-6-yl) carbamic acid tert-butyl ester

6-Bromo-8- (3, 3-difluorocyclobutoxy) imidazo [1,2-a ] pyridine (2.7 g,7.17 mmol) and tert-butyl carbamate (3.4 g,28.68 mmol) are dissolved in 1, 4-dioxane (80 mL), and Xphos (0.72 g,1.44 mmol), tris (dibenzylideneacetone) dipalladium (0.66 g,0.72 mmol) and cesium carbonate (7.2 g,21.6 mmol) are added. The mixture was heated to 90 ℃ under nitrogen for 48 hours. The reaction was filtered through celite, the filter cake was rinsed with ethyl acetate (50 mL) and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give the title compound (450 mg, yellow-green oil), yield: 18.4%. MS (ESI) m/z 340.0[ M+H ] ⁺.

(5) 8- (3, 3-Difluorocyclobutoxy) imidazo [1,2-a ] pyridin-6-amine

Tert-butyl (8- (3, 3-difluorocyclobutoxy) imidazo [1,2-a ] pyridin-6-yl) carbamate (450 mg,1.33 mmol) is dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) is added dropwise and reacted at room temperature for 1 hour. The reaction solution was concentrated to give the title compound (320 mg, brown oil). MS (ESI) m/z 239.9[ M+H ] ⁺.

(6) N- (8- (3, 3-difluorocyclobutoxy) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (477 mg,1.33 mmol) was dissolved in N, N-dimethylformamide (2 mL), HATU (760 mg,2.00 mmol) was added, N, N-diisopropylethylamine (517mg, 3.99 mmol) was stirred for 0.5 hours, a solution of 8- (3, 3-difluorocyclobutoxy) imidazo [1,2-a ] pyridin-6-amine (320 mg,1.33 mmol) in N, N-dimethylformamide (2 mL) was neutralized with N, N-diisopropylethylamine, and then added dropwise to the reaction mixture, and the mixture was reacted at 40℃for 12 hours. The reaction was poured into water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (200 mg, brown oil), yield: 28.6%. MS (ESI) m/z 578.9[ M+H ] ⁺.

(7) N- (8- (3, 3-difluorocyclobutoxy) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (3, 3-difluorocyclobutoxy) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (200 mg,0.35 mmol) was dissolved in 1, 4-dioxane (10 mL), 2-hydroxyethanesulfonamide (143 mg,1.14 mmol), tris (dibenzylideneacetone) dipalladium (110 mg,0.12 mmol), xphos (115 mg,0.23 mmol) and cesium carbonate (1115 mg,3.43 mmol) were added sequentially. The mixture was heated to 80 ℃ under nitrogen and reacted overnight. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (7.7 mg, white powder) in yield ：3.9％.MS(ESI):m/z 576.1[M+H]⁺.¹H NMR(400MHz,CD₃OD)δ9.43(d,J＝1.6Hz,1H),8.29(d,J＝2.0Hz,1H),8.04-8.01(m,2H),7.32(d,J＝2.4Hz,1H),7.23(d,J＝1.2Hz,1H),7.15(dd,J＝8.8,2.4Hz,1H),5.14-5.11(m,1H),3.95(t,J＝6.4Hz,2H),3.39-3.34(m,4H),3.12(t,J＝4.8Hz,4H),3.60-2.99(m,2H),1.70-1.66(m,4H),0.46(s,4H).

Example 49

N- (1- ((3, 3-difluorocyclobutyl) methyl) -4, 5-dimethyl-1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 4-Bromo-1- ((3, 3-difluorocyclobutyl) methyl) -5-methyl-3-nitro-1H-pyrazole

Referring to example 47, step 2, starting with 4-bromo-5-methyl-3-nitro-1H-pyrazole (1.0 g,4.85 mmol) and methyl (3, 3-difluorocyclobutyl) methanesulfonate (1.46 g,7.28mmol, example 27, step 1), the title compound (1.44 g, yellow oil) was obtained in the yield: 95%. MS (ESI) m/z 309.8[ M+H ] ⁺.

(2) 1- ((3, 3-Difluorocyclobutyl) methyl) -4, 5-dimethyl-3-nitro-1H-pyrazole

4-Bromo-1- ((3, 3-difluorocyclobutyl) methyl) -5-methyl-3-nitro-1H-pyrazole (1.44 g,4.64 mmol) was dissolved in 1, 4-dioxane (20 mL), trimethylcyclotriboroxane (1.75 g,13.93 mmol), tetrakis (triphenylphosphine) palladium (537 mg,0.46 mmol) and cesium carbonate (3.03 g,9.29 mmol) were added and the mixture was heated to 110℃under nitrogen protection and stirred for 4 hours. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=9/1) to give the title compound (168 mg, yellow solid), yield: 15%. MS (ESI) m/z 246.0[ M+H ] ⁺.

(3) 1- ((3, 3-Difluorocyclobutyl) methyl) -4, 5-dimethyl-1H-pyrazol-3-amine

Referring to the procedure in example 47, step 3, starting from 1- ((3, 3-difluorocyclobutyl) methyl) -4, 5-dimethyl-3-nitro-1H-pyrazole (168 mg,0.69 mmol) was obtained the title compound (130 mg, yellow solid), yield: 90%. MS (ESI) M/z216.0[ M+H ] ⁺.

(4) N- (1- ((3, 3-difluorocyclobutyl) methyl) -4, 5-dimethyl-1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the procedure in example 47, step 4, starting from 1- ((3, 3-difluorocyclobutyl) methyl) -4, 5-dimethyl-1H-pyrazol-3-amine (130 mg,0.60 mmol) and intermediate 1 (324 mg,0.91 mmol), the title compound (270 mg, white solid) was obtained in yield: 81%. MS (ESI) m/z 555.0[ M+H ] ⁺.

(5) N- (1- ((3, 3-difluorocyclobutyl) methyl) -4, 5-dimethyl-1H-pyrazol-3-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Reference to the method of example 47, step 5, starting with N- (1- ((3, 3-difluorocyclobutyl) methyl) -4, 5-dimethyl-1H-pyrazol-3-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (250 mg,0.45 mmol), gave the title compound (14.9 mg, white solid) in yield ：6％.MS(ESI):m/z 552.1[M+H]⁺.¹H NMR(400 MHz,DMSO-d₆)δ11.74(s,1H),7.83(d,J＝8.4 Hz,1H),7.08(d,J＝1.6 Hz,1H),6.93(dd,J＝8.8 Hz,1.6 Hz,1H),4.08(d,J＝6.4 Hz,2H),3.73(t,J＝9.2 Hz,2H),3.22(t,J＝6.8 Hz,2H),2.95(t,J＝5.2 Hz,4H),2.70-2.54(m,5H),2.17(s,3H),1.86(s,3H),1.63-1.53(m,4H),0.34(s,4H).

Example 50

N- (8- (4, 4-difluorocyclohexyl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) (Tert-Butoxycarbonyl) (8- (4, 4-difluorocyclohex-1-en-1-yl) imidazo [1,2-a ] pyridin-6-yl) carbamic acid tert-butyl ester

Tert-butyl (8-bromoimidazo [1,2-a ] pyridin-6-yl) (tert-butoxycarbonyl) carbamate (300 mg,0.73mmol, example 11, step 3) and 2- (4, 4-difluorocyclohex-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (0.53 g,2.19 mmol) are dissolved in1, 4-dioxane/water (10 mL/10 mL) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (104 mg,0.146 mmol) and potassium carbonate (308 mg,2.19 mmol) are added in sequence and the mixture is heated to 90℃under nitrogen protection overnight with stirring. The reaction solution was filtered through celite. The filtrate was concentrated, water (20 mL) was added, and extracted with ethyl acetate (20 mL 3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (300 mg, black oil), yield: 91%. MS (ESI) m/z 450.0[ M+H ] ⁺.

(2) (Tert-Butoxycarbonyl) (8- (4, 4-difluorocyclohexyl) imidazo [1,2-a ] pyridin-6-yl) carbamic acid tert-butyl ester

Tert-butyl (tert-butoxycarbonyl) (8- (4, 4-difluorocyclohex-1-en-1-yl) imidazo [1,2-a ] pyridin-6-yl) carbamate (1.0 g,2.22 mmol) was dissolved in methanol (20 mL), 10% palladium on charcoal (200 mg) was added, the system was replaced 3 times with hydrogen, and the mixture was stirred at room temperature for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to give the title compound (800 mg, white solid), yield: 80%. MS (ESI) m/z 452.0[ M+H ] ⁺.

(3) 8- (4, 4-Difluorocyclohexyl) imidazo [1,2-a ] pyridin-6-amine

The procedure of example 11, step 5, was followed using tert-butyl (tert-butoxycarbonyl) (8- (4, 4-difluorocyclohexyl) imidazo [1,2-a ] pyridin-6-yl) carbamate (800 mg,1.27 mmol) as a starting material to give the title compound (500 mg, yellow oil). MS (ESI) m/z 252.0[ M+H ] ⁺.

(4) N- (8- (4, 4-difluorocyclohexyl) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the procedure of example 11, step 6, starting from 8- (4, 4-difluorocyclohexyl) imidazo [1,2-a ] pyridin-6-amine (500 mg,1.99 mmol) and intermediate 1 (853 mg,2.39 mmol), the title compound (758 mg, yellow solid) is obtained in yield: 65%. MS (ESI) m/z 590.8[ M+H ] ⁺.

(5) N- (8- (4, 4-difluorocyclohexyl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

According to the method of example 11, in step 7, starting with N- (8- (4, 4-difluorocyclohexyl) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (170 mg,0.29 mmol), the title compound (17.5 mg, white solid) was obtained in yield ：11％.MS(ESI):m/z 588.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.74(s,1H),9.30(d,J＝0.8Hz,1H),8.04(s,1H),7.80(d,J＝8.8Hz,1H),7.52(s,1H),7.15(d,J＝1.6Hz,1H),7.11(s,1H),7.03(dd,J＝8.4,1.6Hz,1H),3.76(t,J＝5.6Hz,2H),3.43-3.34(m,2H),2.98(t,J＝4.8Hz,4H),2.20-2.01(m,7H),1.86-1.76(m,2H),1.59-1.51(m,4H),0.35(s,4H). example 51

N- (3-Cyclopropylpyrazolo [1,5-a ] pyrimidin-5-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5-Chloro-3-cyclopropylpyrazolo [1,5-a ] pyrimidine

5-Chloro-3-iodopyrazolo [1,5-a ] pyrimidine (2.0 g,7.19 mmol) and cyclopropylboronic acid (1.85 g,21.57 mmol) were dissolved in 1, 4-dioxane/water (10 mL/10 mL) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (1.05 g,1.44 mmol) and potassium carbonate (2.97 g,21.57 mmol) were added sequentially and the mixture was heated to 90℃under nitrogen and stirred overnight. The reaction was filtered through celite, the filtrate was concentrated, water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (350 mg, black oil), yield: 25%. MS (ESI) M/z193.9[ M+H ] ⁺.

(2) (3-Cyclopropylpyrazolo [1,5-a ] pyrimidin-5-yl) carbamic acid tert-butyl ester

5-Chloro-3-cyclopropylpyrazolo [1,5-a ] pyrimidine (350 mg,1.81 mmol) and tert-butyl carbamate (0.63 g,5.43 mmol) were dissolved in 1, 4-dioxane (10 mL), xphos (351 mg,0.72 mmol), tris (dibenzylideneacetone) dipalladium (329 mg,0.36 mmol) and cesium carbonate (1.77 g,5.43 mmol) were added sequentially, and the mixture was heated to 100deg.C under nitrogen protection and stirred overnight. The reaction was filtered through celite, the filtrate was concentrated, water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1) to give the title compound (300 mg, yellow solid), yield: 60%. MS (ESI) m/z 275.0[ M+H ] ⁺.

(3) 3-Cyclopropyl pyrazolo [1,5-a ] pyrimidin-5-amines

Tert-butyl (3-cyclopropylpyrazolo [1,5-a ] pyrimidin-5-yl) carbamate (300 mg,1.09 mmol) was added to a 30% solution of trifluoroacetic acid in dichloromethane (3 mL) and reacted at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (180 mg, yellow solid), yield: 94%. MS (ESI) m/z 174.8[ M+H ] ⁺.

(4) N- (3-cyclopropylpyrazolo [1,5-a ] pyrimidin-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

3-Cyclopyrazolo [1,5-a ] pyrimidin-5-amine (70 mg,0.40 mmol) and intermediate 1 (136 mg,0.38 mmol) were dissolved in pyridine (10 mL), phosphorus oxychloride (169 mg,1.2 mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 12 hours. The reaction solution was slowly poured into ice water (30 mL) and extracted with ethyl acetate (30 ml×2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (33 mg, white solid), yield: 16%. MS (ESI) m/z 513.8[ M+H ] ⁺.

(5) N- (3-Cyclopropylpyrazolo [1,5-a ] pyrimidin-5-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (3-Cyclopropylpyrazolo [1,5-a ] pyrimidin-5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (33 mg,0.064 mmol) was dissolved in 1, 4-dioxane solution (2 mL), 2-hydroxyethanesulfonamide (24 mg,0.192 mmol), xphos (6 mg,0.0128 mmol), tris (dibenzylideneacetone) dipalladium (6 mg,0.0064 mmol) and cesium carbonate (62 mg,0.192 mmol) were added sequentially, and the mixture was heated to 100deg.C under nitrogen protection and stirred overnight. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (5 mg, white solid) in yield ：15％.MS(ESI):m/z 511.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.72(s,1H),8.94(d,J＝7.6Hz,1H),8.05(d,J＝8.8Hz,1H),7.98(s,1H),7.91(d,J＝7.6Hz,1H),7.24(d,J＝1.6Hz,1H),7.09(dd,J＝8.8,2.0Hz,1H),3.75(t,J＝6.4Hz,2H),3.31-3.29(m,2H),3.01-2.99(m,4H),1.92-1.88(m,1H),1.84-1.62(m,4H),1.00-0.97(m,2H),0.91-0.84(m,2H),0.40(s,4H).

Example 52

4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (3- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-5-yl) benzamide

(1) 5-Chloro-3- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidines

5-Chloro-3-iodopyrazolo [1,5-a ] pyrimidine (1.0 g,3.6 mmol) was dissolved in N, N-dimethylformamide (20 mL), methyl fluorosulfonyl difluoroacetate (6.8 g,36 mmol), hexamethylphosphoric triamide (4.5 g,25.2 mmol) and cuprous iodide (2.8 g,14.4 mmol) were added and the mixture was heated to 80℃under nitrogen and stirred overnight. The reaction was filtered through celite, and the filtrate was diluted with water (60 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated aqueous sodium chloride (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=95/5) to give the title compound (600 mg, white solid), yield: 75.4%. MS (ESI) m/z 221.9[ M+H ] ⁺.

(2) (3- (Trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-5-yl) carbamic acid tert-butyl ester

Referring to the procedure of example 51, step 2, starting from 5-chloro-3- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine (600 mg,2.8 mmol) the title compound (400 mg, light yellow solid) is obtained in the yield: 47.5%. MS (ESI) m/z 246.9[ M+H-56] ⁺.

(3) 3- (Trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-5-amines

The procedure of example 51, step 3, was followed using tert-butyl (3- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-5-yl) carbamate (320 mg,1.1 mmol) as the starting material to give the title compound (222 mg, pale yellow solid). MS (ESI) m/z 202.9[ M+H ] ⁺.

(4) 4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (3- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-5-yl) benzamide

Referring to the procedure of example 51, step 4, starting from 3- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-5-amine (222 mg,1.1 mmol) and intermediate 1 (356 mg,1.0 mmol) the title compound (100 mg, yellow solid) is obtained in yield: 17%. MS (ESI) m/z 541.7[ M+H ] ⁺.

(5) 4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (3- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-5-yl) benzamide

The procedure of example 51, step 5, was followed using 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (3- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-5-yl) benzamide (100 mg,0.18 mmol) as a starting material to give the title compound (23.4 mg, white solid) in yield ：24％.MS(ESI):m/z 539.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ14.43(s,1H),10.30(brs,1H),9.23(d,J＝7.6Hz,1H),8.53(s,1H),8.16(d,J＝7.6Hz,1H),8.11(d,J＝7.6Hz,1H),7.31(s,1H),7.16(d,J＝7.2Hz,1H),4.91(brs,1H),3.76(t,J＝6.4Hz,2H),3.32-3.29(m,2H),3.04-2.96(m,4H),1.92-1.54(m,4H),0.38(s,4H).

Example 53

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4- ((2-hydroxyethyl) sulfamide) benzamide

(1) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2-fluoro-4-iodobenzamide

2- (4, 4-Difluoropiperidin-1-yl) -6-methylpyrimidin-4-amine (500 mg,2.2mmol, example 19, step 1) and 2-fluoro-4-iodobenzoic acid (583 mg,2.2 mmol) were dissolved in pyridine (10 mL), phosphorus oxychloride (1.0 g,6.6 mmol) was slowly added dropwise and the reaction stirred at room temperature overnight. Ice water (20 mL) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, washed with 1M dilute hydrochloric acid (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (340 mg, yellow solid), yield: 33%. MS (ESI) m/z 477.2[ M+H ] ⁺.

(2) 4-Hydroxy-6-azaspiro [2.5] octane-6-carboxylic acid tert-butyl ester

3-Hydroxy-4-methylenepiperidine-1-carboxylic acid tert-butyl ester (1.5 g,7.0 mmol) was dissolved in methylene chloride (15 mL), diethyl zinc (14.0 mL,14.0mmol,1M in n-hexane) was added under nitrogen protection at 0deg.C, and the reaction was stirred at room temperature for 0.5 hours, diiodomethane (1.5 g,7.0 mmol) was added dropwise thereto, and stirring was continued at room temperature overnight. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (700 mg, colorless oil), yield: 44%. MS (ESI) m/z 250.0[ M+Na ] ⁺.

(3) 6-Azaspiro [2.5] octan-4-ol

4-Hydroxy-6-azaspiro [2.5] octane-6-carboxylic acid tert-butyl ester (200 mg,0.88 mmol) was dissolved in methylene chloride (5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the title compound (112 mg, yellow oil). MS (ESI) m/z 128.1[ M+H ] ⁺.

(4) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4-iodobenzamide

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2-fluoro-4-iodobenzamide (375 mg,0.78 mmol) and 6-azaspiro [2.5] oct-4-ol (100 mg,0.78 mmol) were dissolved in dimethyl sulfoxide (5 mL), potassium carbonate (323 mg,2.3 mmol) was added, and the reaction was stirred at 140℃overnight. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (20 mg, yellow oil), yield: 4%. MS (ESI) m/z 583.8[ M+H ] ⁺.

(5) N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4- ((2-hydroxyethyl) sulfamide) benzamide

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4-iodobenzamide (20 mg,0.03 mmol) was dissolved in 1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (13 mg,0.09 mmol), xphos (5 mg,0.01 mmol), tris (dibenzylideneacetone) dipalladium (5 mg,0.005 mmol) and cesium carbonate (30 mg,0.09 mmol) were added sequentially and the mixture was heated to 100℃under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by Pre-HPLC to give the title compound (5.1 mg, white solid) in yield ：25％.MS(ESI):m/z 581.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.98(s,1H),10.20(brs,1H),8.03(d,J＝8.4Hz,1H),7.40(s,1H),7.22(s,1H),7.12(dd,J＝8.4,1.2Hz,1H),4.97(brs,1H),4.84(d,J＝4.8Hz,1H),3.98-3.91(m,5H),3.75(t,J＝6.4Hz,2H),3.40-3.35(m,2H),3.11-3.09(m,1H),2.97-2.94(m,1H),2.86-2.80(m,1H),2.68-2.64(m,1H),2.31(s,3H),2.18-2.08(m,1H),2.01-1.94(m,4H),1.50-1.40(m,1H),0.66-0.65(m,2H),0.21-0.20(m,2H).

Example 54

N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4- ((2-hydroxyethyl) sulfamide) benzamide

(1) 2- (4-Hydroxy-6-azaspiro [2.5] oct-6-yl) -4-iodobenzoic acid

6-Azaspiro [2.5] oct-4-ol (280 mg,2.2mmol, example 53, step 3) was dissolved in dimethyl sulfoxide (10 mL), 2-fluoro-4-iodobenzoic acid (268 mg,1.76 mmol) and potassium carbonate (607 mg,4.4 mmol) were added, and the mixture was heated to 140℃under nitrogen and stirred overnight. The reaction was poured into water (40 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated aqueous sodium chloride (50 ml x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (dichloromethane/methanol=92/8) to give the title compound (250 mg, white solid), yield: 38%. MS (ESI) m/z 373.8[ M+H ] ⁺.

(2) N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4-iodobenzamide

Referring to the procedure of example 11, step 6, starting from 8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-amine (129 mg,0.51mmol, example 11, step 5) and 2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4-iodobenzoic acid (173 mg,0.46 mmol), the title compound (197 mg, pale yellow solid) is obtained in yield: 70.6%. MS (ESI) m/z 607.7[ M+H ] ⁺.

(3) N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4- ((2-hydroxyethyl) sulfamide) benzamide

Reference to the procedure of example 11, step 7, starting from N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -2- (4-hydroxy-6-azaspiro [2.5] oct-6-yl) -4-iodobenzamide (61 mg,0.1 mmol), the title compound (6.5 mg, white solid) was obtained in yield ：10.8％.MS(ESI):m/z 605.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),10.15(s,1H),9.18(s,1H),8.00(d,J＝8.4Hz,1H),7.97(s,1H),7.45(s,1H),7.21(d,J＝2.0Hz,1H),7.13-7.08(m,2H),5.38(d,J＝3.2Hz,1H),4.94(t,J＝5.6Hz,1H),3.93-3.86(m,2H),3.78-3.70(m,4H),3.35(t,J＝6.4Hz,2H),3.22-3.15(m,2H),3.04-2.97(m,2H),2.80-2.75(m,1H),2.17-2.10(m,5H),1.00-0.96(m,1H),0.61-0.58(m,1H),0.52-0.50(m,1H),0.37-0.29(m,2H).

Example 55

N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 7-Chloro-5- (methylthio) imidazo [1,2-c ] pyrimidine

6-Chloro-2- (methylthio) pyrimidin-4-amine (2.0 g,11.4 mmol) was dissolved in N, N-dimethylformamide (20 mL), 2-bromo-1, 1-diethoxyethane (3.4 g,17.1 mmol) was added thereto, and the reaction was stirred at 140℃for 3 hours. The reaction was directly purified by reverse phase column (acetonitrile/water=1/1) to give the title compound (1.0 g, yellow solid), yield: 43%. MS (ESI) m/z 199.9[ M+H ] ⁺.

(2) 7-Chloroimidazo [1,2-c ] pyrimidin-5-ols

7-Chloro-5- (methylthio) imidazo [1,2-c ] pyrimidine (2.2 g,11.1 mmol) was dissolved in methanol (25 mL), and a 2N aqueous potassium hydroxide solution (25 mL,55.5 mmol) was added thereto, and the reaction was stirred at 80℃for 2 hours. The methanol was dried by spin and the residue was purified directly by reverse phase column (100% water) to give the title compound (1.5 g, white solid), yield: 81%. MS (ESI) m/z 170.0[ M+H ] ⁺.

(3) 5, 7-Dichloro-imidazo [1,2-c ] pyrimidine

7-Chloroimidazo [1,2-c ] pyrimidin-5-ol (1.5 g,8.9 mmol) was dissolved in phosphorus oxychloride (20 mL) and the reaction was stirred at 120℃overnight. The phosphorus oxychloride was dried, diluted with water (20 mL), neutralized with saturated aqueous sodium bicarbonate, and the aqueous phase extracted with ethyl acetate (20 mL x 2). The organics were combined and concentrated to give the title compound (1.0 g, yellow solid), yield: 63%. MS (ESI) m/z 187.9[ M+H ] ⁺.

(4) 7-Chloro-5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidine

5, 7-Dichloroimidazo [1,2-c ] pyrimidine (800 mg,4.3 mmol), 4-difluoropyridine hydrochloride (811 mg,5.1 mmol) was dissolved in dimethyl sulfoxide (10 mL), N-diisopropylethylamine (1.7 g,12.9 mmol) was added, and the reaction stirred at 120℃overnight. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (1.0 g, yellow solid), yield ：86％.MS(ESI):m/z 272.9[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.89(s,1H),7.64(d,J＝1.2Hz,1H),7.35(s,1H),3.57(t,J＝5.6Hz,4H),2.28-2.18(m,4H).

(5) (5- (4, 4-Dihalopiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) carbamic acid tert-butyl ester

7-Chloro-5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidine (800 mg,2.9 mmol), tert-butyl carbamate (1.0 g,8.8 mmol) is dissolved in 1, 4-dioxane (20 mL), xphos (142 mg,0.3 mmol), tris (dibenzylideneacetone) dipalladium (137 mg,0.15 mmol) and cesium carbonate (2.9 g,9.0 mmol) are added and the mixture is heated to 100deg.C under nitrogen and stirred overnight. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (900 mg, yellow solid), yield: 86%. MS (ESI) m/z 353.9[ M+H ] ⁺.

(6) 5- (4, 4-Difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-amine

Tert-butyl (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) carbamate (200 mg,0.57 mmol) is dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) is added and the reaction is stirred at room temperature for 1 hour. The reaction was concentrated, diluted with water (20 mL) and the aqueous phase extracted with dichloromethane (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (143 mg, yellow oil). MS (ESI) m/z 253.9[ M+H ] ⁺.

(7) N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

5- (4, 4-Difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-amine (140 mg,0.5 mmol), intermediate 1 (197mg, 0.5 mmol) is dissolved in pyridine (5 mL) and phosphorus oxychloride (229 mg,1.5 mmol) is slowly added dropwise and the mixture heated to 50deg.C and stirred overnight. The reaction was concentrated, diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (100% ethyl acetate) to give the title compound (20 mg, yellow oil), yield: 6%. MS (ESI) m/z 592.7[ M+H ] ⁺.

(8) N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (5- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-c ] pyrimidin-7-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (20 mg,0.03 mmol) was dissolved in 1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (12.7 mg,0.09 mmol), xphos (2 mg,0.09 mmol), tris (dibenzylideneacetone) dipalladium (3 mg,0.09 mmol) and cesium carbonate (33 mg,0.09 mmol) were added sequentially and the mixture was heated to 100℃under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by Pre-HPLC to give the title compound (2.6 mg, white solid) in yield ：13％.MS(ESI):m/z 590.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.32(s,1H),8.07(d,J＝8.8Hz,1H),7.93(s,1H),7.81(s,1H),7.54(s,1H),7.24(s,1H),7.10(d,J＝8.0Hz,1H),3.76(t,J＝6.4Hz,2H),3.61-3.58(m,4H),3.29-3.26(m,2H),3.00-2.97(m,4H),2.30-2.20(m,4H),1.88-1.62(m,4H),0.40(s,4H).

Example 56

N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (4-methoxy-6-azaspiro [2.5] oct-6-yl) benzamide

(1) 4-Methoxy-6-azaspiro [2.5] octane-6-carboxylic acid tert-butyl ester

4-Hydroxy-6-azaspiro [2.5] octane-6-carboxylic acid tert-butyl ester (545 mg,2mmol, example 53, step 2) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium hydride (160 mg,4mmol, 60%) was added, and after stirring at room temperature for 30 minutes methyl iodide (850 mg,6 mmol) was added, and the reaction was carried out at room temperature overnight. The reaction was poured into water (50 mL) and extracted with ethyl acetate (2X 30 mL). The organic phases were combined, washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to give the title compound (425 mg, pale yellow oil), yield: 88%. MS (ESI) M/z264.0[ M+Na ] ⁺.

(2) 4-Methoxy-6-azaspiro [2.5] octane

4-Methoxy-6-azaspiro [2.5] octane-6-carboxylic acid tert-butyl ester (280 mg,1.16 mmol) was dissolved in methylene chloride (10 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 3 hours. The reaction was concentrated to give the title compound (296 mg, pale yellow oil), yield: 100%. MS (ESI) m/z 142.1[ M+H ] ⁺.

(3) 4-Iodo-2- (4-methoxy-6-azaspiro [2.5] oct-6-yl) benzoic acid

The procedure of step 1 of example 54 was followed using 4-methoxy-6-azaspiro [2.5] octane (292 mg,1.16 mmol) and 2-fluoro-4-iodobenzoic acid (309 mg,1.16 mmol) as starting material to give the title compound (154 mg, white solid), yield: 34%. MS (ESI) m/z 387.8[ M+H ] ⁺.

(4) N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (4-methoxy-6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the procedure of example 11, step 6, starting from 8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-amine (94 mg,0.37mmol, example 11, step 5) and 4-iodo-2- (4-methoxy-6-azaspiro [2.5] oct-6-yl) benzoic acid (143 mg,0.37 mmol), the title compound (120 mg, yellow solid) was obtained in yield: 52%. MS (ESI) m/z 621.8[ M+H ] ⁺.

(5) N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (4-methoxy-6-azaspiro [2.5] oct-6-yl) benzamide

Reference to the procedure of example 11, step 7, starting from N- (8- (4, 4-difluoropiperidin-1-yl) imidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (4-methoxy-6-azaspiro [2.5] oct-6-yl) benzamide (62 mg,0.1 mmol), the title compound (5.6 mg, white solid) was obtained in yield ：9％.MS(ESI):m/z 619.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.48(s,1H),9.17(d,J＝0.8Hz,1H),8.00(d,J＝8.4Hz,1H),7.96(s,1H),7.44(s,J＝0.8Hz,1H),7.20(d,J＝2.0Hz,1H),7.07(dd,J＝8.0,1.6Hz,1H),6.89(s,1H),3.93-3.90(m,2H),3.77-3.70(m,4H),3.32-3.29(m,3H),3.27(s,3H),3.02(d,J＝11.2Hz,2H),2.83-2.77(m,2H),2.40-2.33(m,1H),2.20-2.10(m,4H),0.95(d,J＝13.2Hz,1H),0.67(d,J＝10.4Hz,1H),0.52(d,J＝9.6Hz,1H),0.44-0.39(m,2H).

Example 57

N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 6-Bromo-8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine

6-Bromo-8-chloro- [1,2,4] triazolo [4,3-a ] pyrazine (813 mg,3.5 mmol) was dissolved in dimethyl sulfoxide (15 mL), 4-difluoropiperidine hydrochloride (1.1 g,7 mmol) and N, N-diisopropylethylamine (1.8 g,14 mmol) were added and the mixture was heated to 60℃under nitrogen for 18 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (2X 50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (777 mg, pale yellow solid), yield: 70%. MS (ESI) m/z 317.8[ M+H ] ⁺.

(2) (8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) carbamic acid tert-butyl ester

6-Bromo-8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazine (777 mg,2.45 mmol) was dissolved in 1, 4-dioxane (20 mL), tert-butyl carbamate (458 mg,3.9 mmol), tris (dibenzylideneacetone) dipalladium (229 mg,0.25 mmol), xphos (239 mg,0.5 mmol) and cesium carbonate (3.19 g,9.8 mmol) were added and the mixture was heated to 100deg.C under nitrogen for 16 h. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (343 mg, light brown oil), yield: 39%. MS (ESI) m/z 354.9[ M+H ] ⁺.

(3) 8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-amine

Tert-butyl (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) carbamate (343mg, 0.97 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added and the reaction stirred at room temperature for 3 hours. The reaction was concentrated and the residue was purified by reverse phase column (acetonitrile/water=1/9) to give the title compound (270 mg, yellow oil), yield: 75%. MS (ESI) m/z 255.0[ M+H ] ⁺.

(4) N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (262 mg,0.73 mmol) was dissolved in N, N-dimethylformamide (5 mL), HATU (416 mg,1.1 mmol) and N, N-diisopropylethylamine (471 mg,3.65 mmol) were added, and after stirring at room temperature for 10 minutes, 8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-amine (270 mg,0.73 mmol) was added and reacted at room temperature for 16 hours. The reaction was purified by reverse phase column (100% methanol) to give the title compound (140 mg, yellow solid), yield: 32%. MS (ESI) m/z 593.8[ M+H ] ⁺.

(5) N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [4,3-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (59 mg,0.1 mmol) was dissolved in 1, 4-dioxane (4 mL), 2-hydroxyethanesulfonamide (37.5 mg,0.3 mmol), tris (dibenzylideneacetone) dipalladium (18 mg,0.02 mmol), xphos (19 mg,0.04 mmol) and cesium carbonate (130 mg,0.4 mmol) were added in this order and the mixture was heated to 100℃under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol=92/8) to give a crude product, which was further purified by Prep-HPLC to give the title compound (13.1 mg, white solid), yield ：22％.MS(ESI):m/z 591.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.07(s,1H),10.20(s,1H),9.37(s,1H),8.79(s,1H),8.09(d,J＝8.8Hz,1H),7.30(d,J＝1.6Hz,1H),7.15(dd,J＝8.8,1.6Hz,1H),4.94(brs,1H),4.52-4.39(m,4H),3.76(t,J＝6.4Hz,2H),3.36(t,J＝6.4Hz,2H),3.03-2.95(m,4H),2.21-2.12(m,4H),1.86-1.59(m,4H),0.42(s,4H).

Example 58

N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 6-Chloro-8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazine

6, 8-Dichloro- [1,2,4] triazolo [1,5-a ] pyrazine (300 mg,1.6 mmol) was dissolved in dimethyl sulfoxide (5 mL), 4-difluoropiperidine hydrochloride (498 mg,3.2 mmol) and N, N-diisopropylethylamine (719 mg,4.8 mmol) were added and the mixture was heated to 60℃under nitrogen to react overnight. The reaction was poured into water (20 mL) and extracted with ethyl acetate (2X 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=15/1) to give the title compound (405 mg, white solid), yield ：94％.MS(ESI):m/z 273.9[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.57(s,1H),8.56(s,1H),4.32(s,4H),2.18-2.08(m,4H).

(2) (8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) carbamic acid tert-butyl ester

6-Chloro-8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazine (300 mg,1.1 mmol) was dissolved in 1, 4-dioxane (10 mL), tert-butyl carbamate (257 mg,2.2 mmol), tris (dibenzylideneacetone) dipalladium (45 mg,0.05 mmol), xphos (47 mg,0.1 mmol) and cesium carbonate (1.1 g,3.3 mmol) were added and the mixture was heated to 100deg.C under nitrogen to react overnight. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20/1) to give the title compound (233 mg, yellow oil), yield: 60%. MS (ESI) m/z 355.0[ M+H ] ⁺.

(3) 8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-amine

Tert-butyl (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) carbamate (300 mg,0.85 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added and the reaction stirred at room temperature for 1 hour. The reaction was concentrated, neutralized with saturated aqueous sodium bicarbonate (20 mL) and the aqueous phase extracted with dichloromethane (10 mL. Times.3). The organic phases were combined and concentrated to give the title compound (215 mg, yellow oil). MS (ESI) m/z 255.0[ M+H ] ⁺.

(4) N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

Intermediate 1 (140 mg,0.39 mmol) was dissolved in N, N-dimethylformamide (5 mL), HATU (222 mg,0.59 mmol) and N, N-diisopropylethylamine (155 mg,1.2 mmol) were added, after stirring at room temperature for 10min 8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-amine (100 mg,0.39 mmol) was added and reacted overnight at room temperature. To the reaction mixture was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (10 mL. Times.3). The organic phases were combined and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give the title compound (80 mg, yellow solid), yield: 34%. MS (ESI) m/z 593.8[ M+H ] ⁺.

(5) N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (80 mg,0.1 mmol) was dissolved in 1, 4-dioxane (5 mL), 2-hydroxyethanesulfonamide (25 mg,0.2 mmol), tris (dibenzylideneacetone) dipalladium (5 mg,0.005 mmol), xphos (5 mg,0.01 mmol) and cesium carbonate (130 mg,0.4 mmol) were added sequentially and the mixture was heated to 100℃under nitrogen protection overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (100% ethyl acetate) to give a crude product, which was further purified by Prep-HPLC to give the title compound (15.6 mg, white solid), yield ：20％.MS(ESI):m/z 591.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.30(s,1H),10.24(s,1H),8.96(s,1H),8.50(s,1H),8.10(d,J＝8.8Hz,1H),7.31(d,J＝1.6Hz,1H),7.15(dd,J＝8.4,2.0Hz,1H),4.95(s,1H),3.44-4.34(m,4H),3.76(t,J＝6.4Hz,2H),3.37(t,J＝6.4Hz,2H),3.04-2.96(m,4H),2.19-2.12(m,4H),1.83-1.64(m,4H),0.42(s,4H).

Example 59

N- (4, 4-difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

In a similar manner and with reference to example 58, starting from 4, 6-dichloropyrazolo [1,5-a ] pyrazine, the title compound (81.4 mg, white solid) was obtained ).MS(ESI):m/z 590.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.07(s,1H),10.02(brs,1H),8.95(d,J＝0.8Hz,1H),8.09(d,J＝8.8Hz,1H),7.98(d,J＝2.4Hz,1H),7.29(d,J＝2.0Hz,1H),7.14(dd,J＝8.8,2.0Hz,1H),7.06(dd,J＝2.4,0.4Hz,1H),4.94(brs,1H),3.96-3.93(m,4H),3.76(t,J＝6.4Hz,2H),3.36(t,J＝6.4Hz,2H),3.05-2.93(m,4H),2.19-2.12(m,4H),1.90-1.60(m,4H),0.41(s,4H).

Example 60

N- (8- (4, 4-difluoropiperidin-1-yl) -3-methyl- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

Referring to the procedure of example 22, step 2 substituting triethyl orthoacetate for trimethyl orthoformate, a similar procedure was followed to give the title compound (50.2 mg, white solid ).MS(ESI):m/z 604.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.70(s,1H),10.11(brs,1H),9.11(d,J＝1.6Hz,1H),7.79(d,J＝8.8Hz,1H),7.15(d,J＝2.0Hz,1H),7.02(dd,J＝8.8,2.0Hz,1H),6.95(d,J＝1.2Hz,1H),4.96(brs,1H),3.80-3.75(m,6H),3.37-3.30(m,2H),2.99-2.96(m,4H),2.45(s,3H),2.19-2.12(m,4H),1.58-1.51(m,4H),0.34(s,4H).

Example 61

N- (8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 5-Bromo-3- (4, 4-difluoropiperidin-1-yl) -2-nitropyridine

5-Bromo-3-fluoro-2-nitropyridine (1.73 g,7.83 mmol) was dissolved in N, N-dimethylformamide (20 mL), 4-difluoropyridine hydrochloride (1.36 g,8.61 mmol) and potassium carbonate (2.16 g,15.66 mmol) were added sequentially, and the mixture was heated to 80℃and stirred for 12 hours. To the reaction solution were added ethyl acetate (100 mL) and water (50 mL), and the organic phases were combined and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=95/5) to give the title compound (2.47 g, yellow oil), yield: 88%. MS (ESI) m/z 321.9[ M+H ] ⁺.

(2) 5-Bromo-3- (4, 4-difluoropiperidin-1-yl) pyridin-2-amine

5-Bromo-3- (4, 4-difluoropiperidin-1-yl) -2-nitropyridine (2.47 g,7.69 mmol) was dissolved in a tetrahydrofuran/water (200 mL, 5:1) mixed solvent, ammonium chloride (2.06 g,38.46 mmol) and reduced iron powder (1.29 g,23.08 mmol) were added sequentially at room temperature, and the mixture was heated to 78℃and stirred under reflux for 4 hours. The reaction mixture was filtered through celite to remove insoluble solids, and water (50 mL) and ethyl acetate (100 mL) were added to the filtrate to extract. The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.10 g, black solid), yield: 94%. MS (ESI) m/z 291.9[ M+H ] ⁺.

(3) 6-Bromo-8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridine

5-Bromo-3- (4, 4-difluoropiperidin-1-yl) pyridin-2-amine (2.1 g,7.19 mmol) and 2-bromo-1, 1-diethoxypropane (3.04 g,14.38 mmol) were dissolved in a mixed solvent of ethanol/water (30 mL, 1:1), concentrated hydrochloric acid (5 mL) was added dropwise at room temperature, and the mixture was heated to 100deg.C and stirred for 60 hours. To the reaction solution were added water (50 mL) and ethyl acetate (100 mL). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=85/15) to give the title compound (190 mg, yellow oil), yield: 8%. MS (ESI) m/z 329.9[ M+H ] ⁺.

(4) (8- (4, 4-Difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridin-6-yl) carbamic acid tert-butyl ester

6-Bromo-8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridine (190 mg,0.58 mmol) was dissolved in 1, 4-dioxane (20 mL), and tert-butyl carbamate (337 mg,2.88 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (55 mg,0.12 mmol), tris (dibenzylideneacetone) dipalladium (53 mg,0.06 mmol) and cesium carbonate (375 mg,1.15 mmol) were added sequentially. The mixture was heated to 90℃under nitrogen and stirred for 12 hours. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=67/33) to give the title compound (80 mg, yellow oil), yield: 38%. MS (ESI) M/z367.0[ M+H ] ⁺.

(5) 8- (4, 4-Difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridin-6-amine

Tert-butyl (8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridin-6-yl) carbamate (80 mg,0.22 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated to give the title compound (100 mg, yellow oil), yield: 100%. MS (ESI) m/z 266.8[ M+H ] ⁺.

(6) N- (8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8- (4, 4-Dihalopiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridin-6-amine (100 mg,0.38 mmol) and intermediate 1 (201 mg,0.56 mmol) were dissolved in dichloromethane (20 mL), N-diisopropylethylamine (147 mg,1.13 mmol) and HATU (216 mg,0.56 mmol) were added and stirred at room temperature for 12 hours. To the reaction solution was added saturated sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=70/30) to give the title compound (70 mg, yellow oil), yield: 31%. MS (ESI) m/z 605.9[ M+H ] ⁺.

(7) N- (8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-Dihalopiperidin-1-yl) -3-methylimidazo [1,2-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (70 mg,0.12 mmol) was dissolved in 1, 4-dioxane solution (10 mL), and 2-hydroxyethanesulfonamide (72 mg,0.58 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (11 mg,0.02 mmol), tris (dibenzylideneacetone) dipalladium (11 mg,0.01 mmol), and cesium carbonate (75 mg,0.23 mmol) were added sequentially. The mixture was heated to 85 ℃ under nitrogen and stirred for 12 hours. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (13.7 mg, white solid) in yield ：20％.MS(ESI):m/z 603.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.71(s,1H),10.11(brs,1H),8.72(d,J＝1.2Hz,1H),7.82(d,J＝8.8Hz,1H),7.28(d,J＝0.4Hz,1H),7.16(d,J＝2.0Hz,1H),7.04(dd,J＝8.4Hz,2.0Hz,1H),6.57(s,1H),4.96(brs,1H),3.81-3.75(m,6H),3.35-3.34(m,2H),2.98(t,J＝5.2Hz,4H),2.42(s,3H),2.21-2.09(m,4H),1.62-1.53(m,4H),0.35(s,4H).

Example 62

N- (8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 6-Bromo-8-chloro-3-methylimidazo [1,2-a ] pyrazines

5-Bromo-3-chloropyrazin-2-amine (480 mg,4.7 mmol) and 2-bromo-1, 1-diethoxypropane (1 g,4.7 mmol) were dissolved in an ethanol/water mixed solution (10 mL/10 mL), then hydrochloric acid was added dropwise to adjust the pH to acidity, and the mixture was heated to 80 ℃ and stirred for 18 hours. The reaction was concentrated to remove ethanol, water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.0 g, yellow oil), yield: 85%. MS (ESI) m/z 245.8[ M+H ] ⁺.

(2) 6-Bromo-8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin

6-Bromo-8-chloro-3-methylimidazo [1,2-a ] pyrazine (1.0 g,4.0 mmol) was dissolved in acetonitrile (20 mL), 4-difluoropyridine hydrochloride (756 mg,4.8 mmol) and cesium carbonate (3.9 g,12 mmol) were added and the mixture heated to 75deg.C and stirred for 16 hours. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=92/8) to give the title compound (950 mg, white solid), yield: 71%. MS (ESI) m/z 330.9[ M+H ] ⁺.

(3) (8- (4, 4-Dihalopiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin-6-yl) carbamic acid tert-butyl ester

6-Bromo-8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazine (900 mg,2.7 mmol) was dissolved in 1, 4-dioxane (20 mL), and tert-butyl carbamate (1.6 g,13.5 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (257 mg,0.54 mmol), tris (dibenzylideneacetone) dipalladium (247 mg,0.27 mmol) and cesium carbonate (1.8 g,5.4 mmol) were added sequentially. The mixture was heated to 85 ℃ under nitrogen and stirred for 16 hours. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=97/3) to give the title compound (900 mg, yellow solid), yield: 90%. MS (ESI) M/z368.0[ M+H ] ⁺.

(4) 8- (4, 4-Difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin-6-amine

Tert-butyl (8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin-6-yl) carbamate (350 mg,0.95 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated to give the title compound (255 mg, yellow oil), yield: 100%. MS (ESI) m/z 268.0[ M+H ] ⁺.

(5) N- (8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8- (4, 4-Dihalopiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin-6-amine (255 mg,0.95 mmol) and intermediate 1 (271mg, 0.76 mmol) were dissolved in N, N-dimethylformamide (5 mL), N-diisopropylethylamine (803 mg,4.75 mmol) and HATU (720 mg,1.9 mmol) were added and stirred at room temperature for 1 hour. To the reaction solution was added saturated sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (30 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=90/10) to give the title compound (230 mg, pale yellow solid), yield: 50%. MS (ESI) m/z 606.9[ M+H ] ⁺.

(6) N- (8- (4, 4-difluoropiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-Dihalopiperidin-1-yl) -3-methylimidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (230 mg,0.38 mmol) was dissolved in 1, 4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (143 mg,1.14 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (72 mg,0.152 mmol), tris (dibenzylideneacetone) dipalladium (70 mg,0.076 mmol), and cesium carbonate (310 mg,0.95 mmol) were added sequentially. The mixture was heated to 90 ℃ under nitrogen and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=92/8) to give a crude product, which was further purified by Prep-HPLC to give the title compound (96.5 mg, white solid), yield ：42％.MS(ESI):m/z604.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ12.90(s,1H),10.22(s,1H),8.50(s,1H),8.08(d,J＝8.4Hz,1H),7.39(s,1H),7.29(d,J＝1.6Hz,1H),7.14(dd,J＝8.4,2.0Hz,1H),4.95(t,J＝5.6Hz,1H),4.47-4.40(m,4H),3.79-3.74(m,2H),3.36(t,J＝6.4Hz,2H),3.02-2.95(m,4H),2.42(s,3H),2.17-2.03(m,4H),1.85-1.23(m,4H),0.41(s,4H).

Example 63

N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) (E) -N- (3-bromo-5-nitropyridin-2-yl) -N' -hydroxycarboxamide

3-Bromo-5-nitropyridin-2-amine (5.0 g,23.0 mmol) and N, N-dimethylformamide dimethyl acetal (4.1 g,34.5 mmol) were dissolved in isopropanol (50 mL) and heated to 100deg.C for 3 hours. The reaction solution was cooled to room temperature, hydroxylamine hydrochloride (2.4 g,34.5 mmol) was added, and the mixture was heated to 100℃again to react overnight. The reaction solution was concentrated, dichloromethane and petroleum ether were added, stirred for half an hour, and filtered to give the title compound (5.8 g, yellow solid), yield: 97%. MS (ESI) m/z 260.8[ M+H ] ⁺.

(2) 8-Bromo-6-nitro- [1,2,4] triazolo [1,5-a ] pyridine

(E) -N- (3-bromo-5-nitropyridin-2-yl) -N' -hydroxyformamide (4.0 g,15 mmol) was dissolved in tetrahydrofuran (40 mL) and trifluoroacetic anhydride (6.3 g,30 mmol) was added dropwise at 0deg.C and stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate (40 mL), and the aqueous phase was extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, concentrated, dichloromethane and petroleum ether were added, the reaction stirred for half an hour and filtered to give the title compound (2.2 g, yellow solid), yield: 59%. MS (ESI) M/z242.8[ M+H ] ⁺.

(3) 8-Bromo- [1,2,4] triazolo [1,5-a ] pyridin-6-amine

8-Bromo-6-nitro- [1,2,4] triazolo [1,5-a ] pyridine (2.0 g,8 mmol) was dissolved in a tetrahydrofuran/water (20 mL/5 mL) mixture solvent, iron powder (1.3 g,24 mmol) and ammonium chloride (1.7 g,32 mmol) were added, and the mixture was heated to 80℃and stirred overnight. The reaction was filtered through celite, water (20 mL) was added to the filtrate, and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.6 g, yellow solid), yield: 94%. MS (ESI) m/z 212.8[ M+H ] ⁺.

(4) (8-Bromo- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) (t-butoxycarbonyl) carbamic acid tert-butyl ester

8-Bromo- [1,2,4] triazolo [1,5-a ] pyridin-6-amine (1.6 g,7.5 mmol), di-tert-butyl dicarbonate (4.1 g,18.8 mmol) was dissolved in tetrahydrofuran (20 mL), triethylamine (2.3 g,22.5 mmol) and 4-dimethylaminopyridine (85 mg,0.7 mmol) were added and the reaction was stirred at room temperature overnight. To the reaction mixture was added water (30 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (2.3 g, white solid), yield: 74%. MS (ESI) m/z 412.8[ M+H ] ⁺.

(5) (8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) carbamic acid tert-butyl ester

Tert-butyl (8-bromo- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) (tert-butoxycarbonyl) carbamate (1.5 g,3.6 mmol) was dissolved in 1, 4-dioxane (20 mL), 4-difluoropyridine hydrochloride (1.1 g,7.2 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (224 mg,0.36 mmol), tris (dibenzylideneacetone) dipalladium (264 mg,0.29 mmol) and sodium tert-butoxide (1.0 g,10.8 mmol) were added sequentially. The mixture was heated to 110 ℃ under nitrogen and stirred overnight. The reaction was concentrated, water (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to give the title compound (530 mg, yellow solid), yield: 41%. MS (ESI) m/z 354.0[ M+H ] ⁺.

(6) 8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyridin-6-amine

Tert-butyl (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) carbamate (530 mg,1.5 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the title compound (296 mg, yellow oil). MS (ESI) m/z 254.0[ M+H ] ⁺.

(7) N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8- (4, 4-Difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyridin-6-amine (294 mg,1.2 mmol) and intermediate 1 (321 mg,0.9 mmol) were dissolved in N, N-dimethylformamide (5 mL), HATU (646 mg,1.7 mmol) and triethylamine (264 mg,3.6 mmol) were added and stirred at room temperature overnight. To the reaction solution was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (200 mg, yellow oil), yield: 29%. MS (ESI) m/z 592.9[ M+H ] ⁺.

(8) N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-difluoropiperidin-1-yl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (200 mg,0.3 mmol) was dissolved in 1, 4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (75 mg,0.6 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (14 mg,0.03 mmol), tris (dibenzylideneacetone) dipalladium (14 mg,0.015 mmol), and cesium carbonate (293 mg,0.9 mmol) were added sequentially. The mixture was heated to 100 ℃ under nitrogen and stirred overnight. To the reaction solution was added water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (100% ethyl acetate) to give the crude product, which was further purified by Prep-HPLC to give the title compound (40 mg, white solid) in yield ：20％.MS(ESI):m/z 590.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.71(s,1H),10.11(s,1H),9.21(s,1H),8.39(s,1H),7.79(d,J＝8.4Hz,1H),7.16(d,J＝1.6Hz,1H),7.03(dd,J＝8.4,1.6Hz,1H),6.98(s,1H),4.97(s,1H),3.82-3.75(m,6H),3.40-3.35(m,2H),3.00-2.97(m,4H),2.21-2.11(m,4H),1.61-1.49(m,4H),0.34(s,4H). example 64

N- (4, 4-difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 4, 6-Dibromopyrazolo [1,5-a ] pyridines

4, 6-Dibromopyrazolo [1,5-a ] pyridine-3-carbonitrile (5.5 g,18.28 mmol) was dissolved in methanol (200 mL), concentrated sulfuric acid (30 mL) was slowly added dropwise at room temperature, and the mixture was heated to 110℃and reacted under stirring for 48 hours. The reaction mixture was concentrated to remove methanol, and water (200 mL) and methylene chloride (500 mL) were added. The organic phase was washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (2.05 g, white solid), yield: 41%. MS (ESI) m/z 274.8[ M+H ] ⁺.

(2) 6-Bromo-4- (4, 4-difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyridine

4, 6-Dibromopyrazolo [1,5-a ] pyridine (1.0 g,3.62 mmol) was dissolved in toluene (50 mL), and 4, 4-difluoropyridine hydrochloride (439 mg,3.62 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (226 mg,0.36 mmol), tris (dibenzylideneacetone) dipalladium (332 mg,0.36 mmol) and sodium t-butoxide (1.04 g,10.87 mmol) were added sequentially. The mixture was heated to 80 ℃ under nitrogen and stirred for 12 hours. To the reaction solution were added ethyl acetate (100 mL) and water (50 mL). The organic phase was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (197 mg, yellow-green solid), yield ：17％.MS(ESI):m/z 315.9[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ8.71(d,J＝1.2Hz,1H),8.01(d,J＝2.0Hz,1H),6.78(d,J＝2.4Hz,1H),6.74(d,J＝1.2Hz,1H),3.35-3.33(m,4H),2.28-2.19(m,4H).

(3) (4- (4, 4-Dihalopiperidin-1-yl) pyrazolo [1,5-a ] pyridin-6-yl) carbamic acid tert-butyl ester

6-Bromo-4- (4, 4-difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyridine (200 mg,0.6 mmol) was dissolved in 1, 4-dioxane (20 mL), and tert-butyl carbamate (224 mg,1.9 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (60 mg,0.13 mmol), tris (dibenzylideneacetone) dipalladium (58 mg,0.06 mmol) and cesium carbonate (412 mg,1.27 mmol) were added sequentially. The mixture was heated to 85 ℃ under nitrogen and stirred for 12 hours. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=70/30) to give the title compound (197 mg, yellow solid), yield: 88%. MS (ESI) m/z 353.0[ M+H ] ⁺.

(4) 4- (4, 4-Difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyridin-6-amine

Tert-butyl (4- (4, 4-difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyridin-6-yl) carbamate (197mg, 0.56 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 3 hours. The reaction was concentrated to give the title compound (210 mg, yellow solid), yield: 100%. MS (ESI) m/z 253.0[ M+H ] ⁺.

(5) N- (4, 4-difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

4- (4, 4-Dihalopiperidin-1-yl) pyrazolo [1,5-a ] pyridin-6-amine (150 mg,0.59 mmol) and 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (255 mg,0.71 mmol) were dissolved in dichloromethane (20 mL), N-diisopropylethylamine (232 mg,1.78 mmol) and HATU (340 mg,0.89 mmol) were added and stirred at room temperature for 12 hours. To the reaction mixture was added saturated sodium bicarbonate solution (20 mL), and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=82/18) to give the title compound (150 mg, pale yellow solid), yield: 43%. MS (ESI) m/z 591.9[ M+H ] ⁺.

(6) N- (4, 4-difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyridin-6-yl) -4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (4, 4-difluoropiperidin-1-yl) pyrazolo [1,5-a ] pyridin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (150 mg,0.25 mmol) was dissolved in 1, 4-dioxane (10 mL), 2-hydroxyethanesulfonamide (95 mg,0.76 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (24 mg,0.05 mmol), tris (dibenzylideneacetone) dipalladium (23 mg,0.03 mmol) and cesium carbonate (165 mg,0.51 mmol) were added in this order, and the mixture was heated to 85℃under nitrogen protection and stirred for 12 hours. The reaction solution was concentrated, and the residue was purified by Prep-HPLC to give the title compound (59.0 mg, white solid) in yield ：40％.MS(ESI):m/z 589.1[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.66(s,1H),10.10(brs,1H),9.16(s,1H),7.91(s,1H),7.80(d,J＝8.4Hz,1H),7.15(s,1H),7.03(d,J＝8.4Hz,1H),6.74(s,1H),6.67(s,1H),4.96(brs,1H),3.76(t,J＝6.4Hz,2H),3.35-3.33(m,6H),3.02-2.94(m,4H),2.25-2.19(m,4H),1.61-1.50(m,4H),0.34(s,4H).

Example 65

N- (8- (4, 4-difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

(1) 6-Bromo-8-chloroimidazo [1,2-a ] pyrazines

5-Bromo-3-chloropyrazin-2-amine (2.0 g,9.59 mmol) was dissolved in a mixed solvent of ethanol/water (50 mL/50 mL), 2-bromo-1, 1-diethoxyethane (9.45 g,47.97 mmol) was added, 2mL hydrochloric acid was added dropwise to adjust pH to acidity, and the mixture was heated to 80℃and stirred for 16 hours. The reaction was concentrated to remove ethanol, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.8 g,7.74 yellow solid), yield: 81%. MS (ESI) m/z 231.6[ M+H ] ⁺.

(2) 6-Bromo-8-chloro-3-fluoroimidazo [1,2-a ] pyrazines

6-Bromo-8-chloroimidazo [1,2-a ] pyrazine (1.8 g,7.74 mmol) and SelectFluor fluoro reagent (3.02 g,8.51 mmol) were dissolved in acetonitrile (100 mL) and the mixture heated to 50deg.C and stirred for 16 h. The reaction was concentrated to remove acetonitrile, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=90/10) to give the title compound (550 mg, yellow solid), yield: 28%. MS (ESI) m/z 249.6[ M+H ] ⁺.

(3) 6-Bromo-8- (4, 4-difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazines

6-Bromo-8-chloro-3-fluoroimidazo [1,2-a ] pyrazine (550 mg,2.21 mmol) was dissolved in acetonitrile (20 mL), 4-difluoropyridine hydrochloride (399 mg,3.29 mmol) and cesium carbonate (2.15 g,6.59 mmol) were added and the mixture heated to 75℃and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=95/5) to give the title compound (740 mg, white solid), yield: 99%. MS (ESI) m/z 334.6[ M+H ] ⁺.

(4) (8- (4, 4-Difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazin-6-yl) carbamic acid tert-butyl ester

6-Bromo-8- (4, 4-difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazine (740 mg,2.21 mmol) was dissolved in 1, 4-dioxane (20 mL), tert-butyl carbamate (1.29 g,11.04 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (211 mg,0.44 mmol), tris (dibenzylideneacetone) dipalladium (202 mg,0.22 mmol) and cesium carbonate (1.80 g,5.50 mmol) were added sequentially and the mixture was heated to 85℃under nitrogen and stirred for 16 hours. The reaction was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=95/5) to give the title compound (700 mg, yellow solid), yield: 85%. MS (ESI) M/z371.8[ M+H ] ⁺.

(5) 8- (4, 4-Difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazin-6-amine

Tert-butyl (8- (4, 4-difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazin-6-yl) carbamate (700 mg,1.88 mmol) is dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) is added and the reaction stirred at room temperature for 1 hour. The reaction was concentrated to give the title compound (700 mg, yellow oil), yield: 97%. MS (ESI) m/z 271.8[ M+H ] ⁺.

(6) N- (8- (4, 4-difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

8- (4, 4-Difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazin-6-amine (700 mg,1.81 mmol) and intermediate 1 (775 mg,2.17 mmol) are dissolved in dichloromethane (20 mL) and N, N-diisopropylethylamine (1.17 g,9.05 mmol) and HATU (1.03 g,2.72 mmol) are added and the mixture stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=85/15) to give the title compound (885 mg, yellow solid), yield: 80%. MS (ESI) M/z611.0[ M+H ] ⁺.

(7) N- (8- (4, 4-difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazin-6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (8- (4, 4-difluoropiperidin-1-yl) -3-fluoroimidazo [1,2-a ] pyrazin-6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (400 mg,0.66 mmol) was dissolved in 1, 4-dioxane (20 mL), and 2-hydroxyethanesulfonamide (246 mg,1.97 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (62 mg,0.13 mmol), tris (dibenzylideneacetone) dipalladium (60 mg,0.07 mmol), and cesium carbonate (427 mg,1.31 mmol) were added sequentially. The mixture was heated to 90 ℃ under nitrogen and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol=85/15) to give a crude product, which was further purified by Prep-HPLC to give the title compound (49.5 mg, white solid), yield ：12％.MS(ESI):m/z 608.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ13.03(s,1H),10.22(s,1H),8.44(s,1H),8.08(d,J＝8.8Hz,1H),7.40(d,J＝7.2Hz,1H),7.29(d,J＝2.0Hz,1H),7.14(dd,J＝8.4,2.0Hz,1H),4.94(t,J＝4.2Hz,1H),4.46-4.35(m,4H),3.79-3.74(m,2H),3.36(t,J＝6.8Hz,2H),3.03-2.92(m,4H),2.21-2.07(m,4H),1.90-1.47(m,4H),0.41(s,4H).

Other compounds were prepared according to the previous routes.

Reference example:

N- (2- (4, 4-difluoropiperidin-1-yl) -6-methylpyrimidin-4-yl) -4- ((2-hydroxyethyl) sulfamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (i.e., AMG 650) was prepared according to CN113226473A example 4,

Test example:

Test example 1: inhibition of KIF18A protein activity

The testing method comprises the following steps:

The KIF18A activity of the compounds was tested using the ADP-Glo KINASE ASSAY method, which was performed as follows: test compounds were dissolved in DMSO to prepare 10mM stock solutions. The final initial concentration of the compounds was 10. Mu.M, diluted 3-fold with DMSO, and 10 concentration gradients.

The diluted compounds were transferred 25nL with ECHO in 384 reaction plates, ensuring a DMSO content of 0.5%. Transfer 2.5. Mu.L of 2 XKIF18A enzyme solution to 384 reaction plates, centrifuge at 1000rpm for 1min, incubate at 25℃for 10min. Transfer 2.5. Mu.L of 2 XATP solution to 384 reaction plates, centrifuge at 1000rpm for 1min, incubate at 25℃for 60min. Transfer 4. Mu.L ADP-Glo Reagent into 384 reaction plates, centrifuge at 1000rpm for 1min, incubate at 25℃for 40min. Transfer 8. Mu.L ADP-Glo Detection reagent to 384 reaction plates, centrifuge at 1000rpm for 1min, incubate at 25℃for 40min. The BMG microplate reader was used to read RLU (Relative luminescence unit) signals. The signal intensity was used to characterize the extent of activity of KIF18A enzyme.

The calculation method comprises the following steps:

The IC50 value of the compound for KIF18A enzyme activity was calculated using GraphPad analysis software fit-up curve, the calculation formula was: y=bottom+ (Top-Bottom)/(1+10+ (LogIC-X) × HillSlope), where X is the log of the compound concentration and Y is the inhibition (% inhibition).

Test results:

The results of the compounds of the examples are shown in Table 1, wherein A represents < 20nM, B represents 20-50nM, C represents 50-100nM, and D represents 100-1000nM.

TABLE 1 results of KIF18A protein Activity assay

Test example 2: inhibiting cell proliferation activity

The testing method comprises the following steps:

The cell lines were cultured in an incubator at 37℃under 5% CO ₂ and without CO ₂, respectively. Cells in the logarithmic growth phase were taken for plating at regular passages. Cell staining with trypan blue and counting living cells requires a cell viability of 90% or more. The cell concentration was adjusted to the appropriate concentration, 100. Mu.L of the cell suspension was added to each well of the cell plate, and the mixture was incubated in a CO ₂ -free and CO ₂ -free incubator at 37℃for 24 hours. The 24-hour incubation plate was removed, the compound was 3-fold diluted to 10 concentration gradients, and 7.5 μl of compound working fluid was added to the cell culture plate. 7.5. Mu.L of DMSO-cell culture medium mixture was added to the control wells. The plates were incubated at 37℃for 6 days in a 5% CO ₂ and CO ₂ -free incubator. The cell culture plates were removed and allowed to stand for 10 minutes to equilibrate to room temperature. mu.L of CellTiter-Glo working fluid was added to each well. The plates were shaken on an orbital shaker for 2 minutes to induce cell lysis. The plates were left at room temperature for 10 minutes to stabilize the luminescence signal. And detecting the luminescence signal on a SpectraMax Paradigm plate reader, and reading to obtain a corresponding fluorescence value RLU of each hole.

The calculation method comprises the following steps:

Cell proliferation Inhibition Rate (Inhibition Rate) data were processed using the following formula: inhibition Rate (inh%) =100- (RLUDrug-RLUMin)/(RLUMax-RLUMin) ×100%. Inhibition ratios corresponding to the different concentrations of compounds were calculated in Excel, then GRAPHPAD PRISM software was used for inhibition ratio profiling and IC ₅₀ values were calculated. The results are shown in Table 2, wherein++ + represents < 10nM of the drug, ++ means 10-50nM, + means > 50nM.

TABLE 2 cellular Activity

Examples numbering	OVCAR3(IC50 nM)
		AMG650	+
9	++
		22	+++
28	++
		57	+++
58	+++
		59	++
60	++
		61	++
62	++
		63	+++
64	++
		65	+++

Test example 3: mouse drug substitution test

1. Experimental method

Experimental animals: ICR mice, SPF grade, male, weigh group.

Preparing a test sample: the compound of example and AMG650 were weighed separately, 5% dmso+10% solutol+85% (6% hp- β -CD IN WATER) was added, vortexed and sonicated until the compound was colorless clear, and formulated into PO (gavage) and IV (intravenous administration) dosing solutions of the indicated concentrations for use.

Route of administration: oral/intravenous injection.

Sample collection: blood is collected through cheeks, about 0.05mL of each sample is collected, heparin sodium is anticoagulated, and the collected samples are placed on wet ice.

The blood sampling time points are as follows:

IV: 0.083h,0.25h,0.5h,1h,2h,4h,6h,8h,24h after administration;

PO: 0.083h,0.25h,0.5h,1h,2h,4h,6h,8h,24h post administration.

2. Sample analysis and results

Sample analysis: blood samples were collected and placed on ice and the plasma was centrifuged within 1 hour (centrifugation conditions: 6000g,3 minutes, 2-8 ℃). The plasma samples were stored in a-80 ℃ freezer prior to analysis. And detecting the collected sample by adopting an LC-MS/MS method.

Pharmacokinetic data analysis: pharmacokinetic parameters were calculated using Phoenix winnonlin8.2.0 from blood concentration data at different time points.

The above experiments show that the bicyclic compounds of the invention generally have better kinase or cellular activity than AMG 650. Meanwhile, substitution of methyl or halogen (such as F) on the bicyclo ring can obviously improve the drug substitution property of the compound, and particularly can reduce the clearance rate, improve the C _max (maximum blood concentration), improve the exposure and the like. Wherein the pharmacokinetic properties of examples 60, 61, 62, 65 are significantly better than those of the compounds not substituted in the bicyclic ring.

Unless otherwise defined, all terms used herein are intended to have the meanings commonly understood by those skilled in the art.

The described embodiments of the present invention are intended to be illustrative only and not to limit the scope of the invention, and various other alternatives, modifications, and improvements may be made by those skilled in the art within the scope of the invention, and therefore the invention is not limited to the above embodiments but only by the claims.

Claims

1. A compound having a structure represented by general formula (I), a deuterated, a stereoisomer, or a pharmaceutically acceptable salt thereof:

Wherein,

X ₁ and X ₂ are independently CH or an N atom, preferably CH;

the ring a is optionally oxo with 1 to 2C atoms;

R ₇ is selected from H, R _7a or R _7b;

R _7b is selected from C _1-6 alkyl optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-6 alkoxy or C _1-6 haloalkoxy;

R ₄ is selected from H, R _4a or R _4b;

The R ₅ is selected from H, R _5a or R _5b;

The R ₆ is selected from H, C _1-3 alkyl or C _3-6 cycloalkyl;

The preferable technical scheme is as follows:

Further preferred, the ring a is an 8-, 9-or 10-membered bicyclic heteroaryl group containing 2-4N atoms and substituted with 0, 1,2 or 3R ₃; r ₃ is selected from halogen, 3-5 membered cycloalkyl, C _1-3 alkyl, C _1-3 haloalkyl or cyano;

the more preferable technical scheme is as follows:

Ring A is selected from

Ring A is preferably

Ring A is more preferred

Ring A is further preferred

ring a is optionally substituted with 0, 1 or 2R ₃;

2. The compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein:

R ₇ is selected from H, R _7a or R _7b;

R _7a is preferably More preferably/>

R _7a is further preferred More preferably/>

R _7a is optionally substituted with 1 or 2 groups selected from: halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylene, C _1-3 haloalkyl, C _1-3 haloalkoxy or C _1-3 haloalkylene, more preferably halogen, C _1-3 alkyl, C _1-3 alkylene, C _1-3 haloalkyl or C _1-3 haloalkylene, further preferably F, methyl, =ch ₂、＝C(CH₃)₂, trifluoromethyl, =cf ₂;R_7b is selected from C _1-6 alkyl, more preferably C _1-3 alkyl, further preferably methyl, ethyl, n-propyl, isopropyl;

3. The compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 2, wherein: ring B isOptionally substituted with 1,2, 3 or 4R ₄;

R ₄ is selected from H, R _4a or R _4b;

Said R _4a or R _4b is independently selected from halogen, hydroxy, cyano, C _1-3 alkyl, C _1-3 alkoxy, or R _4a、R_4b forms a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl group with the atom to which it is attached;

Still more preferably, ring B is Preference/> More preferably/>

The R ₅ is selected from R _5b;

the R ₆ is selected from H, C _1-3 alkyl;

further preferably, R ₁ is

4. A compound according to claim 3, a deuterated, a stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure according to formula (X):

Ring A is preferably Wherein the terminal is connected with R ₂, and the terminal # is connected with an amido;

Ring A is more preferred

Ring A is more preferred Wherein the terminal is connected with R ₂, and the terminal # is connected with an amido;

R ₇ is selected from H, R _7a or R _7b;

r _7b is preferably methyl, n-propyl, isopropyl, optionally substituted with 1,2 or 3 groups selected from: halogen, C _1-3 alkoxy or C _1-3 haloalkoxy, more preferably F, methoxy, trifluoromethoxy, still more preferably F;

R ₄ is selected from halogen, hydroxy, cyano, C _1-3 alkyl, C _1-3 alkoxy, preferably F, hydroxy, cyano, methyl, methoxy; m is selected from 0, 1 or 2.

5. A compound having a structure represented by general formula (II), a deuterated, a stereoisomer, or a pharmaceutically acceptable salt thereof:

Wherein,

Ring a is selected from 5-6 membered monocyclic heteroaryl, 6 membered monocyclic unsaturated heterocyclyl or 9-10 membered fused ring heteroaryl containing 1-6 heteroatoms selected from N, O, S, said ring a being substituted with 0, 1, 2 or 3R ₃; preferably ring a is selected from 5-6 membered monocyclic heteroaryl, 6 membered monocyclic unsaturated heterocyclyl or 9-10 membered fused ring heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, said ring a being substituted with 0, 1, 2 or 3R ₃;

The R ₃ is selected from halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy or 3-6 membered cycloalkyl; r ₂ is-L ₂-R₇, wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from H, R _7a or R _7b;

The preferable technical scheme is as follows:

Ring a is selected from:

And ring a is substituted with 0, 1,2 or 3R ₃;

Ring a is preferably:

And ring a is substituted with 0, 1,2 or 3R ₃;

Further preferably, ring a is selected from: And ring a is substituted with 0, 1,2 or 3R ₃;

Ring a further preferably:

And ring a is substituted with 0, 1,2 or 3R ₃;

Said R ₃ is selected from F, cl, methyl, ethyl, propyl, cyclopropyl, cyclopentyl, cyclohexyl, -OCH ₃、-CF₃, or-OCF ₃, preferably F, methyl, ethyl, cyclopropyl, -OCH ₃、-CF₃, or-OCF ₃;

the more preferable technical scheme is as follows:

R ₂ is L ₂-R₇, wherein,

L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from H, R _7a or R _7b;

More preferably, R _7a is selected from

More preferably, R _7a is selected from/>

Further preferably, the R _7b is selected from the group consisting of-CHF ₂、-CF₃、-CH₂-CHF₂、-(CH₂)₂-CF₃ or- (CH ₂)₂-OCF₃);

the further preferable technical scheme is as follows:

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a or R _7b;

More preferably, R _7a is selected from

More preferably, R _7a is selected from/>

6. The compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 5 having a structure according to formula (III):

n is selected from 0, 1 or 2;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a;

Preferably, R _7a is selected from the group consisting of-CH ₂ - (3-7) membered cycloalkyl, -CH ₂ - (3-7) membered heterocycloalkyl, And optionally substituted with 1,2 or 3F;

further preferably, said R _7a is selected from the group consisting of:

7. The compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 5, wherein: ring a is a 6 membered unsaturated heterocyclyl containing 1,2 or 3 heteroatoms selected from N, O or S, and 1-2C atoms of ring a are oxo; the ring a is substituted with 0, 1,2 or 3R ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a;

R _7a is selected from And optionally substituted with 1,2 or 3 groups selected from: F. cl, C _1-3 alkylene, C _1-3 haloalkylene, preferably F; further preferably, R _7a is selected fromThe preferable technical scheme is as follows:

the compound has a structure shown in a general formula (V):

z ₁ is selected from N, CH or C-R ₃;

Z ₂ is selected from NH or N-R ₃;

R ₂ is-L ₂-R₇,

Wherein L ₂ is selected from-O-, -CO-, or a covalent bond;

R ₇ is selected from R _7a;

R _7a is selected from And optionally substituted with 1,2 or 3F;

Further preferably, R _7a is selected from />

8. A compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof, comprising any one of the following:

/>

9. a pharmaceutical composition comprising a compound according to any one of claims 1-14, a deuterated, a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.

10. Use of a compound according to any one of claims 1-8, a deuterated, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment and/or prevention of KIF 18A-related diseases;

The preferable technical scheme is as follows: the KIF 18A-related disease is selected from a late or metastatic solid tumor associated with a p53 gene mutation, or with one or more abnormal gene expression selected from RB deletion, BRCA1 mutation/inactivation, or CCNE amplification;

The preferable technical scheme is as follows: the KIF 18A-related disease is selected from colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, peritoneal cancer, fallopian tube cancer, ovarian cancer or endometrial cancer; preferably triple negative breast cancer, platinum-resistant advanced serous ovarian cancer, primary peritoneal cancer, fallopian tube cancer or serous endometrial cancer.