CN116731038A

CN116731038A - Nitrogen-containing heterocyclic compound, and preparation method and application thereof

Info

Publication number: CN116731038A
Application number: CN202310223905.4A
Authority: CN
Inventors: 胡建涛; 陈建勇; 何宝林; 赵雷磊; 朱研
Original assignee: Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Current assignee: Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Priority date: 2022-03-10
Filing date: 2023-03-09
Publication date: 2023-09-12

Abstract

The invention discloses a nitrogen-containing heterocyclic compound, a preparation method and application thereof. Specifically, the invention discloses a compound shown in a formula I or pharmaceutically acceptable salt thereof. The compound provided by the invention has better SHP2 inhibition activity and/or tumor cell inhibition activity.

Description

Nitrogen-containing heterocyclic compound, and preparation method and application thereof

Technical Field

The invention relates to a nitrogen-containing heterocyclic compound, a preparation method and application thereof.

Background

SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 is widely expressed in most tissues, participates in the signal transmission path of various growth factors and cytokines, and plays an important role in regulating and controlling cell proliferation, migration, differentiation, death and the like. SHP2 is currently known to be associated with a variety of diseases in humans, such as noonan syndrome, leopard syndrome, diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, acute myelogenous leukemia, HER2 positive breast cancer, triple negative breast cancer, breast ductal cancer, invasive breast ductal cancer, non-small cell lung cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, neutropenia, systemic lupus erythematosus, and the like, and SHP2 inhibitors would be expected to be useful in the treatment of these diseases.

There are several patent applications disclosing SHP2 inhibitors including CN111825700A, WO2019158019A1, WO2020094104A1, WO2021148010A1, WO2021115286A1, CN112166110A, WO2021143680A1. Some SHP2 inhibitors have entered the clinical trial phase, including RMC-4630, JAB-3068, JAB-3312 and TNO-155.

Although research on SHP2 has been advanced to some extent, no effective drugs are currently marketed, and there is still a need to continue to research and develop new SHP2 inhibitors.

Disclosure of Invention

The technical problem to be solved by the invention is that the known SHP2 inhibitor has fewer structural types, so that the invention provides a SHP2 inhibitor with a novel structure. Specifically, the invention provides a compound shown in a formula I or pharmaceutically acceptable salt thereof, which has better SHP2 inhibitory activity and/or tumor cell inhibitory activity.

The invention provides a compound shown in a formula I or pharmaceutically acceptable salt thereof:

wherein X is CH or N;

b is

Wherein the a end of the structure is connected with L, and the b end is connected with N atom in the structure of the formula I;

B ₁ o, S, NH or NR _b1 ；R _b1 Is C ₁ -C ₄ An alkyl group;

B ₃ h, NH of a shape of H, NH ₂ Or C ₁ -C ₄ An alkyl group;

B ₄ 、B ₇ 、B ₈ 、B ₁₁ 、B ₁₂ 、B ₁₄ 、B ₁₆ 、B ₁₈ 、B ₂₀ and B ₂₂ Each independently is CH or N;

B ₅ is N or CR _b5 ；R _b5 Is H or C ₁ -C ₄ An alkyl group;

B ₆ h, NH of a shape of H, NH ₂ Or C ₁ -C ₄ An alkyl group;

B ₉ h, OH or C ₁ -C ₄ An alkyl group;

B ₁₀ h, NH of a shape of H, NH ₂ Halogen or C ₁ -C ₄ An alkyl group;

B ₁₃ is H or halogen;

B ₁₅ is H or C ₁ -C ₄ An alkyl group;

B ₁₇ is H, halogen, CN, C ₁ -C ₄ Alkyl or-C ₁ -C ₄ An alkylene-OH;

B ₁₉ is H or NH ₂ ；

B ₂₁ O, NH or NR _b21 ；R _b21 Is C ₁ -C ₄ An alkyl group;

l is a single bond, -O-, -S-, -NH-, -N (R) ₁ )-、-CH ₂ -、-CH(R ₁ )-、-C(R ₁ )(R ₂ ) -or

Each R ₁ And R is ₂ Each independently is C ₁ -C ₄ An alkyl group;

a is a saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group, a saturated or partially unsaturated 3-10 membered heterocyclic group, a phenyl group, a 5-6 membered heteroaryl group, a naphthyl group or an 8-10 membered fused heteroaryl group; the hydrogen atoms on the 3-10 membered cyclic hydrocarbon group, 3-10 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group, naphthyl group and 8-10 membered fused heteroaryl group are unsubstituted or substituted with n R ₃ Substitution;

n is 1, 2, 3, 4 or 5;

each R ₃ Each independently F, cl, br, I, NH ₂ OH, cyano, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, m R _3a Substituted C ₁ -C ₄ Alkyl or m R _3b Substituted C ₁ -C ₄ An alkoxy group;

each m is independently 1, 2, 3, 4, or 5;

each R _3a And R is _3b Each independently F, cl, br, I, NH ₂ OH or cyano;

the number of heteroatoms in the 3-10 membered heterocyclic group, the 5-6 membered heteroaryl group and the 8-10 membered fused heteroaryl group is 1, 2, 3 or 4, and each heteroatom is N, O or S independently.

In some embodiments, in the compounds of formula I as described in any of the preceding embodiments, B is

In some embodiments, when B is a compound of formula I as described in any of the preceding embodimentsWhen (I)>Can be +.>

In some embodiments, when B is a compound of formula I as described in any of the preceding embodimentsWhen (I)>Is->

In some embodiments, the compound of formula I has a structure according to any one of formulas I-1 to I-11:

in some embodiments, R in a compound of formula I or I-3 as described in any one of the preceding embodiments _b5 Is H or C ₁ -C ₄ Alkyl groups such as H or methyl.

In some embodiments, B is a compound of formula I or I-4 as described in any one of the preceding embodiments ₃ Is H or C ₁ -C ₄ Alkyl groups such as H or methyl.

In some embodiments, B is a compound of formula I or I-9 as described in any one of the preceding embodiments ₃ Is NH ₂ 。

In some embodiments, R in a compound of formula I or I-10 as described in any one of the preceding embodiments _b1 Is C ₁ -C ₄ Alkyl groups such as methyl, ethyl or isopropyl.

In some embodiments, the compound of formula I or I-1 is a compound of:

in some embodiments, the compound of formula I or I-2 is any one of the following:

in some embodiments, the compound of formula I or I-3 is a compound of:

in some embodiments, the compound of formula I or I-4 is any one of the following:

in some embodiments, the compound of formula I or I-5 is a compound of:

in some embodiments, the compound of formula I or I-6 is any one of the following:

in some embodiments, the compound of formula I or I-7 is any one of the following:

in some embodiments, the compound of formula I or I-8 is any one of the following:

in some embodiments, the compound of formula I or I-9 is any one of the following:

in some embodiments, the compound of formula I or I-10 is any one of the following:

in some embodiments, the compound of formula I or I-11 is the following:

In some embodiments, when B is a compound of formula I as described in any of the preceding embodiments When (I)>Can be +.>

In some embodiments, the compound of formula I has a structure of formula I-12 or I-13 as follows:

in some embodiments, B is a compound of formula I or I-12 as described in any one of the preceding embodiments ₆ Is NH ₂ 。

In some embodiments, B is a compound of formula I or I-13 as described in any one of the preceding embodiments ₆ Is H or NH ₂ 。

In some embodiments, the compound of formula I or I-12 is any one of the following:

in some embodiments, the compound of formula I or I-13 is any one of the following:

In some embodiments, the compound of formula I has a structure as shown in any one of formulas I-14 through I-17:

In some embodiments, the compound of formula I has the structure of formulas I-18 as follows:

in some embodiments, B is a compound of formula I, I-15 or I-16 as described in any one of the preceding embodiments ₁₀ H, NH of a shape of H, NH ₂ Cl or CH ₃ Preferably H.

In some embodiments, B is a compound of formula I or I-15 as described in any one of the preceding embodiments ₁₀ H, NH of a shape of H, NH ₂ Or C ₁ -C ₄ Alkyl (e.g., methyl) is preferably H.

In some embodiments, B is a compound of formula I or I-16 as described in any one of the preceding embodiments ₁₀ H or halogen (e.g., cl), preferably H.

In some embodiments, B is a compound of formula I or I-17 as described in any one of the preceding embodiments ₉ H or OH, preferably H.

In some embodiments, the compound of formula I or I-14 is any one of the following:

in some embodiments, the compound of formula I, I-15 or I-18 is any one of the following:

in some embodiments, the compound of formula I or I-16 is any one of the following:

in some embodiments, the compound of formula I or I-17 is any one of the following:

In some embodiments, the compounds of formula I have the structure of formulas I-19 as follows:

in some embodiments, B in the compound of formula I or I-19 ₁₃ H or F, preferably F.

In some embodiments, the compound of formula I or I-19 is any one of the following:

In some embodiments, when B is a compound of formula I as described in any of the preceding embodimentsWhen (I)>May be

In some embodiments, the compound of formula I has a structure according to any one of formulas I-20 to I-23:

in some embodiments, a compound of formula I, I-20 or I-21 as described in any one of the preceding embodiments, B ₁₅ Is H or C ₁ -C ₄ Alkyl (e.g., methyl) is preferably H.

In some embodiments, a compound of formula I or I-22 as described in any one of the preceding embodiments, B ₁₇ Is H, halogen (e.g. F), CN, C ₁ -C ₄ Alkyl (e.g. methyl) or-C ₁ -C ₄ alkylene-OH (e.g. -CH ₂ OH), preferably H.

In some embodiments, the compound of formula I or I-20 is any one of the following:

in some embodiments, the compound of formula I or I-21 is any one of the following:

in some embodiments, the compound of formula I or I-22 is any one of the following:

in some embodiments, the compound of formula I or I-23 is a compound of:

in some embodiments of the present invention, in some embodiments,in the compounds of formula I as described in any one of the preceding schemes, B is

In some embodiments, the compound of formula I has a structure of formula I-24 or I-25 as follows:

in some embodiments, the compound of formula I or I-24 is a compound of:

in some embodiments, the compound of formula I or I-25 is a compound of:

In some embodiments, the compound of formula I has a structure of formula I-26 or I-27 as follows:

in some embodiments, B is a compound of formula I, I-26 or I-27 as described in any one of the preceding embodiments ₁₉ Is NH ₂ . In some embodiments, the compound of formula I or I-26 is the following:

in some embodiments, the compound of formula I or I-27 is any one of the following structural compounds:

in some embodiments, in the compounds of formula I as described in any of the preceding embodiments, B isIn some embodiments, the compound of formula I has the structure of formulas I-28 as follows:

in some embodiments, the compound of formula I or I-28 is the following:

in some embodiments, in the compounds of formula I as described in any of the preceding embodiments, B isIn some embodiments, the compounds of formula IThe compounds have the structure shown in the following formulas I-29:

in some embodiments, the compound of formula I or I-29 is the following:

in some embodiments, in the compounds of formula I as described in any of the preceding embodiments, B isIn some embodiments, the compound of formula I has the structure of formula I-30:

in some embodiments, the compound of formula I or I-30 is any one of the following:

in some embodiments, in the compounds of formula I as described in any of the preceding embodiments, B isIn some embodiments, when B is a compound of formula I as described in any of the preceding embodiments When (I)>Can be +.>

In some embodiments, the compounds of formula I have the structures of formulas I-31 through I-34 as follows:

in some embodiments, the compound of formula I has the structure of formula I-31:

in some embodiments, R in a compound of formula I or I-33 as described in any one of the preceding embodiments _b21 Is methyl, ethyl or isopropyl.

In some embodiments, the compound of formula I or I-31 is any one of the following:

in some embodiments, the compound of formula I or I-32 is the following:

in some embodiments, the compound of formula I or I-34 is any one of the following:

in some embodiments, in the compounds of formula I and any one of formulas I-1 to I-34 as described in any one of the preceding embodiments, L is a single bond.

In some embodiments, in the compounds of formula I and any one of formulas I-1 to I-34 as described in any one of the preceding embodiments, L is-O-.

In some embodiments, in the compounds of formula I and any one of formulas I-1 to I-34 as described in any one of the preceding embodiments, L is-S-.

In some embodiments, in the compounds of formula I and any one of formulas I-1 to I-34 as described in any one of the preceding embodiments, L is-NH-.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, L is-N (R ₁ )-。

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, L is-CH ₂ -。

In some embodiments of the present invention, in some embodiments,in the compounds of formula I and any one of formulas I-1 to I-34 as described in any one of the preceding schemes, L is-CH (R ₁ )-。

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, L is-C (R ₁ )(R ₂ )-。

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, L is

In some embodiments, R in a compound of formula I as described in any of the preceding embodiments and in any of formulas I-1 through I-34 ₁ Is methyl.

In some embodiments, R in a compound of formula I as described in any of the preceding embodiments and in any of formulas I-1 through I-34 ₂ Is methyl.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, A is a saturated or partially unsaturated 3-10 membered cycloalkyl, the hydrogen atom on the 3-10 membered cycloalkyl being unsubstituted or substituted with n R ₃ And (3) substitution.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, in the definition of A, the saturated or partially unsaturated 3-10 membered cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,(e.g.)>) Or->(e.g.)>)。

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, A is a saturated or partially unsaturated 3-10 membered heterocyclyl, the hydrogen atom on the 3-10 membered heterocyclyl being unsubstituted or substituted with n R ₃ And (3) substitution.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, in the definition of A, the saturated or partially unsaturated 3-10 membered heterocyclic group may be(e.g.)、(e.g.)>)、(e.g.)>) Or->(e.g.)>)。

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, A is phenyl, the hydrogen atom on the phenyl is unsubstituted or substituted with n R ₃ And (3) substitution.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, A is a 5-6 membered heteroaryl The hydrogen atom on the 5-6 membered heteroaryl is unsubstituted or is substituted with n R ₃ And (3) substitution.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, in the definition of A, the 5-6 membered heteroaryl group may be pyrrole, furan, thiophene, oxazole, isoxazoleThiazole (e.g.)>) Isothiazole, pyrazole (e.g.)>) Imidazoles, pyridines (e.g) Pyrimidine or pyrazine.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, A is naphthyl, the hydrogen atom on the naphthyl is unsubstituted or substituted with n R ₃ And (3) substitution.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, in the definition of A, the naphthyl group may be

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, A is an 8-10 membered fused heteroaryl, the hydrogen atom on the 8-10 membered fused heteroaryl is unsubstituted or substituted with n R ₃ And (3) substitution.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, in the definition of A, the 8-10 membered fused heteroaryl may be (e.g.)>)、(e.g.) Or->(e.g.)>)。

In some embodiments, in the compounds of formula I and any of formulas I-1 to I-34 as described in any of the preceding embodiments, n is 1, 2 or 3.

In some embodiments, each R in a compound of formula I as set forth in any one of the preceding embodiments and in any one of formulas I-1 through I-34 _3a And R is _3b Each independently is F or OH.

In some embodiments, each R in a compound of formula I as set forth in any one of the preceding embodiments and in any one of formulas I-1 through I-34 ₃ Each independently F, cl, br, NH ₂ OH, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl or hydroxymethyl.

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, when A is a saturated or partially unsaturated 3-10 membered cycloalkyl, the hydrogen atom on the 3-10 membered cycloalkyl is unsubstituted or is substituted with n R ₃ When substituted, A can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, when A is a saturated or partially unsaturated 3-10 membered heterocyclyl, the hydrogen atom on the 3-10 membered cycloalkyl is unsubstituted or substituted with n R ₃ When substituted, A may be

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, when A is phenyl, the hydrogen atom on the phenyl is unsubstituted or substituted with n R ₃ When substituted, A may be

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, when A is a 5-6 membered heteroaryl, the hydrogen atom on the 5-6 membered heteroaryl is unsubstituted or is substituted with n R ₃ When substituted, A may be

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, when A is naphthyl, the hydrogen atom on the naphthyl is unsubstituted or substituted with n R ₃ When substituted, A may be

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, when A is an 8-10 membered fused heteroaryl, the hydrogen atom on the 8-10 membered fused heteroarylUnsubstituted or substituted by n R ₃ When substituted, A may be

In some embodiments, in the compounds of formula I and any of formulas I-1 through I-34 as described in any of the preceding embodiments, A-L-is

In some embodiments, in the compounds of formula I and any one of formulas I-1 to I-34 as described in any one of the preceding embodiments, X is CH.

In some embodiments, in the compounds of formula I and any one of formulas I-1 to I-34 as described in any one of the preceding embodiments, X is N.

The invention also discloses a preparation method of the compound shown in the formula I, which comprises the following steps: removing tert-butylsulfinyl from a compound of formula II in the presence of an acid (e.g., HCl) in a solvent (e.g., dioxane) to obtain a compound of formula I;

wherein A, L, B and X are as defined above.

The invention also provides a compound shown in a formula II:

wherein A, L, B and X are as defined above.

The invention also provides a preparation method of the compound shown in the formula II, which can be in schemes 1, 2, 3 or 4:

scheme 1 includes the steps of: carrying out the coupling reaction of a compound shown in a formula III-1 and a compound shown in a formula IV in a solvent in the presence of a palladium catalyst, a ligand and a base to obtain a compound shown in a formula II;

wherein Hal is halogen (e.g. Cl or Br), A, L, B and X are as defined above;

scheme 2 includes the steps of: carrying out the coupling reaction of a compound shown in a formula III-2 and a compound shown in a formula IV in a solvent in the presence of a base to obtain the compound shown in a formula II;

Wherein A, L, B and X are as defined above;

scheme 3 includes the steps of: carrying out the coupling reaction of a compound shown in a formula III-3 and a compound shown in a formula V in a solvent in the presence of a palladium catalyst and a base to obtain a compound shown in a formula II;

wherein Hal is halogen (e.g. Br), A, L, B and X are as defined above;

scheme 4 includes the steps of: carrying out the coupling reaction of a compound shown in a formula III-4 and a compound shown in a formula V in a solvent in the presence of a palladium catalyst and a base to obtain a compound shown in a formula II;

wherein Hal is halogen (e.g., br), A, L, B and X are as defined above.

The invention also provides a compound shown in formula III-1, III-2 or V:

wherein Hal, A, L, B and X are as defined above.

The invention also discloses a pharmaceutical composition which comprises the compound or the pharmaceutically acceptable salt thereof according to any one of the previous schemes and at least one pharmaceutical excipient.

The invention also discloses application of the compound according to any one of the previous schemes or pharmaceutically acceptable salts thereof or the pharmaceutical composition according to the previous schemes in preparation of SHP2 inhibitors.

The invention also discloses application of the compound according to any one of the previous schemes or pharmaceutically acceptable salts thereof or the pharmaceutical composition according to the previous schemes in preparing medicines for treating SHP2 related diseases.

Also disclosed is a method of inhibiting SHP2 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of the preceding schemes, or a pharmaceutically acceptable salt thereof.

Also disclosed is a method of treating an SHP 2-associated disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of the preceding schemes, or a pharmaceutically acceptable salt thereof.

In some embodiments, the SHP 2-associated disease is noonan syndrome, leopard syndrome, diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, acute myelogenous leukemia, HER 2-positive breast cancer, triple negative breast cancer, ductal carcinoma, invasive ductal carcinoma, non-small cell lung carcinoma, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, neutropenia, or systemic lupus erythematosus.

Definition and description

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

In this context, the term "substitution" or "substituent" is the replacement of a hydrogen atom in a group by the indicated group. When no substitution positions are indicated, substitution may be at any position, but only formation of a stable or chemically feasible chemical is allowed. The following are illustrated:the structure represents that the hydrogen atom on the ring A is replaced by m R ₁ Substituted.

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 one of the linking groups is a single bond, the groups attached to both sides of the linking group are directly linked by a single bond. For example, the structure formed when L in A-L-Z is a single bond is A-Z.

As used herein, the term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon radical. C (C) ₁ -C ₄ Alkyl means an alkyl group having 1 to 4 carbon atoms, which is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In this context, the term "hydrocarbyl" refers to a group consisting of carbon and hydrogen atoms.

Herein, the term "halogen" refers to F, cl, br or I.

As used herein, the term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined above。C ₁ -C ₄ Alkoxy means-O- (C) ₁ -C ₄ Alkyl), wherein C ₁ -C ₄ Alkyl is as defined above, i.e. C ₁ -C ₄ The alkoxy group may be specifically methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

As used herein, the term "cyclic hydrocarbyl" refers to a monocyclic or polycyclic (e.g., fused, spiro, or bridged) cyclic hydrocarbyl group, which may be saturated, partially unsaturated, or aromatic. In saturated cyclic hydrocarbon groups, each carbon atom on the ring is saturated; examples of saturated cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, In aromatic cyclic hydrocarbon groups, each ring is aromatic; examples of aromatic cyclic hydrocarbon groups include, but are not limited to, phenyl, naphthyl. In a partially unsaturated cyclic hydrocarbon group, at least one carbon atom on the ring is saturated and at least one carbon atom is unsaturated; examples of partially unsaturated cyclic hydrocarbon groups include, but are not limited to +. > In some embodiments, the partially unsaturated cyclic hydrocarbon group is a polycyclic cyclic hydrocarbon group and wherein at least one ring is an aromatic ring and at least one ring is a non-aromatic ring, which may be attached to other structures through an atom on the aromatic ring or may be attached to other structures through an atom on the non-aromatic ring. The 3-10 membered cyclic hydrocarbon group may specifically be a 3, 4, 5, 6, 7, 8, 9 or 10 membered cyclic hydrocarbon group. In some embodiments, the cyclic hydrocarbon group is monocyclic. In some embodiments, the cyclic hydrocarbon group is polycyclic (e.g., fused, spiro, or bridged).

Herein, a text isThe term "heterocyclyl" refers to a monocyclic or polycyclic (e.g., parallel, spiro, or bridged) cyclic group formed from a carbon atom and at least one heteroatom, wherein the heteroatoms are independently selected from N, O and S. The heterocyclic group may be saturated, partially unsaturated or aromatic. The heterocyclic group may be attached to other structures through carbon and heteroatoms in the ring. In saturated heterocyclic groups, all atoms on the ring are saturated, examples of saturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl. In aromatic heterocyclic groups, each ring is aromatic, i.e., heteroaryl herein. In partially unsaturated heterocyclic groups, examples of partially unsaturated heterocyclic groups include, but are not limited to, where at least one atom on the ring is saturated and at least one atom is unsaturated In some embodiments, the partially unsaturated heterocyclyl is a polycyclic heterocyclyl and wherein at least one ring is an aromatic ring and at least one ring is a non-aromatic ring, which may be attached to other structures through an atom on the aromatic ring or may be attached to other structures through an atom on the non-aromatic ring. The 3-to 10-membered heterocyclic group may be specifically a 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocyclic group. In some embodiments, the heterocyclyl is monocyclic. In some embodiments, the heterocyclyl is polycyclic (e.g., fused, spiro, or bridged).

Herein, the term "heteroaryl" refers to an aromatic monocyclic or fused ring group formed from a carbon atom and at least one heteroatom, wherein the heteroatoms are independently selected from N, O and S. Each ring in the heteroaryl group is aromatic. Specific examples of 5-6 membered heteroaryl groups are monocyclic and include, but are not limited to, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine. Examples of 8-to 10-membered fused heteroaryl groups include, but are not limited to, benzopyrrole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzopyrazole, benzimidazole, benzopyridine, benzopyrimidine, benzopyrazine, thiazolothiazole, pyridopyridine, pyridopyrazine, pyridopyrimidine.

Herein, in the chemical structural formulaIndicating the connection location. When->Is contained in a cyclic group and is not indicated +.>When the ring atoms are attached, < >>May be attached to any ring atom, but only the formation of a stable or chemically feasible chemical is allowed. For example, a->Comprises-> And the like.

As used herein, the term "pharmaceutically acceptable salt" refers to salts formed with suitable non-toxic organic acids, inorganic acids, organic bases, or inorganic bases with a compound that retain the biological activity of the compound. The organic acid may be various organic acids capable of forming salts, which are conventional in the art, preferably one or more of methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid and salicylic acid. The mineral acid may be any of a variety of mineral acids conventionally known in the art capable of salt formation, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic base can be various organic bases capable of forming salts, which are conventional in the art, and preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines. The tertiary amine organic base is preferably triethylamine and/or N, N-diisopropylethylamine. The aniline organic base is preferably N, N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine. The inorganic base may be various inorganic bases capable of forming salts, which are conventional in the art, preferably one or more of alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate and sodium bicarbonate. The alkali metal hydride is preferably sodium hydride and/or potassium hydride. The alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.

In this context, the term "subject" includes any animal, preferably a mammal, more preferably a human.

As used herein, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the intended effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

In this context, the reagents and starting materials used are commercially available.

The invention has the positive progress effects that: the invention provides a compound with a novel structure, which has better SHP2 inhibition activity and/or tumor cell inhibition activity.

Detailed Description

The present disclosure is further illustrated by way of examples below, but is not thereby limited to the scope of the examples described. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Example 1

(S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1: 4-azido-6-bromonicotinaldehyde

At N ₂ Triazidosilane (115 mg,1.0mmol,1.0 eq) and TBAF (262 mg,1.0mmol,1.0 eq) were added to a suspension of 4-azido-6-bromonicotinaldehyde (221 mg,1.0mmol,1.0 eq) in tetrahydrofuran (10 ml), and the reaction mixture was stirred overnight at 25 ℃. After the completion of the reaction, water and ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with brine. The organic layer was taken up with Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with hexane and ethyl acetate (ethyl acetate ranging from 0-50%) to give the product as a white solid (146 mg, 64.2%).

Step 2: (E) -1- (4-azido-6-bromopyridin-3-yl) -N- (2, 3-dichlorophenyl) azomethine

2, 3-dichloroaniline (104 mg,0.643mmol,1.0 eq) was added to 4-azido-6-bromonicotinaldehyde (146 mg,0.643mmol,1.0 eq) in CH at 25 ℃ ₂ Cl ₂ (20 ml) of the above-mentioned solution. Triethylamine (195 mg,1929mmol,3 eq) and titanium (IV) chloride (73.2 mg, 0.383 mmol,0.6 eq) were then added in succession at 0 ℃. The mixture was stirred at 0deg.C for 3h, then at room temperatureStirring for 3h. The solvent was evaporated under vacuum. The product was suspended in toluene, filtered and the solution concentrated to give the crude product as a yellow solid for the next step without further purification. MS (ESI) m/z341.9[ m-28+H ] ⁺ 。

Step 3: 6-bromo-2- (2, 3-dichlorophenyl) -2H-pyrazolo [4,3-c ] pyridine

A solution of (E) -1- (4-azido-6-bromopyridin-3-yl) -N- (2, 3-dichlorophenyl) toluidine (239 mg, 0.640 mmol,1.0 eq) in toluene (20 ml) was stirred at 110℃under N ₂ Stir overnight. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel using (DCM/CH ₃ Oh=30/1) to give 6-bromo-2- (2, 3-dichlorophenyl) -2H-pyrazolo [4,3-c as a white solid]Pyridine (127 mg,57, 5%). MS (ESI) m/z 342.1[ m+H ]] ⁺ 。

Step 4: n- ((S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfamide

To 6-bromo-2- (2, 3-dichlorophenyl) -2H-pyrazolo [4,3-c ] at 25 DEG C]To a solution of pyridine (30 mg,0.087mmol,1.0 eq) in dioxane (8 ml) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (40.2 mg,0.131mmol,1.5 eq), BINAP (10.89 mg,0.017mmol,0.2 eq), sodium 2-methylpropan-2-ol (8.41 mg,0.087mmol,1.0 eq) and Pd ₂ (dba) ₃ (8.01 mg, 8.75. Mu. Mol,0.1 eq.). The mixture was stirred at 90℃for 1h under microwaves. After cooling to room temperature, the solution was concentrated and the residue was purified by flash column chromatography on silica gel using (DCM/CH ₃ Oh=30/1) to give N- ((S) -1' - (2, 3-dichlorophenyl) -2H-pyrazolyl [4, 3-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropane-2-sulfinamide (37 mg, 74.4%) as a yellow solid. MS (ESI) m/z 568.3[ m+H ]] ⁺ 。

Step 5: (S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

N- ((S) -1' - (2- (2- (2, 3-dichlorophenyl) -2H-pyrazolo [4, 3-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (37 mg,0.065mmol,1.0 eq) was dissolved in hydrochloric acid/dioxane (3 ml) and stirred at 25 ℃ for 30 min. The mixture was concentrated and the residue purified by prep. HPLC to give (S) -1' - (2, 3-dichlorophenyl) -2H-pyrazolo [4, 3-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-amine (3, 6mg,11, 91%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.98(s,1H),8.82(s,1H),7.84(dd,J＝8.1,1.2Hz,1H),7.68(dd,J＝7.9,1.2Hz,1H),7.60–7.51(m,1H),7.32–7.24(m,1H),7.20–7.06(m,3H),6.56(s,1H),4.17–4.01(m,2H),3.83(s,1H),3.08–2.92(m,3H),2.60(d,J＝15.6Hz,1H),1.89–1.74(m,1H),1.75–1.63(m,1H),1.51–1.39(m,1H),1.16–1.04(m,1H).MS(ESI)m/z 464.4[M+H] ⁺ .

The compounds of examples 2-7 were prepared with reference to example 1.

Example 2

(S) -1'- (2, 3-dichlorobenzyl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.86(s,1H),8.54(s,1H),7.60(d,J＝8.0Hz,1H),7.39–7.22(m,2H),7.20–7.07(m,3H),7.03(d,J＝7.6Hz,1H),6.50(s,1H),5.69(s,2H),4.09–3.87(m,2H),3.80(s,1H),3.04–2.81(m,3H),2.57(d,J＝15.6Hz,1H),1.86–1.73(m,1H),1.76–1.60(m,1H),1.51–1.39(m,1H),1.13–0.99(m,1H).MS(ESI)m/z 478.3[M+H] ⁺ .

Example 3

(1S) -1'- (2, 3-dihydro-1H-inden-1-yl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.82(s,1H),8.43(s,1H),7.40–7.32(m,1H),7.33–7.22(m,2H),7.19–6.99(m,5H),6.48(s,1H),6.18–6.04(m,1H),4.10–3.89(m,2H),3.79(s,1H),3.29–3.13(m,1H),3.06–2.81(m,5H),2.75–2.62(m,1H),2.62–2.43(m,1H),1.90–1.74(m,1H),1.74–1.58(m,1H),1.53–1.37(m,1H),1.16–0.98(m,1H).MS(ESI)m/z 436.4[M+H] ⁺ .

Example 4

(S) -1'- (2- (3-chloro-2-fluorophenyl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.00(s,1H),8.92(s,1H),7.95–7.85(m,1H),7.76–7.66(m,1H),7.46–7.38(m,1H),7.34–7.25(m,1H),7.21–7.07(m,3H),6.58(s,1H),4.17–4.01(m,2H),3.82(s,1H),3.11–2.90(m,3H),2.60(d,J＝15.6Hz,1H),1.89–1.76(m,1H),1.76–1.62(m,1H),1.56–1.40(m,1H),1.15–1.04(m,1H)；MS(ESI)m/z 449.4[M+H] ⁺ .

Example 5

(S) -1'- (2- (3-chloro-2-methylphenyl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.00(s,1H),8.74(s,1H),7.68(d,J＝7.7Hz,1H),7.55–7.39(m,2H),7.37–7.28(m,1H),7.27–7.08(m,3H),6.63(s,1H),4.24–4.02(m,2H),3.85(s,1H),3.13–2.91(m,3H),2.62(d,J＝15.6Hz,1H),2.51(s,2H),2.17(s,3H),1.94–1.80(m,1H),1.80–1.68(m,1H),1.60–1.43(m,1H),1.21–1.05(m,1H).MS(ESI)m/z 445.4[M+H] ⁺ .

Example 6

(1S) -1'- (2- (1, 2,3, 4-tetrahydronaphthalen-1-yl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.83(s,1H),8.29(s,1H),7.29(d,J＝6.2Hz,1H),7.24–7.10(m,5H),7.10–7.02(m,1H),6.75(d,J＝7.7Hz,1H),6.52(s,1H),5.88–5.76(m,1H),4.10–3.94(m,2H),3.82(s,1H),3.08–2.85(m,4H),2.85–2.75(m,1H),2.59(d,J＝15.6Hz,1H),2.43–2.29(m,1H),2.29–2.14(m,1H),1.99–1.88(m,1H),1.88–1.75(m,2H),1.76–1.63(m,1H),1.53–1.42(m,1H),1.16–1.04(m,1H).MS(ESI)m/z 450.5[M+H] ⁺ 。

Example 7

(S) -1'- (2- (naphthalen-1-yl) -2H-pyrazolo [4,3-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.03(s,1H),8.86(s,1H),8.16–8.03(m,2H),7.79–7.50(m,5H),7.37–7.23(m,1H),7.22–7.06(m,3H),6.66(s,1H),4.22–4.02(m,2H),3.84(s,1H),3.10–2.94(m,3H),2.61(d,J＝15.6Hz,1H),1.94–1.80(m,1H),1.80–1.66(m,1H),1.57–1.42(m,1H),1.19–1.06(m,1H).MS(ESI)m/z 446.4[M+H] ⁺

Example 8

(S) -1'- (4-amino-2- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1: 4-azido-6-chloro-2- (methylthio) pyrimidine-5-carbaldehyde

To a solution of 4, 6-dichloro-2- (methylthio) pyrimidine-5-carbaldehyde (779 mg,3.53mmol,1.0 eq) in tetrahydrofuran (10 ml) was added sequentially azido trimethylsilane (407 mg,3.53mmol,1.0 eq) and TBAF (924 mg,3.53mmol,1.0 eq) and the mixture was stirred overnight at 25 ℃. To the mixture was added water, the solution was extracted with ethyl acetate, and the organic layer was washed with brine (100 ml) and with Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with PE/ea=4/1 to give 4-azido-6-bromonaphthalene aldehyde as a white solid (534 mg, 66.8%).

Step 2 (E) -1- (4-azido-6-chloro-2- (methylthio) pyrimidin-5-yl) -N- (2, 3-dichlorophenyl) azomethine

2, 3-dichloroaniline (437mg, 2.70mmol,1.0 eq), triethylamine (82mg, 8.10mmol,3.0 eq) and titanium tetrachloride (307 mg,1.620mmol,0.6 eq) were added sequentially to 4-azido-6-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (620 mg,2.70mmol,1.0 eq) in CH at 0deg.C ₂ Cl ₂ (20 ml) of the above-mentioned solution. The mixture was stirred at 0 ℃ for 3h, then at room temperature for 3h. After concentration, the residue was suspended in toluene. The solution was filtered and concentrated to give (E) -1- (4-azido-6-chloro-2- (methylsulfanyl) pyrimidin-5-yl) -N- (2, 3-dichlorophenyl) azomethine (1009 mg, 100%) as a yellow solid. MS (ESI) m/z 345.0[ M-28+H] ⁺ .

Step 3: 4-chloro-2- (2, 3-dichlorophenyl) -6- (methylthio) -2H-pyrazolo [3,4-d ] pyrimidine

At N ₂ A solution of (E) -1- (4-azido-6-chloro-2- (methylthio) pyrimidin-5-yl) -N- (2, 3-dichlorophenyl) azomethine (1.0 g,2.68mmol,1.0 eq) in toluene (20 ml) was stirred overnight at 110 ℃. The solution was concentrated and the residue purified by flash column chromatography on silica gel using DCM/CH ₃ Oh=30/1 to give 4-chloro-2- (2, 3-dichlorophenyl) -6- (methylthio) -2H-pyrazolo [3,4-d as a white solid]Pyrimidine (580 mg, 62.7%).

MS(ESI)m/z 345.1[M+H] ⁺ .

Step 4:2- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -6- (methylthio) -2H-pyrazolo [3,4-d ] pyrimidin-4-amine

To 4-chloro-2- (2, 3-dichlorophenyl) -6- (methylthio) -2H-pyrazolo [3,4-d]To a solution of pyrimidine (200 mg,0.579mmol,1.0 eq) in dimethyl sulfoxide (10 ml) were added (2, 4-dimethoxyphenyl) methylamine (116 mg,0.694mmol,1.2 eq) and N-ethyl-N-isopropyl-propan-2-amine (112 mg,0.868mmol,1.5 eq), and after stirring at 25℃for 2h, water and ethyl acetate were added to the mixture. The combined organic layers were washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with PE/ea=1/1 to give 2- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -6- (methylthio) -2H-pyrazolo [3,4-d as a white solid]Pyrimidin-4-amine (262 mg, 95%). MS (ESI) m/z 477.6[ M+H ]] ⁺ .

Step 5:2- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -6- (methylsulfonyl) -2H-pyrazolo [3,4-d ] pyrimidin-4-amine

To 2- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -6- (methylthio) -2H-pyrazolo [3,4-d]Pyrimidine-4-amine (262 mg,0.550mmol,1.0 eq) CH ₂ Cl ₂ To a solution (10 ml) was added 1-chloro-3-hydroperoxybenzene (80 mg,0.550mmol,1.0 eq). The mixture was stirred at 0 ℃ for 30 minutes. Saturated NaHCO was added to the mixture ₃ (aq). The solution was extracted with ethyl acetate, and the organic layer was washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated to give 2- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -6- (methylsulfinyl) -2H-pyrazolo [3,4-d as a white solid]Pyrimidin-4-amine (270 mg, 100%).

Step 6: n- ((S) -1'- (2, 3-dichlorophenyl) -4- ((2, 4-dimethoxybenzyl) amino) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 2- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -6- (methylsulfonyl) -2H-pyrazolo [3,4-d ] at room temperature]To a solution of pyrimidin-4-amine (90 mg,0.183mmol,1.0 eq) in butanol (5 ml) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (84 mg,0.274mmol,1.5 eq) and N-ethyl-N-isopropylpropan-2 (70.9 mg, 0.268 mmol,3.0 eq). The mixture was stirred at 140℃under N ₂ Stirred for 1.5h. To the mixture was added water and ethyl acetate. The organic layer was washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by flash column chromatography on silica gel using DCM/CH ₃ Oh=50/1 elution to give N- ((S) -1- (2, 3-dichlorophenyl) -4- ((2, 4-dimethoxybenzyl) amino) -2H-pyrazolo [3, 4-d) as a white solid ]Pyrimidin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (75 mg, 55.8%).

MS(ESI)m/z 736.4[M+H] ⁺

Step 7: (S) -1'- (4-amino-2- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

At N ₂ Next, N- ((S) -1' - (2, 3-dichlorophenyl) -4- ((2, 4-dimethoxybenzyl) amino) -2H-pyrazolo [3, 4-d)]Pyrimidin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (90 mg,0.122mmol,1.0 eq) was stirred at 60℃for 2 hours. After concentration, it was dissolved with HCl/dioxane (8 ml). The mixture was stirred at room temperature for 2 hours, and the solution was concentrated. To the residue was added an methanolic ammonia solution. The solution was concentrated and the residue purified by prep. HPLC to give (S) -1' - (4-amino-2- (2, 3-dichlorophenyl) -2H-pyrazolo [3, 4-d) as a white solid]Pyrimidin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]1-amine (5.5 mg, 9.35%). ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.50(s,1H),7.80(d,J＝8.0Hz,1H),7.69(d,J＝7.0Hz,1H),7.57(t,J＝8.1Hz,1H),7.52–7.38(m,1H),7.36–7.28(m,1H),7.26–7.11(m,3H),4.73–4.56(m,2H),3.86(s,1H),3.20–3.01(m,3H),2.66(d,J＝15.6Hz,1H),1.81–1.66(m,1H),1.67–1.53(m,1H),1.49–1.39(m,1H),1.14–1.01(m,1H).MS(ESI)m/z 480.3[M+H] ⁺ .

Example 9

(S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1: 4-azido-2- (methylthio) pyrimidine-5-carbaldehyde

To a solution of 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (500 mg,2.65mmol,1.0 eq) in tetrahydrofuran (10 ml) was added azido trimethylsilane (305 mg,2.65mmol,1.0 eq) and TBAF (693 mg,2.65mmol, 1.0 eq). The mixture was stirred at 0℃for 3h. To the reaction solution were added water and ethyl acetate. The organic layer was separated and washed with brine (100 ml), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with PE/ea=4/1 to give 4-azido-2- (methylthio) pyrimidine-5-carbaldehyde as a white solid (460 mg, 89%). MS (ESI) m/z 168.1[ M-28+H] ⁺

Step 2: (E) -1- (4-azido-2- (methylthio) pyrimidin-5-yl) -N- (2, 3-dichlorophenyl) azomethine

To 4-azido-2- (methylthio) pyrimidine-5-carbaldehyde (516 mg,2.64mmol,1.0 eq) in CH ₂ Cl ₂ To a solution (20 ml) were added 2, 3-dichloroaniline (428 mg,2.64mmol,1.0 eq), triethylamine (803 mg,7.93mmol,3.0 eq) and titanium tetrachloride (301 mg,1.586mmol,0.6 eq) in this order. The mixture was stirred at 0℃for 3h and then at rt for 3h. After concentration, the product was suspended in toluene. The solution was filtered and concentrated to give the crude product as a yellow solid (897 mg, 100%) which was used in the next step without further purification. MS (ESI) m/z 311.1[ M-28+H] ⁺

Step 3 2- (2, 3-dichlorophenyl) -6- (methylthio) -2H-pyrazolo [3,4-d ] pyrimidine

At N ₂ A solution of (E) -1- (4-azido-2- (methylthio) pyrimidin-5-yl) -N- (2, 3-dichlorophenyl) azomethine (897 mg,2.64mmol,1.0 eq) in toluene (20 ml) was stirred overnight at 110 ℃. After concentration, the crude product was purified by flash column chromatography on silica gel using DCM/CH ₃ Oh=30/1 elution to give 2- (2, 3-dichlorophenyl) -6- (methylthio) -2H-pyrazolo [3,4-d as a yellow solid]Pyrimidine (442 mg, 53.7%). MS (ESI) m/z 311.2[ M+H ]] ⁺

Step 4:2- (2, 3-dichlorophenyl) -6- (methylsulfonyl) -2H-pyrazolo [3,4-d ] pyrimidine

To 2- (2, 3-dichlorophenyl) -6- (methylthio) -2H-pyrazolo [3,4-d]CH of pyrimidine (100 mg,0.321mmol,1.0 eq) ₂ Cl ₂ To a solution (10 ml) was added 1-chloro-3-hydroperoxybenzene (46.5 mg,0.321mmol,1.0 eq) and the mixture was stirred at 0deg.C for 30 min. Slowly adding saturated NaHCO ₃ (aq). The solution was extracted with ethyl acetate, and the organic layer was washed with brine (100 ml), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give 2- (2, 3-dichlorophenyl) -6- (methylsulfonyl) -2H-pyrazolo [3,4-d as a yellow solid]Pyrimidine (105 mg, 100%). MS (ESI) m/z 327.2[ M+H ]] ⁺ 。

Step 5N- ((S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

At N ₂ Next, 2- (2, 3-dichlorophenyl) -6- (methylsulfonyl) -2H-pyrazolo [3,4-d]To a solution of pyrimidine (105 mg,0.321mmol,1.0 eq) in butanol (5 ml) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (148 mg,0.481mmol,1.5 eq) and N-ethyl-N-isopropyl-propan-2-amine (124 mg,0.963mmol,3 eq) were stirred at 140℃for 1.5h. Water and ethyl acetate were added. The organic layer was separated and washed with brine (100 ml), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using DCM/CH ₃ Oh=50/1 elution to give N- ((S) -1' - (2, 3-dichlorophenyl) -2H-pyrazolo [3, 4-d) as a white solid]Pyrimidin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (83 mg, 45.4%). MS (ESI) m/z 571.3[ M+H ]] ⁺

Step 6: (S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To N- ((S) -1' - (2, 3-dichlorophenyl) -2H-pyrazolo [3, 4-d)]Pyrimidin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (90 mg,0.158mmol,1.0 eq) in dioxane was added HCl/dioxane (8 ml). The mixture was stirred at room temperature for 2 hours. After concentration, an methanolic ammonia solution was added. The solution was concentrated again. The crude product was purified by prep. HPLC to give (S) -1' - (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-d as a white solid]Pyrimidin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]1-amine (13.6 mg, 18.49%) ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.19(s,1H),8.74(s,1H),7.83(d,J＝8.1Hz,1H),7.70–7.63(m,1H),7.61–7.49(m,1H),7.31–7.23(m,1H),7.20–7.04(m,3H),4.68–4.47(m,2H),3.80(s,1H),3.19–3.00(m,3H),2.62(d,J＝15.6Hz,1H),1.79–1.67(m,1H),1.65–1.53(m,1H),1.51–1.40(m,1H),1.14–0.99(m,1H)；MS(ESI)m/z 465.4[M+H] ⁺

The compounds of examples 10-40 were prepared as described in reference to example 9.

Example 10

(S) -1'- (2-chloro-3-methylphenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.22(s,1H),8.70(s,1H),7.60–7.41(m,3H),7.37–7.26(m,1H),7.25–7.10(m,3H),4.72–4.52(m,2H),3.84(s,1H),3.26–3.17(m,2H),3.13(d,J＝11.3Hz,1H),2.65(d,J＝15.6Hz,1H),2.46(s,3H),1.82–1.71(m,1H),1.70–1.57(m,1H),1.57–1.45(m,1H),1.16–1.05(m,1H)；MS(ESI)m/z 445.8[M+H] ⁺ 。

Example 11

(S) -1'- (2-chloro-6-methylphenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.26(s,1H),8.65(s,1H),7.65–7.44(m,3H),7.40–7.29(m,1H),7.30–7.11(m,3H),4.79–4.54(m,2H),3.88(s,1H),3.30–3.21(m,2H),3.15(d,J＝15.5Hz,1H),2.68(d,J＝15.5Hz,1H),2.07(s,3H),1.90–1.76(m,1H),1.76–1.63(m,1H),1.62–1.47(m,1H),1.23–1.08(m,1H)；MS(ESI)m/z 445.4[M+H] ⁺

Example 12

(S) -1'- (2, 6-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.24(s,1H),8.72(s,1H),7.81–7.70(m,2H),7.70–7.58(m,1H),7.36–7.26(m,1H),7.23–7.06(m,3H),4.80–4.42(m,2H),3.84(s,1H),3.33–3.16(m,2H),3.11(d,J＝15.6Hz,1H),2.65(d,J＝15.6Hz,1H),1.87–1.70(m,1H),1.70–1.57(m,1H),1.58–1.44(m,1H),1.16–1.02(m,1H)；MS(ESI)m/z 465.4[M+H] ⁺

Example 13

(S) -1'- (2- (3-bromo-2-chlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.19(s,1H),8.73(s,1H),7.95(dd,1H),7.68(dd,J＝7.9,1.1Hz,1H),7.54–7.42(m,1H),7.34–7.22(m,1H),7.22–7.07(m,3H),4.68–4.48(m,2H),3.82(s,1H),3.27–3.14(m,2H),3.07(d,J＝15.7Hz,1H),2.63(d,J＝15.6Hz,1H),1.78–1.66(m,1H),1.66–1.52(m,1H),1.52–1.40(m,1H),1.14–1.02(m,1H)；MS(ESI)m/z 511.4[M+H] ⁺

Example 14

(S) -1'- (2-chloro-4, 5-difluorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.25(s,1H),8.78(s,1H),8.18–7.96(m,2H),7.40–7.26(m,1H),7.27–7.05(m,3H),4.76–4.51(m,2H),3.84(s,1H),3.32–3.18(m,2H),3.13(d,J＝15.6Hz,1H),2.66(d,J＝15.5Hz,1H),1.86–1.71(m,1H),1.71–1.57(m,1H),1.57–1.40(m,1H),1.17–1.04(m,1H)；MS(ESI)m/z 467.4[M+H] ⁺ 。

Example 15

(S) -1'- (2-chloro-3-fluorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.25(s,1H),8.82(s,1H),7.74–7.54(m,3H),7.42–7.26(m,1H),7.25–7.04(m,3H),4.75–4.51(m,2H),3.84(s,1H),3.34–3.16(m,2H),3.12(d,J＝15.6Hz,1H),2.66(d,J＝15.7Hz,1H),1.83–1.71(m,1H),1.72–1.58(m,1H),1.58–1.40(m,1H),1.18–1.01(m,1H)；MS(ESI)m/z 449.4[M+H] ⁺

Example 16

(S) -1'- (2-chloro-3-methoxyphenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.22(s,1H),8.73(s,1H),7.53(t,J＝8.2Hz,1H),7.43–7.33(m,1H),7.32–7.25(m,2H),7.26–7.09(m,3H),4.76–4.50(m,2H),3.97(s,3H),3.84(s,1H),3.32–3.17(m,1H),3.13(d,J＝15.6Hz,1H),2.66(d,J＝15.7Hz,1H),1.84–1.72(m,1H),1.71–1.60(m,1H),1.59–1.45(m,1H),1.19–1.04(m,1H)；MS(ESI)m/z 461.4[M+H] ⁺

Example 17

(S) -1'- (2- (pyridin-4-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.27(s,1H),9.24(s,1H),8.73(dd,J＝4.8,1.5Hz,2H),8.03(dd,J＝4.8,1.6Hz,2H),7.37–7.23(m,1H),7.23–7.04(m,3H),4.74–4.50(m,2H),3.83(s,1H),3.27–3.17(m,2H),3.10(d,J＝15.6Hz,1H),2.64(d,J＝15.7Hz,1H),1.81–1.70(m,1H),1.71–1.56(m,1H),1.60–1.46(m,1H),1.20–1.01(m,1H)；MS(ESI)m/z 398.3[M+H] ⁺

Example 18

(S) -1'- (2-chloro-6-methoxyphenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.16(s,1H),8.52(s,1H),7.64–7.50(m,1H),7.33–7.21(m,3H),7.21–7.07(m,3H),4.71–4.47(m,2H),3.82(s,1H),3.75(s,3H),3.27–3.13(m,2H),3.09(d,J＝15.7Hz,1H),2.63(d,J＝15.6Hz,1H),1.80–1.68(m,1H),1.69–1.55(m,1H),1.54–1.41(m,1H),1.15–1.01(m,1H)；MS(ESI)m/z 461.3[M+H] ⁺

Example 19

(S) -3- (6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -2H-pyrazolo [3,4-d ] pyrimidin-2-yl) -2-chlorophenol

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.19(s,1H),8.67(s,1H),7.38–7.24(m,2H),7.25–6.95(m,5H),4.72–4.46(m,2H),3.84(s,1H),3.32–3.15(m,2H),3.10(d,J＝15.7Hz,1H),2.65(d,J＝15.6Hz,1H),1.84–1.69(m,1H),1.69–1.56(m,1H),1.56–1.40(m,1H),1.16–0.99(m,1H).

Example 20

(S) -2- (6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -2H-pyrazolo [3,4-d ] pyrimidin-2-yl) -3-chlorophenol

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.18(s,1H),8.52(s,1H),7.40–7.28(m,2H),7.27–7.12(m,3H),7.12–6.93(m,2H),4.73–4.46(m,2H),3.87(s,1H),3.33–3.19(m,2H),3.13(d,J＝15.7Hz,1H),2.68(d,J＝15.7Hz,1H),1.85–1.72(m,1H),1.73–1.58(m,1H),1.59–1.44(m,1H),1.18–1.07(m,1H)；MS(ESI)m/z 447.4[M+H] ⁺

Example 21

(S) -1'- (2- (3-amino-2-chlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS(ESI)m/z 446.4[M+H] ⁺

Example 22

(S) -1'- (2- (2-chloro-6-isopropylphenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS(ESI)m/z 473.3[M+H] ⁺

Example 23

(S) -1'- (2- (2-chloro-6-ethylphenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS(ESI)m/z 459.4[M+H] ⁺

Example 24

(S) -1'- (2, 6-dichloro-4-fluorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.23(s,1H),8.68(s,1H),7.85(d,J＝8.4Hz,2H),7.36–7.25(m,1H),7.24–7.04(m,3H),4.70–4.50(m,2H),3.87(s,1H),3.27–3.16(m,2H),3.10(d,J＝15.7Hz,1H),2.67(d,J＝15.7Hz,1H),1.87–1.70(m,1H),1.67–1.56(m,1H),1.54–1.42(m,1H),1.20–1.06(m,1H)；MS(ESI)m/z 483.5[M+H] ⁺

Example 25

(S) -1'- (2, 6-dimethylphenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.18(s,1H),8.53(s,1H),7.43–7.32(m,1H),7.32–7.23(m,3H),7.23–7.11(m,3H),4.72–4.51(m,2H),3.83(s,1H),3.31–3.15(m,2H),3.10(d,J＝15.6Hz,1H),2.64(d,J＝15.6Hz,1H),1.96(s,6H),1.82–1.70(m,1H),1.71–1.58(m,1H),1.58–1.43(m,1H),1.16–1.04(m,1H)；MS(ESI)m/z 425.5[M+H] ⁺

Example 26

(S) -2- (6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -2H-pyrazolo [3,4-d ] pyrimidin-2-yl) -3-chlorobenzonitrile

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.30(s,1H),8.86(s,1H),8.13(d,J＝8.0Hz,2H),7.83(t,J＝8.0Hz,1H),7.34–7.26(m,1H),7.26–7.07(m,3H),4.73–4.44(m,2H),3.85(s,1H),3.31–3.17(m,2H),3.12(d,J＝15.6Hz,1H),2.66(d,J＝15.6Hz,1H),2.05–1.92(m,1H),1.83–1.73(m,1H),1.72–1.59(m,1H),1.57–1.48(m,1H),1.17–1.04(m,1H)；MS(ESI)m/z 456.4[M+H] ⁺

Example 27

(S) -1'- (2- (2-chloro-6- (trifluoromethyl) phenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.28(s,1H),8.76(s,1H),8.13(d,J＝8.0Hz,1H),8.03(d,J＝7.6Hz,1H),7.90(t,J＝8.1Hz,1H),7.38–7.29(m,1H),7.28–7.11(m,3H),4.77–4.51(m,2H),3.87(s,1H),3.33–3.20(m,2H),3.14(d,J＝15.6Hz,1H),2.68(d,J＝15.6Hz,1H),1.84–1.75(m,1H),1.75–1.61(m,1H),1.58–1.49(m,1H),1.20–1.07(m,1H)；MS(ESI)m/z 499.7[M+H] ⁺

Example 28

(S) -4- (6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -2H-pyrazolo [3,4-d ] pyrimidin-2-yl) -3, 5-dichlorobenzonitrile

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.30(s,1H),8.77(s,1H),8.46(s,2H),7.37–7.27(m,1H),7.27–7.11(m,4H),4.75–4.51(m,2H),3.86(s,1H),3.32–3.20(m,2H),3.14(d,J＝15.6Hz,1H),2.68(d,J＝15.4Hz,1H),1.86–1.73(m,1H),1.72–1.61(m,1H),1.61–1.44(m,1H),1.21–1.06(m,1H)；MS(ESI)m/z 490.3[M+H] ⁺

Example 29

(S) -1'- (2, 6-dichloro-3-methylphenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.26(s,1H),8.71(s,1H),7.67(s,2H),7.32(d,J＝6.1Hz,1H),7.25–7.09(m,3H),4.78–4.52(m,2H),3.86(s,1H),3.32–3.18(m,2H),3.14(d,J＝15.7Hz,1H),2.67(d,J＝15.5Hz,1H),2.45(s,3H),1.85–1.72(m,1H),1.72–1.61(m,1H),1.61–1.46(m,1H),1.17–1.07(m,1H)；MS(ESI)m/z 479.3[M+H] ⁺

Example 30

(S) -1'- (2- (1H-indazol-4-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)13.47(s,1H),9.22(s,1H),9.16(s,1H),8.56(s,1H),7.68(d,J＝7.4Hz,1H),7.62(d,J＝8.3Hz,1H),7.57–7.44(m,1H),7.38–7.27(m,1H),7.27–7.09(m,4H),4.83–4.49(m,2H),3.89(s,1H),3.34–3.19(m,2H),3.12(d,J＝15.7Hz,1H),2.69(d,J＝15.7Hz,1H),1.83–1.71(m,1H),1.73–1.58(m,1H),1.55–1.43(m,1H),1.18–1.05(m,1H)；MS(ESI)m/z 437.7[M+H] ⁺

Example 31

(S) -1'- (2- (6-chloroquinolin-5-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.31(s,1H),9.04(dd,J＝3.5,2.3Hz,1H),8.86(s,1H),8.31(d,J＝9.1Hz,1H),8.09(d,J＝9.1Hz,1H),7.75–7.52(m,2H),7.38–7.27(m,1H),7.26–7.09(m,3H),4.77–4.55(m,2H),3.86(s,1H),3.33–3.18(m,2H),3.14(d,J＝15.6Hz,1H),2.67(d,J＝15.7Hz,1H),1.87–1.73(m,1H),1.72–1.61(m,1H),1.59–1.47(m,1H),1.18–1.07(m,1H)；MS(ESI)m/z 482.4[M+H] ⁺

Example 32

(S) -1'- (2- (7-chloroquinolin-8-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.24(s,1H),8.88(dd,J＝4.2,1.6Hz,1H),8.68(s,1H),8.58(dd,J＝8.4,1.6Hz,1H),8.29(d,J＝8.9Hz,1H),7.93(d,J＝8.9Hz,1H),7.80–7.55(m,1H),7.34–7.23(m,1H),7.23–7.04(m,3H),4.76–4.48(m,2H),3.83(s,1H),3.29–3.16(m,1H),3.11(d,J＝15.7Hz,1H),2.65(d,J＝15.6Hz,1H),1.88–1.71(m,1H),1.70–1.57(m,1H),1.56–1.43(m,1H),1.16–1.00(m,1H)；MS(ESI)m/z 482.5[M+H] ⁺

Example 33

(S) -1'- (2, 4-dichlorophthal-1-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.30(s,1H),8.83(s,1H),8.33(d,J＝8.5Hz,1H),8.19(s,1H),7.91–7.81(m,1H),7.78–7.67(m,1H),7.37–7.27(m,1H),7.24–7.09(m,4H),4.80–4.54(m,2H),3.85(s,1H),3.32–3.19(m,2H),3.13(d,J＝15.6Hz,1H),2.67(d,1H),1.88–1.74(m,1H),1.71–1.59(m,1H),1.59–1.42(m,1H),1.18–1.02(m,1H)；MS(ESI)m/z 515.4[M+H] ⁺

Example 36

(S) -1'- (2- (2-methylquinolin-8-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.53(s,1H),9.25(s,1H),8.42(d,J＝8.3Hz,1H),8.31(d,J＝7.5Hz,1H),8.02(d,J＝7.8Hz,1H),7.78–7.64(m,1H),7.57(d,J＝8.4Hz,1H),7.39–7.25(m,1H),7.23–7.05(m,3H),4.77–4.51(m,2H),3.83(s,1H),3.30–3.18(m,2H),3.10(d,J＝15.5Hz,1H),2.71(s,3H),2.64(d,J＝15.6Hz,1H),1.83–1.68(m,1H),1.72–1.56(m,1H),1.55–1.38(m,1H),1.15–1.03(m,1H)；MS(ESI)m/z 462.4[M+H] ⁺

Example 35

(S) - (2- (6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -2H-pyrazolo [3,4-d ] pyrimidin-2-yl) -3-chlorophenyl) methanol

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.22(s,1H),8.62(s,1H),7.70–7.58(m,3H),7.41–7.25(m,1H),7.23–7.06(m,3H),5.47–5.25(m,1H),4.80–4.49(m,2H),4.20(s,2H),3.83(s,1H),3.31–3.17(m,2H),3.14(d,1H),2.65(d,J＝15.6Hz,1H),1.88–1.71(m,1H),1.69–1.56(m,1H),1.57–1.41(m,1H),1.15–0.98(m,1H)；MS(ESI)m/z 461.7[M+H] ⁺

Example 36

(S) -1'- (2- (5-Chloropheno [ d ] [1,3] dioxol-4-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.22(s,1H),8.68(s,1H),7.37–7.24(m,1H),7.23–7.07(m,5H),6.18(s,2H),4.72–4.47(m,2H),3.83(s,1H),3.30–3.15(m,2H),3.11(d,J＝15.6Hz,1H),2.65(d,J＝15.7Hz,1H),1.82–1.70(m,1H),1.70–1.56(m,1H),1.56–1.43(m,1H),1.19–1.01(m,1H)；MS(ESI)m/z 475.5[M+H] ⁺

Example 37

(S) -1'- (2, 6-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-amine

MS(ESI)m/z 466.2[M+H] ⁺

Example 38

(S) -1'- (2- (5-chloro-1H-indazol-4-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS(ESI)m/z 471.7[M+H] ⁺

Example 39

(S) -1'- (2- (5, 7-dichloropquinolin-6-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.33(s,1H),9.24(d,J＝3.7Hz,2H),8.85(s,1H),8.60(s,1H),7.43–7.28(m,1H),7.28–7.10(m,3H),4.79–4.58(m,2H),3.88(s,1H),3.34–3.19(m,2H),3.15(d,J＝15.7Hz,1H),2.69(d,J＝15.7Hz,1H),1.90–1.76(m,1H),1.75–1.60(m,1H),1.61–1.50(m,1H),1.20–1.07(m,1H)；MS(ESI)m/z 517.2[M+H] ⁺

Example 40

(S) -1'- (2- (5, 7, 8-trichloroquinoxalin-6-yl) -2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.38–9.29(m,1H),8.84(s,1H),7.41–7.30(m,1H),7.30–7.14(m,1H),4.81–4.56(m,2H),3.90(s,1H),3.35–3.23(m,2H),3.16(d,J＝15.7Hz,1H),2.71(d,J＝15.4Hz,1H),1.89–1.76(m,1H),1.76–1.62(m,1H),1.64–1.48(m,1H),1.24–1.08(m,1H)；MS(ESI)m/z 551.4[M+H] ⁺

Example 41:

(S) -1'- (2, 3-dichlorophenyl) -4-methyl-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1:2- (2, 3-dichlorophenyl) -4-methyl-6- (methylthio) -2H-pyrazolo [3,4-d ] pyrimidine

To 4-chloro-2- (2, 3-dichlorophenyl) -6- (methylthio) -2H-pyrazolo [3,4-d]To a solution of pyrimidine (100 mg,0.289mmol,1.0 eq) in dioxane (12 ml)/water (3 ml) was added 2,4, 6-trimethyl-1,3,5,2,4,6-trioxadiborane (803 mg,1.447mmol,5.0 eq), na ₂ CO ₃ (153 mg,1.447mmol,5.0 eq) and PdCl ₂ (dppf) (42.3 mg,0.058mmol,0.2 eq). The mixture was stirred at 110℃for 3 hours. To the solution was added water and ethyl acetate. The organic layer was separated and washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated. The crude product was passed through a silica gel flash columnChromatography purification by PE/EA=1/1 afforded 2- (2, 3-dichlorophenyl) -4-methyl-6- (methylthio) -2H-pyrazolo [3,4-d as a white solid ]Pyrimidine (36 mg, 38.3%). MS (ESI) m/z 325.2[ M+H ]] ⁺

Step 2- (2, 3-dichlorophenyl) -4-methyl-6- (methylsulfonyl) -2H-pyrazolo [3,4-d ] pyrimidine

To 2- (2, 3-dichlorophenyl) -4-methyl-6- (methylthio) -2H-pyrazolo [3,4-d]CH of pyrimidine (36 mg,0.111mmol,1.0 eq) ₂ Cl ₂ To a solution (10 ml) of 1-chloro-3-hydroperoxybenzene (16.00 mg,0.111mmol,1.0 eq) was added at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes. Addition of saturated NaHCO to the reaction mixture ₃ (aq). The solution was extracted with ethyl acetate. The combined organic layers were washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated to give 2- (2, 3-dichlorophenyl) -4-methyl-6- (methylsulfonyl) -2H-pyrazolo [3,4-d as a yellow solid]Pyrimidine (37.8 mg, 100%).

Step 3:N- ((S) -1'- (2, 3-dichlorophenyl) -4-methyl-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 2- (2, 3-dichlorophenyl) -4-methyl-6- (methylsulfonyl) -2H-pyrazolo [3,4-d]To a solution of pyrimidine (37.8 mg,0.111mmol,1.0 eq) in butan-1-ol (5 ml) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (40.7 mg,0.133mmol,1.2 eq) and N-ethyl-N-isopropyl-propan-2-amine (43.0 mg,0.332mmol,3 eq). The mixture was stirred under microwaves at 130 ℃ for 1.0 hour. Water and ethyl acetate were added, the organic layer was separated, and washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated. The crude product was added to the column and DCM/CH was used ₃ Oh=50/1 of the elution,obtaining N- ((S) -1' - (2, 3-dichlorophenyl) -4-methyl-2H-pyrazolo [3, 4-d) as a white solid]Pyrimidin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (40 mg, 61.9%). MS (ESI) m/z 584.7[ M+H ]] ⁺

Step 4: (S) -1'- (2, 3-dichlorophenyl) -4-methyl-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To dioxane (5 ml) of N- ((S) -1'- (2, 3-dichlorophenyl) -4-methyl-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide (40 mg,0.069mmol,1.0 eq) was added HCl/dioxane and the mixture stirred at rt for 2H. After concentration, an methanolic ammonia solution was added and the solution was concentrated again. The crude product was purified by prep. HPLC to give (S) -1'- (2, 3-dichlorophenyl) -4-methyl-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine (5.9 mg, 17.95%) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.90(s,1H),7.88(d,J＝8.0Hz,1H),7.75–7.68(m,1H),7.65–7.56(m,1H),7.38–7.27(m,1H),7.26–7.10(m,3H),4.80–4.55(m,2H),3.84(s,1H),3.29–3.17(m,2H),3.12(d,J＝15.6Hz,1H),2.74–2.59(m,4H),1.84–1.68(m,1H),1.71–1.57(m,1H),1.57–1.47(m,1H),1.19–1.04(m,1H)；MS(ESI)m/z 479.4[M+H] ⁺

Example 42

(S) -1'- (2, 3-dichlorophenyl) -2H-indazol-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine

Step 1: 2-azido-4-bromobenzaldehyde

Triazidomethylsilane (1.152 g,10.00mmol,1.0 eq) and TBAF (2.61 g,10.00mmol,1.0 eq) were added continuously to a solution of 4-bromo-2-fluorobenzaldehyde (2.03 g,10.00mmol,1.0 eq) in tetrahydrofuran (15 ml) at room temperature. The mixture was stirred at 25 ℃ overnight. To the mixture was added water and ethyl acetate. The organic layer was washed with brine (100 ml), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with PE/ea=99/1 to give 2-azido-4-bromobenzaldehyde as a white solid (1.53 g, 67.7%).

Step 2: (E) -1- (2-azido-4-bromophenyl) -N- (2, 3-dichlorophenyl) azomethine

To CH of 2-azido-4-bromobenzaldehyde (227 mg, 1.04 mmol,1.0 eq) at 0deg.C ₂ Cl ₂ To a solution (20 ml) were added 2, 3-dichloroaniline (163 mg, 1.04 mmol,1.0 eq), triethylamine (305 mg,3.01mmol,3.0 eq) and titanium (IV) chloride (114 mg,0.603mmol,0.6 eq). The mixture was stirred at 0 ℃ for 3 hours, then at room temperature for 3 hours. After concentration, the residue was suspended in toluene. The concentrated residue (372 mg, 100%) was filtered without further purification and used for the next step.

Step 3: 6-bromo-2- (2, 3-dichlorophenyl) -2H-indazole

At N ₂ A solution of (E) -1- (2-azido-4-bromophenyl) -N- (2, 3-dichlorophenyl) azomethine (372 mg,1.0mmol,1.0 eq) in toluene (20 ml) was stirred overnight at 110 ℃. After concentration, the residue was purified by flash chromatography on silica gel using DCM/CH ₃ Oh=30/1 to give 6-bromo-2- (2, 3-dichlorophenyl) -2H-indazole (254 mg, 73.9%) as a white solid. MS (ESI) m/z 341.0[ M+H ]] ⁺ .

Step 4N- ((S) -1'- (2, 3-dichlorophenyl) -2H-indazol-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To a solution of 6-bromo-2- (2, 3-dichlorophenyl) -2H-indazole (70 mg,0.205mmol,1.0 eq) in dioxane (8 ml) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine at 25 ℃]-1-yl) -2-methylpropan-2-sulfinamide (94 mg,0.307mmol,1.5 eq), xantphos (11.84 mg,0.020mmol,0.1 eq), cs ₂ CO ₃ (133 mg, 0.09 mmol,2.0 eq) and Pd ₂ (dba) ₃ (9.37 mg, 10.23. Mu. Mol,0.05 eq). At N ₂ The mixture was heated to 120 ℃ overnight. After concentration, the residue was purified by flash column chromatography on silica gel with DCM/CH ₃ Oh=30/1 elution to give N- ((S) -1'- (2, 3-dichlorophenyl) -2H-indazol-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) as a yellow solid]-1-yl) -2-methylpropan-2-sulfinamide (40 mg, 34.4%). MS (ESI) m/z 567.5[ M+H ]] ⁺ .

Step 5

(S) -1'- (2, 3-dichlorophenyl) -2H-indazol-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

N- ((S) -1'- (2, 3-dichlorophenyl) -2H-indazol-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) at 25 ℃]-1-yl) -2-methylpropan-2-sulfinamide (40 mg,0.070mmol,1.0 eq) was stirred in HCl/dioxane (3 ml) for 30 min. After concentration, the residue was purified by prep. HPLC to give (S) -1'- (2, 3-dichlorophenyl) -2H-indazol-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine as a white solid ]-1-amine (1.25 mg, 3.83%). ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.51(s,1H),7.87–7.74(m,1H),7.70–7.61(m,1H),7.60–7.48(m,2H),7.36–7.26(m,2H),7.23–7.08(m,4H),7.06–6.97(m,1H),6.81(s,1H),3.90(s,1H),3.68–3.52(m,2H),3.06–2.80(m,3H),2.70–2.57(m,1H),2.02–1.71(m,2H),1.59–1.47(m,1H),1.48–1.35(m,1H).MS(ESI)m/z 463.3[M+H] ⁺ .

Example 43

(S) -1'- (4-chloro-2- (2, 3-dichlorophenyl) -2H-indazol-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Prepared in accordance with example 42. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.67(s,1H),7.86(d,J＝8.1Hz,1H),7.70(d,J＝6.9Hz,1H),7.58(t,J＝8.1Hz,1H),7.37–7.27(m,1H),7.23–7.10(m,4H),6.82(s,1H),3.87(s,1H),3.70–3.53(m,2H),3.07–2.86(m,3H),2.61(d,J＝15.7Hz,1H),1.97–1.85(m,1H),1.79(d,J＝11.9Hz,1H),1.59–1.48(m,1H),1.21–1.10(m,1H).

Example 44

(S) -1'- (2, 3-dichlorophenyl) -3-methyl-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1

1- (4-azido-2- (methylthio) pyrimidin-5-yl) ethan-1-one

To 1- (4-chloro-2- (methylthio) pyrimidin-5-yl) ethan-1-one (0.49 mmol,100.0 mg) and TMSN ₃ To a solution of (1.5 eq, 0.74mmol,85.0 mg) in DCM (5 mL) was added TBAF (1.5 eq, 0.74mmol,194.0 mg). The reaction mixture was then stirred at rt for 12 hours. After removal of the solvent, the residue was diluted with DCM and washed with brine. Separating the organic layer, na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography (PE and EA, EA ranging from 0 to 80%)) 102.0mg of product was obtained as a yellow solid in 99% yield. MS (ESI) m/z 210.22[ M+H ]] ⁺ .

Step 2

(E) -4-azido-5- (1- (2, 3-dichlorophenyl) prop-1-en-2-yl) -2- (methylthio) pyrimidine

To 1- (4-azido-2- (methylthio) pyrimidin-5-yl) ethan-1-one (0.49 mmol,102.0 mg), 2, 3-dichloroaniline (1.2 eq, 0.59mmol,95.0 mg) and Et ₃ TiCl was added to a solution of N (3.0 eq, 1.46mmol,148.0 mg) in DCM (5 mL) ₄ (0.5 eq, 0.24mmol,46.2 mg). The reaction mixture was then stirred at 25 ℃ for 12 hours. After removal of the solvent, the residue was diluted with toluene and concentrated in vacuo to give 172.0mg of crude product as a brown solid, which was used directly in the next step. MS (ESI) m/z 352.10 and 354.05[ M+H ]] ⁺ .

Step 3:2- (2, 3-dichlorophenyl) -3-methyl-6- (methylthio) -2H-pyrazolo [3,4-d ] pyrimidine

To the vial were added (E) -4-azido-5- (1- (2, 3-dichlorophenyl) prop-1-en-2-yl) -2- (methylthio) pyrimidine (0.49 mmol,172.0 mg) and toluene (5 mL). The reaction mixture was then stirred at 120℃for 20 hours. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography (PE and EA ranging from 0 to 80%) to afford 16% (two-step yield) of 26.0mg of a yellow solid product, MS (ESI) m/z 325.10 and 327.05[ M+H ]] ⁺ .

Step 4 2- (2, 3-dichlorophenyl) -3-methyl-6- (methylsulfonyl) -2H-pyrazolo [3,4-d ] pyrimidine

To 2- (2, 3-dichlorophenyl) -3-methyl-6- (methylthio) -2H-pyrazolo [3,4-d under ice water bath]To a solution of pyrimidine (0.08 mmol,26.0 mg) in DCM (2 mL) was added m-CPBA (1.05 eq, 0.08mmol,14.49 mg). The reaction mixture was then stirred at 0 ℃ for 1 hour. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ Washing the solution. Separating the organic layer, na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give 27.3mg of crude product as a pale yellow solid, which is used directly in the next step, MS (ESI) m/z 341.10 and 343.05[ M+H ]] ⁺ .

Step 5N- ((S) -1'- (2, 3-dichlorophenyl) -3-methyl-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-thioamide

To 2- (2, 3-dichlorophenyl) -3-methyl-6- (methylsulfonyl) -2H-pyrazolo [3,4-d]To a solution of pyrimidine (0.08 mmol,27.3 mg) and DIEA (5.0 eq, 0.4mmol,51.7 mg) in N-BuOH (2 mL) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (1.5 eq, 0.12mmol,36.8 mg). The reaction mixture was then stirred under microwaves at 140 ℃ for 1 hour. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give 46.7mg of crude product as a pale brown solid, which is used directly in the next step, MS (ESI) m/z 583.10 and 585.15[ M+H ]] ⁺ .

Step 6 (S) -1'- (2, 3-dichlorophenyl) -3-methyl-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To N- ((S) -1' - (2, 3-dichlorophenyl) -3-methyl-2H-pyrazolo [3, 4-d) ]Pyrimidin-6-yl) -1, 3-dihydro-spiro[ indene-2, 4' -piperidine]To a solution of 1-yl) -2-methylpropan-2-sulfinamide (0.08 mmol,46.7 mg) in THF (2 mL) was slowly added HCl/dioxane (1N, 1 mL) and the reaction mixture was stirred at rt for 1 h. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography to give 5.3mg of the product as a white solid (three steps yield 14%).

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 9.22 (s, 1H), 7.92 (dd, j=7.9, 1.7hz, 1H), 7.68-7.60 (m, 2H), 7.30 (d, j=6.0 hz, 1H), 7.21-7.15 (m, 3H), 4.61 (t, j=14.3 hz, 2H), 3.82 (s, 1H), 3.28-3.16 (m, 2H), 3.11 (d, j=15.6 hz, 1H), 2.64 (d, j=15.7 hz, 1H), 2.41 (s, 3H), 1.75 (td, j=12.6, 4.0hz, 1H), 1.62 (td, j=12.6, 3.8hz, 1H), 1.50 (d, j=12.7 hz, 1H), 1.08 (d, j=12.7 hz, 1H) [ 1H ]) m/479.46.481 and [ m+25.m/3H ]] ⁺ .

Example 45

(S) -6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -2- (2, 6-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-3-ol

Step 1 2-chloro-4- (2, 6-dichlorophenyl) hydrazino) pyrimidine-5-carboxylic acid methyl ester

To 2, 4-dichloropyrimidine-5-carboxylic acid methyl ester (7.73 mmol,1.6 g) and Et ₃ To a solution of N (3.0 eq, 23.19mmol,2.35 g) in DMF (70 mL) was added (2, 6-dichlorophenyl) hydrazine (1.2 eq, 9.27mmol,1.64 g). The reaction mixture was then stirred at rt for 2 hours. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the crude product, which was purified by column chromatography (PE and EA ranging from 0 to 60%) to give 2.32g yield86% pale yellow solid product. ¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 9.98 (d, j=2.9 hz, 1H), 8.69 (s, 1H), 7.74 (d, j=3.0 hz, 1H), 7.37 (d, j=8.1 hz, 2H), 6.98 (t, j=8.1 hz, 1H), 3.89 (s, 3H) MS (ESI) m/z 347.04 and 349.06[ m+h ]] ⁺ .

Step 2 6-chloro-2- (2, 6-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-3-ol

To a solution of methyl 2-chloro-4- (2, 6-dichlorophenyl) hydrazino) pyrimidine-5-carboxylate (0.58 mmol,200.0 mg) in THF (5 mL) was added KHMDS (1N in THF, 1.15 mL) under an ice water bath. The reaction mixture was then stirred at 0 ℃ for 1 hour. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the crude product, which was purified by column chromatography (DCM and MeOH, meOH ranging from 0 to 10%) to give 112.0mg of a brown solid in 62% yield. MS (ESI) m/z 315.07 and 317.06[ M+H ]] ⁺ .

Step 3N- ((S) -1'- (2, 6-dichlorophenyl) -3-hydroxy-2H-pyrazolo [3,4-d ] pyrimidin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 6-chloro-2- (2, 6-dichlorophenyl) -2H-pyrazolo [3,4-d ]To a solution of pyrimidin-3-ol (0.09 mmol,27.0 mg) and DIEA (5.0 eq, 0.43mmol,55.3 mg) in N-BuOH (2 mL) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (1.5 eq, 0.13mmol,39.3 mg). The reaction mixture was then stirred under microwaves at 140 ℃ for 1 hour. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give 50.1mg of crude product as a pale brown solid, which was used directly in the next step. MS (ESI) m/z 585.31and 587.57[M+H] ⁺ .

Step 4 (S) -6- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -2- (2, 6-dichlorophenyl) -2H-pyrazolo [3,4-d ] pyrimidin-3-ol

To N- ((S) -1' - (2, 6-dichlorophenyl) -3-hydroxy-2H-pyrazolo [3, 4-d)]Pyrimidin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of-1-yl) -2-methylpropan-2-sulfinamide (0.09 mmol,50.1 mg) in tetrahydrofuran (2 mL) was slowly added HCl/dioxane (1N, 1 mL) and the reaction mixture was stirred at rt for 1 h. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography to give 16% (two-step yield) of the product as a yellow solid, 6.6mg.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.34(s,1H),7.56(d,J＝8.1Hz,2H),7.44(d,J＝7.5Hz,2H),7.31(d,J＝4.0Hz,2H),7.28–7.24(m,1H),4.57(t,J＝14.2Hz,2H),4.22(s,1H),3.16–3.08(m,3H),2.92(d,J＝16.1Hz,1H),1.73–1.61(m,2H),1.39(dd,J＝34.4,13.0Hz,2H).MS(ESI)m/z 481.41and 483.40[M+H] ⁺ .

Example 46

(S) -1'- (2, 3-dichlorophenyl) imidazo [2,1-b ] [1,3,4] thiadiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 2-bromo-6- (2, 3-dichlorophenyl) imidazo [2,1-b ] [1,3,4] thiadiazole

5-bromo-1, 3, 4-thiadiazol-2-amine (0.2 g,1.111 mmol) was reacted under Ar1.0 eq) and 2-bromo-1- (2, 3-dichlorophenyl) ethan-1-one (0.4476 g,1.666mmol,1.5 eq) were dissolved in ethanol (10 mL) to give a yellow solution. The reaction mixture was stirred at 85 ℃ for 12 hours. The reaction mixture was diluted with ethyl acetate. The reaction mixture was filtered through a buchner funnel and the filter cake was rinsed with ethyl acetate to give the product as a brown solid (0.31 g, 80%). MS (ESI) m/z 347.97[ M+H ]] ⁺ .

Step 2 (R) -N- ((S) -1'- (6- (2, 3-dichlorophenyl) imidazo [2,1-b ] [1,3,4] thiadiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

Under Ar, 2-bromo-6- (2, 3-dichlorophenyl) imidazo [2,1-b][1,3,4]Thiadiazole (0.1 g,0.287mmol,1.0 eq), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (0.105 g,0.344mmol,1.2 eq) and DIEA (0.111 g,0.860mmol, 3) were dissolved in DMF (3 mL) to give a yellow solution. The reaction mixture was stirred at 90℃for 12 hours. Addition of H to the reaction mixture ₂ O (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol in dichloromethane to give the product as a yellow oil (0.12 g, 72.9%) MS (ESI) m/z 547.32[ M+H)] ⁺ .

Step 3 (S) -1'- (6- (2, 3-dichlorophenyl) imidazo [2,1-b ] [1,3,4] thiadiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

(R) -N- ((S) -1' - (6- (2, 3-dichlorophenyl) imidazo [2, 1-b) under argon][1,3,4]Thiadiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (0.12 g,0.209mmol, 1.000) and HCl (0.076 g,2.085mmol, 9.98) were dissolved in 1, 4-dioxane (3 mL),a yellow solution was obtained. The reaction mixture was stirred at room temperature for 1 hour. Addition of saturated NaHCO to the reaction mixture ₃ (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column chromatography to give the product as a white solid (25.4 mg, 25.9%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.42(s,1H),8.03(dd,J＝7.9,1.5Hz,1H),7.54(dd,J＝7.9,1.5Hz,1H),7.40(t,J＝8.0Hz,1H),7.31(d,J＝6.0Hz,1H),7.21–7.13(m,3H),3.89(s,1H),3.74(t,J＝14.4Hz,2H),3.41(d,J＝12.3Hz,2H),3.07(d,J＝15.6Hz,1H),2.65(d,J＝15.9Hz,1H),1.93–1.72(m,2H),1.58(d,J＝13.9Hz,1H),1.19(d,J＝13.1Hz,1H).MS(ESI)m/z 470.29[M+H] ⁺ .

Example 47

(R) -N- ((S) -1'- (6-cyclopropylimidazo [2,1-b ] [1,3,4] thiadiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

Step 1 (R) -N- ((S) -1'- (5-amino-1, 3, 4-thiadiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfamide

5-bromo-1, 3, 4-thiadiazol-2-amine (0.070 g, 0.399mmol, 1 eq), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) was reacted under Ar]-1-yl) -2-methylpropan-2-sulfinamide (0.12 g, 0.390 mmol,1.0 eq) and TEA (0.119 g,1.175mmol,3 eq) were dissolved in ethanol (20 mL) to give a brown solution. The reaction mixture was stirred at 85 ℃ for 2 hours. The crude product was added to a silica gel column and eluted with 0% to 4% methanol in dichloromethane to give the product as a brown solid (0.14 g, 88%). MS (ESI) m/z 406.38[ M+H ]] ⁺ .

Step 2

Under Ar, (R) -N- ((S) -1'- (5-amino-1, 3, 4-thiadiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (0.14 g,0.345mmol,1.0 eq) and 2-bromo-1-cyclopropyl-1-one (0.113 g,0.690mmol,2 eq) were dissolved in ethanol (10 mL) to give a yellow solution. The reaction mixture was stirred at 85 ℃ for 12 hours. Addition of H to the reaction mixture ₂ O (10 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column chromatography to give the product as a white solid (16.0 mg, 9.9%), ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.53(s,1H),7.31(d,J＝5.3Hz,1H),7.21–7.14(m,3H),3.89(s,1H),3.74–3.59(m,2H),3.30–3.22(m,2H),3.05(d,J＝15.8Hz,1H),2.64(d,J＝15.8Hz,1H),1.89–1.79(m,2H),1.74(td,J＝12.7,4.4Hz,1H),1.53(d,J＝14.9Hz,1H),1.16(d,J＝13.8Hz,1H),0.80–0.75(m,2H),0.68–0.62(m,2H).MS(ESI)m/z366.26[M+H] ⁺ .

example 48

(S) -1'- (6- (2, 3-dichlorophenyl) -5-fluoroimidazo [2,1-b ] [1,3,4] thiadiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

(S) -1' - (6- (2, 3-dichlorophenyl) imidazo [2, 1-b) under Ar][1,3,4]Thiadiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidines]-1-amine (0.025 g,0.053mmol,1.0 eq) and 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo [2.2.2 ]]Octane bis (tetrafluoroborate) (0.028 g,0.080mmol,1.5 eq) was dissolved in acetonitrile (10 mL) to give a yellow solution. The reaction mixture was stirred at 50 ℃ for 12 hours. To the reaction mixtureAdding H into ₂ O (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column chromatography to give the product as a white solid (3.2 mg, 12.3%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.65(dd,J＝8.0,1.5Hz,1H),7.59(dd,J＝7.8,1.5Hz,1H),7.44(t,J＝7.9Hz,1H),7.31(d,J＝6.2Hz,1H),7.22–7.12(m,3H),3.88(s,1H),3.75(dd,J＝19.2,8.8Hz,2H),3.44(s,2H),3.06(d,J＝15.7Hz,1H),2.64(d,J＝15.7Hz,1H),1.88(td,J＝13.0,4.4Hz,1H),1.82–1.71(m,1H),1.57(d,J＝13.5Hz,1H),1.18(d,J＝13.9Hz,1H).MS(ESI)m/z 488.28[M+H] ⁺ .

Example 49

(S) -1'- (5- (2, 3-dichlorophenyl) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1N- ((S) -1'- (5-bromothiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

At N ₂ Down to 2, 5-dibromothiazolo [5,4-d ]]To a solution of thiazole (100 mg,0.333mmol,1.0 eq) in acetonitrile (15 ml) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (153 mg,0.500mmol,1.5 eq) and triethylamine (67.5 mg,0.667mmol,2.0 eq). The mixture was stirred at 110℃for 3 hours. Water and ethyl acetate were added. The organic layer was separated, washed with brine (100 ml), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated, and the crude product was purified by flash column chromatography on silica gel eluting with PE/ea=1/1 to give N- ((S) -1' - (5-bromothiazolo [5, 4-d) as a white solid]Thiazol-2-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (129 mg, 73.6)％)。MS(ESI)m/z 525.3[M+H] ⁺

Step 2N- ((S) -1'- (5- (2, 3-dichlorophenyl) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

At room temperature, at N ₂ Next, N- ((S) -1' - (5-bromothiazolo [5, 4-d)]Thiazol-2-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (129 mg,0.245mmol,1.0 eq) in dioxane (10 ml) and water (2 ml) was added (2, 3-dichlorobenzene) boric acid (56.2 mg,0.295mmol,1.2 eq), pdCl ₂ (17.96 mg,0.025mmol,0.1 eq) and K ₂ CO ₃ (102 mg,0.736mmol,3.0 eq). The mixture was heated to 110℃N ₂ Stirred for 16 hours. Water and ethyl acetate were added. The organic layer was separated and washed with brine (100 ml), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with PE/ea=1/1 to give N- ((S) -1' - (5- (2, 3-dichlorophenyl) thiazolo [5, 4-d) as a white solid]Thiazol-2-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (88 mg, 60.6%). MS (ESI) m/z 591.4[ M+H ]] ⁺

Step 3: (S) -1'- (5- (2, 3-dichlorophenyl) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To a solution of N- ((S) -1'- (5- (2, 3-dichlorophenyl) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide (87 mg,0.147mmol,1.0 eq) in dioxane was added HCl/dioxane (8 ml) and the mixture was stirred at rt for 2h. After concentration, an methanolic ammonia solution was added and the solution was concentrated again. The crude product was purified by prep. HPLC to give (S) -1'- (5- (2, 3-dichlorophenyl) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine (5.8 mg, 8.09%) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.10(dd,J＝8.0,1.5Hz,1H),7.72(dd,J＝8.0,1.5Hz,1H),7.49(t,J＝8.0Hz,1H),7.38–7.27(m,1H),7.24–7.10(m,3H),4.04–3.83(m,3H),3.56–3.37(m,2H),3.08(d,J＝15.7Hz,1H),2.65(d,J＝15.8Hz,1H),1.92–1.82(m,1H),1.81–1.71(m,1H),1.64–1.53(m,1H),1.23–1.14(m,2H)；MS(ESI)m/z 487.3[M+H] ⁺

Example 50:

(S) -1'- (5- ((2, 3-dichlorophenyl) thio) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1N- ((S) -1'- (5- ((2, 3-dichlorophenyl) thio) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

At room temperature, N ₂ Next, 2, 3-dichlorobenzethiol (51.1 mg, 0.284 mmol,1.5 eq) Pd ₂ (dba) ₃ (8.71 mg, 9.51. Mu. Mol, 0.05), xantphos (11.01 mg,0.019mmol,0.1 eq) and N-ethyl-N-isopropyl-propane-2-amine (49.2 mg,0.381mmol,2.0 eq) were added to N- ((S) -1' - (5-bromothiazolo [5, 4-d) in dioxane (3 ml)]Thiazol-2-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (100 mg,0.190mmol,1.0 eq). The mixture was stirred under microwaves at 90℃for 1.5h. To the solution was added water and ethyl acetate. The organic layer was washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with PE/ea=1/1 to give N- ((S) -1' - (5- ((2, 3-dichlorophenyl) thio) thiazolo [5, 4-d) as a white solid]Thiazol-2-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl)-2-methylpropane-2-sulfinamide (100 mg, 84%). MS (ESI) m/z 623.3[ M+H ] ] ⁺

Step 2: (S) -1'- (5- ((2, 3-dichlorophenyl) thio) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To a solution of dioxane in N- ((S) -1'- (5- ((2, 3-dichlorophenyl) thio) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide (100 mg,0.160mmol,1.0 eq) was added a 4N HCl/dioxane solution (8 ml). The mixture was stirred at room temperature for 2 hours. After concentration, an methanolic ammonia solution was added and the solution was concentrated again. The crude product was purified by prep. HPLC to give (S) -1'- (5- ((2, 3-dichlorophenyl) thio) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine (14.1 mg, 16.93%) as a white solid

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.57(dd,J＝8.0,1.2Hz,1H),7.38–7.27(m,2H),7.21–7.11(m,3H),7.03(dd,J＝8.0,1.2Hz,1H),4.01–3.80(m,3H),3.51–3.38(m,2H),3.07(d,J＝15.7Hz,1H),2.64(d,J＝15.7Hz,1H),1.91–1.80(m,1H),1.80–1.67(m,1H),1.64–1.51(m,1H),1.28–1.10(m,1H)；MS(ESI)m/z 519.1[M+H] ⁺

The compounds of examples 51 and 52 were prepared with reference to example 50.

Example 51

(S) -1'- (5- ((2-amino-3-chloropyridin-4-yl) thio) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS(ESI)m/z 501.2[M+H] ⁺

Example 52

(S) -1'- (5- ((2-amino-3-chloropyridin-4-yl) thio) thiazolo [5,4-d ] thiazol-2-yl) -5, 7-dihydrospiro [ b ] pyridin-6, 4' -piperidin ] -5-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.32(d,J＝4.3Hz,1H),7.73(d,J＝5.4Hz,1H),7.66(d,J＝7.4Hz,1H),7.27–7.09(m,1H),6.49(s,2H),5.93(d,J＝5.4Hz,1H),4.03–3.75(m,3H),3.60–3.39(m,2H),3.13(d,J＝16.3Hz,1H),2.77(d,J＝16.3Hz,1H),1.96–1.71(m,2H),1.68–1.55(m,1H),1.30–1.16(m,1H)；MS(ESI)m/z 501.0[M+H] ⁺

Example 53 (S) -1'- (5- (2, 3-dichlorophenoxy) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 2-bromo-5- (2, 3-dichlorophenoxy) thiazolo [5,4-d ] thiazole

Under Ar, 2, 5-dibromothiazolo [5,4-d ]]Thiazole (0.2 g,0.667mmol,1.0 eq), 2, 3-dichlorophenol (0.109 g,0.667mmol,1 eq) and K ₂ CO ₃ (0.184 g,1.333mmol,2 eq) was dissolved in DMF (3 mL) to give a yellow suspension. The reaction mixture was stirred at 80℃for 2 hours. By H ₂ O (20 mL) dilutes the reaction mixture. The reaction mixture was filtered through a Buchner funnel and the filter cake was rinsed with water to give the product as a brown solid (0.23 g, 90%), MS (ESI) m/z 382.17[ M+H ]] ⁺ .

Step 2N- ((S) -1'- (5- (2, 3-dichlorophenoxy) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

Under Ar, 2-bromo-5- (2, 3-dichlorophenoxy) thiazolo [5,4-d]Thiazole (0.05 g,0.131mmol,1.0 eq), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (0.060 g,0.196mmol,1.5 eq) and K ₂ CO ₃ (0.054 g,0.393mmol,3 eq) was dissolved in NMP (2 mL) to give a yellow suspension. The reaction mixture was stirred at 115 ℃ for 3 hours. Addition of H to the reaction mixture ₂ O (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was applied to a silica gel column and eluted with 0% to 3% methanol in dichloromethane to give the product as a yellow oil (0.05 g, 62.9%), MS (ESI) m/z 607.28[ M+H ]] ⁺ .

Step 3 (S) -1'- (5- (2, 3-dichlorophenoxy) thiazolo [5,4-d ] thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Under Ar, N- ((S) -1' - (5- (2, 3-dichlorophenoxy) thiazolo [5, 4-d)]Thiazol-2-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (0.05 g,0.082mmol,1.0 eq) and HCl (0.030 g,0.823mmol,10 eq) were dissolved in 1, 4-dioxane (2 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Addition of saturated NaHCO to the reaction mixture ₃ (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column chromatography to give the product as a white solid (3.3 mg, 7.9%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.64(dd,J＝8.0,1.5Hz,1H),7.57(dd,J＝8.3,1.5Hz,1H),7.49(t,J＝8.2Hz,1H),7.31(d,J＝5.3Hz,1H),7.20–7.14(m,3H),3.88(s,1H),3.80(ddd,J＝13.2,9.6,3.9Hz,2H),3.24(d,J＝3.0Hz,2H),3.05(d,J＝15.7Hz,1H),2.63(d,J＝15.7Hz,1H),1.88–1.79(m,1H),1.73(dd,J＝12.4,8.4Hz,1H),1.54(d,J＝13.5Hz,1H),1.17(d,J＝13.8Hz,1H).MS(ESI)m/z 503.23[M+H] ⁺ .

The compounds of examples 54-55 were prepared according to example 53.

EXAMPLE 54 (S) -5- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -N- (2, 3-dichlorophenyl) thiazolo [5,4-d ] thiazol-2-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.19(d,J＝8.3Hz,1H),7.36–7.29(m,2H),7.26(d,J＝7.9Hz,1H),7.18(d,J＝4.3Hz,3H),3.91(s,1H),3.78(t,J＝11.4Hz,2H),3.24(d,J＝12.4Hz,3H),3.06(d,J＝15.8Hz,1H),2.66(d,J＝15.5Hz,1H),1.85(td,J＝12.5,4.0Hz,1H),1.74(t,J＝10.5Hz,1H),1.54(d,J＝13.1Hz,1H),1.19(d,J＝13.9Hz,1H).MS(ESI)m/z 502.26[M+H] ⁺ .

Example 55

(S) -5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -N- (2, 3-dichlorophenyl) -N-methylthiazol [5,4-d ] thiazol-2-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.73(dd,J＝8.1,1.5Hz,1H),7.65–7.61(m,1H),7.52(t,J＝8.0Hz,1H),7.30(d,J＝5.9Hz,1H),7.20–7.12(m,3H),3.85(s,1H),3.78–3.67(m,2H),3.37(s,3H),3.26–3.14(m,2H),3.03(d,J＝15.7Hz,1H),2.61(d,J＝15.7Hz,1H),1.83(td,J＝12.9,4.5Hz,1H),1.71(td,J＝12.7,4.3Hz,1H),1.51(d,J＝13.4Hz,1H),1.13(d,J＝13.6Hz,1H).MS(ESI)m/z 516.17[M+H] ⁺ .

Example 56

(S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1:3, 5-dichloropyrazine-2-carbonyl

Step 1:3, 5-dichloropyrazine-2-carbaldehyde

At N ₂ To a solution of 2, 6-tetramethylpiperidine (2.133 g,15.10mmol,1.5 eq) in 2-methyltetrahydrofuran (15 ml) was added 2.5N N-butyllithium (0.774 g,12.08mmol,1.2 eq) at-30 ℃. The mixture was stirred at 0℃for 1 hour. Then 2, 6-dichloropyrazine (1.5 g,10.07mmol,1.0 eq) was added at-78℃and N at-78 ℃ ₂ The mixture was stirred for 2 hours. Methyl formate (0.227 g,15.10mmol,1.5 eq) was added under nitrogen at-78℃and the mixture stirred at-78℃for 2 hours. Acetic acid and water were slowly added to neutralize the solution. The solution was extracted with ethyl acetate. The organic layer was separated and washed with brine (100 ml), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with PE/ea=5/1 to give 3, 5-dichloropyrazine-2-carbaldehyde as a white solid (480 mg, 55.0%). MS (ESI) m/z 177.0[ M+H ]] ⁺

Step 2: n- ((S) -1'- (6-chloro-5-formylpyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

N- ((S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine) at room temperature]-1-yl) -2-methylpropan-2-sulfinamide (100 mg,0.326mmol,1.0 eq) and CsF (248 mg,1.63mmol,5.0 eq) were added to a solution of 3, 5-dichloropyrazine-2-carbaldehyde (87 mg, 0.4819 mmol,1.5 eq) in DMF (5 ml). At 140℃under N ₂ The mixture was stirred for 1.5h. Water and ethyl acetate were added. The organic layer was separated, washed with saturated brine (100 ml), and dried over Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using DCM/CH ₃ OH＝50/1 elution to give N- ((S) -1'- (6-chloro-5-formylpyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) as a yellow solid]-1-yl) -2-methylpropan-2-sulfinamide (81 mg, 55.5%). MS (ESI) m/z 448.4[ M+H ]] ⁺

Step 3: n- ((S) -1'- (6-azido-5-formylpyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To N- ((S) -1'- (6-chloro-5-formylpyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (81 mg,0.181mmol,1.0 eq) in tetrahydrofuran (10 ml) were added azido trimethylsilane (20.88 mg,0.181mmol,1.0 eq) and tetrabutylammonium fluoride (47.4 mg,0.181mmol,1.0 eq). The mixture was stirred at 0℃for 3 hours. Ethyl acetate and water were added. The organic layer was separated, washed with saturated brine (100 ml), and dried over Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using DCM/CH ₃ Oh=50/1 elution to give a white solid N- ((S) -1'- (6-azido-5-formylpyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (60 mg, 73.0%). MS (ESI) m/z 454.6[ M+H ]] ⁺

Step 4: n- ((S) -1'- (6-azido-5- ((E) - (2, 3-dichlorophenyl) imino) methyl) pyrazin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To a solution of N- ((S) -1'- (6-chloro-5-formylpyrazin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide (60 mg,0.134mmol,1.0 eq) in DCM (15 ml) was added 2, 3-dichloroaniline (21.75 mg,0.134mmol,1.0 eq), triethylamine (40.7 mg,0.403mmol,3.0 eq) and titanium (IV) chloride (15.28 mg,0.081mmol,0.6 eq) in this order at 0 ℃. The mixture was stirred at 0℃for 3h and then at rt for 3h. After concentration, the product was suspended in toluene. The solution was filtered and concentrated to ((S) -1'- (6-azido-5- ((E) - (2, 3-dichlorophenyl) imino) methyl) pyrazin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide (80 mg, 100%) in the form of a yellow solid.

Step 5N- ((S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

At N ₂ (N- ((S) -1'- (6-azido-5- ((E) - (2, 3-dichlorophenyl) imino) methyl) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]A solution of (1-yl) -2-methylpropan-2-sulfinamide (80 mg,0.134mmol,1.0 eq) in toluene (15 ml) was stirred overnight at 110 ℃. After concentration, the crude product was purified by flash column chromatography on silica gel using DCM/CH ₃ Oh=50/1 elution to give N- ((S) -1' - (2, 3-dichlorophenyl) -2H-pyrazolo [3, 4-b) as a yellow solid]Pyrazin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (30 mg, 39.3%).

Step 6: (S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To a solution of N- ((S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide (30 mg,0.053mmol,1.0 eq) dioxane (5 ml) was added HCl/dioxane. The mixture was stirred at room temperature for 2 hours. After concentration, an methanolic ammonia solution was added and the solution was concentrated again. The crude product was purified by prep. HPLC to give (S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-b ] pyrazin-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine (1 mg, 4.08%) as a white solid.

MS(ESI)m/z 465.3[M+H] ⁺

Example 57:

(S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-c ] pyridin-6-yl) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine

Step 12, 3-dichloro-N- (4, 6-dibromopyridin-3-yl) benzamide

To CH of 4, 6-dibromopyridin-3-amine (100 mg,0.397mmol,1.0 eq) at 0deg.C ₂ Cl ₂ To a solution of (10 ml) were added pyridine (94 mg,1.191mmol,3.0 eq) and 2, 3-dichlorobenzoyl chloride (125 mg,0.595mmol,1.5 eq). The mixture was stirred at 25℃under N ₂ Stirred for 16 hours. Water and dichloromethane were added. The organic layer was separated and washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel using DCM/CH ₃ Oh=50/1 to give 2, 3-dichloro-N- (4, 6-dibromopyridin-3-yl) benzamide (150 mg, 89%) as a white solid. MS (ESI) m/z 423.0[ M+H ]] ⁺

Step 2: 6-bromo-2- (2, 3-dichlorophenyl) oxazolo [4,5-c ] pyridine

To a solution of 2, 3-dichloro-N- (4, 6-dibromopyridin-3-yl) benzamide (280 mg,0.659mmol,1.0 eq) in DMF (10 ml) was added Na at 25 ℃ ₂ CO ₃ (698 mg,6.59mmol,10 eq). The mixture was stirred at 110℃for 16 hours. Water and ethyl acetate were added. The organic layer was separated and washed with brine (100 ml), na ₂ SO ₄ Dried, filtered and concentrated. The crude product was passed through a silica gel flash column layer Purification by DCM/CH ₃ Oh=50/1 elution to give 6-bromo-2- (2, 3-dichlorophenyl) oxazolo [4,5-c ] as a white solid]Pyridine (140 mg, 61.8%). MS (ESI) m/z 343.0[ M+H ]] ⁺

Step 3: n- ((S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

N- ((S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine) was reacted under nitrogen at 25 ℃]-1-yl) -2-methylpropan-2-sulphoxide amide (134 mg, 0.433 mmol,1.5 eq), sodium 2-methylpropan-2-alkoxide (84 mg,0.872mmol,3.0 eq), 2 '-bis (diphenylphosphino) -1,1' -binaphthyl (36.2 mg,0.058mmol,0.2 eq) and Pd ₂ (dba) ₃ (26.6 mg,0.029mmol,0.1 eq) to 6-bromo-2- (2, 3-dichlorophenyl) oxazolo [4, 5-c)]In a dioxane (5 ml) solution of pyridine, the mixture was stirred under microwaves at 90℃for 1 hour. The solution was cooled to room temperature and concentrated. The residue was purified by flash column chromatography on silica gel using DCM/CH ₃ Oh=30/1 elution to give N- ((S) -1' - (2, 3-dichlorophenyl) oxazolo [4,5-c ] as a yellow solid]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (23 mg, 13.89%). MS (ESI) m/z 570.9[ M+H ]] ⁺

Step 4: (S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To N- ((S) -1' - (2, 3-dichlorophenyl) oxazolo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (22 mg,0.039mmol,1.0 eq) in dioxane (5 ml) was added HCl/dioxane (5 ml). The mixture was stirred at room temperature for 2 hours. After concentration, an methanolic ammonia solution was added and the solution was concentrated again. Purification of the residue by pre-HPLC gave (S) -1' - (2, 3-dichlorophenyl) oxazolo [4,5-c ] as a white solid]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-amine (3.9 mg, 21.70%). MS (ESI) m/z 465.4[ M+H ]] ⁺

Example 58

(S) -4-amino-6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -2- (2, 3-dichlorobenzyl) isoindolin-1-one

Step 1: 5-bromo-3- (tert-butoxycarbonyl) amino) -2-methylbenzoic acid methyl ester

To 3-amino-5-bromo-2-methylbenzoic acid methyl ester (10.0 mmol,2.44 g), DMAP (5 mol%,0.5mmol,61.0 mg) and Et ₃ N (3.0 eq, 30.0mmol,3.04 g) to a suspension of MeCN (100 mL) Boc was added ₂ O (1.05 eq, 10.5mmol,2.29 g). The reaction mixture was then stirred at rt for 12 hours. After the reaction was completed, the resulting mixture was diluted with ethyl acetate and washed with brine. The separated organic layer was dried over MgSO ₄ The upper was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA ranging from 0 to 60%) to give 1.94g of the product as a pale yellow solid in 56% yield. MS (ESI) m/z 344.20 and 346.14[ M+H ]] ⁺ .

Step 2: 5-bromo-2- (bromomethyl) -3- (tert-butoxycarbonyl) amino) benzoic acid methyl ester

To methyl 5-bromo-3- (tert-butoxycarbonyl) amino) -2-methylbenzoate (5.64 mmol,1.94 g) and AIBN (20 mol%,1.13mmol,185.0 mg) in CCl ₄ NBS (1.1 eq, 6.2mmol,1.1 g) was added to the suspension in (50 mL). The reaction mixture was then stirred at 80℃for 3 hours. After completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The separated organic layer was dried over MgSO ₄ Drying, filtering and concentrating in vacuo to give the crude product, and purifying by column chromatographyPurification (PE and EA ranging from 0 to 40%) gave 1.14g of the product as a pale yellow oil in 48% yield. MS (ESI) m/z 421.95 and 423.87[ M+H ]] ⁺ .

Step 3: (6-bromo-2- (2, 3-dichlorobenzyl) -1-oxoisoindolin-4-yl) carbamic acid tert-butyl ester

To methyl 5-bromo-2- (bromomethyl) -3- ((tert-butoxycarbonyl) amino) benzoate (0.84 mmol,356.0 mg) and Cs ₂ CO ₃ (4.0 eq, 3.37mmol,1.09 g) to a suspension of (2, 3-dichlorophenyl) methylamine (1.2 eq, 1.01mmol,178.0 mg) in THF (8 mL). The reaction mixture was then stirred at rt for 12 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO ₄ The upper was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to give 338.0mg of a pale brown solid in 83% yield. MS (ESI) m/z 485.16 and 487.11[ M+H ]] ⁺ .

Step 4: tert-butyl (6- ((1S) -1- ((tert-butylsulfoxide) amino) -1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -2- (2, 3-dichlorobenzyl) -1-oxoisoindolin-4-yl) carbamate

N- ((S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine under Ar]-1-yl) -2-methylpropan-2-sulfinamide (1.2 eq, 0.37mmol,113.0 mg) was added to tert-butyl (6-bromo-2- (2, 3-dichlorobenzyl) -1-oxoisoindolin-4-yl) carbamate (0.31 mmol,150.0 mg), pd ₂ (dba) ₃ (10 mol%,0.03mmol,28.3 mg), xantphos (20 mol%,0.06mmol,35.7 mg) and Cs ₂ CO ₃ (3.0 eq, 0.93mmol,302.0 mg) in dioxane (3 ml). The reaction mixture was then stirred at 120℃for 12 hours. After removal of the solvent, the residue was diluted with EA and washed with brine.Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography (DCM and MeOH, meOH ranging from 0 to 10%) to afford 111.0mg of product in 51% yield as a light brown solid. MS (ESI) m/z 710.85 and 712.89[ M+H ] ] ⁺ .

Step 5: (S) -4-amino-6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -2- (2, 3-dichlorobenzyl) isoindolin-1-one

To tert-butyl (6- ((1S) -1- ((tert-butyl sulfoxide) amino) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine)]To a solution of (1' -yl) -2- (2, 3-dichlorobenzyl) -1-oxoisoindolin-4-yl) carbamate (0.16 mmol,111.0 mg) in dioxane (2 ml) was added HCl/dioxane (1.0 ml,2.0 ml). The reaction mixture was then stirred at room temperature for 2 hours. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography to give 1.5mg of the product as a white solid in 2% yield.

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 7.61 (d, j=8.6 hz, 1H), 7.39-7.31 (m, 1H), 7.19-7.13 (m, 5H), 6.47 (d, j=25.5 hz, 2H), 5.20 (s, 2H), 4.82 (s, 2H), 4.07 (s, 2H), 3.86 (s, 1H), 3.51 (t, j=11.2 hz, 1H), 3.00 (d, j=15.7 hz, 1H), 2.93-2.84 (m, 1H), 2.67-2.58 (m, 1H), 2.03-1.96 (m, 2H), 1.89-1.72 (m, 1H), 1.51-1.42 (m, 1H), 1.33-1.14 (m, 3H), 0.85 (t, j=6.5 hz, 1H) MS (ESI) m/507.36 +z and [ m/507.36.23H ]] ⁺ .

The compound of example 59 was prepared as described in example 58.

Example 59

(S) -4-amino-6- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -2- (2, 3-dichlorophenyl) isoindolin-1-one

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 7.71 (dd, j=8.1, 1.4hz, 1H), 7.59 (dd, j=7.9, 1.4hz, 1H), 7.52-7.45 (m, 1H), 7.35 (d, j=4.5 hz, 1H), 7.20 (dd, j=7.5, 3.6hz, 4H), 6.53 (dd, j=11.5, 1.7hz, 1H), 5.32 (d, j=7.7 hz, 1H), 4.52 (s, 1H), 3.96 (s, 1H), 3.55 (d, j=13.0 hz, 1H), 3.03 (d, j=15.6 hz, 1H), 2.96-2.90 (m, 2H), 2.71-2.66 (m, 2H), 2.03-1.94 (m, 2H), 1.89-1.75 (m, 1.75), 1.52 (s, 1H), 3.96 (s, 1H), 3.55 (d, j=13.0 hz, 1H), 3.03 (d, 1H), 2.71-2.66 (m, 2H), 2.03-1.03 (2H), 2.82 (m, 35 (2H), 1.82 (2 m, 35 (2H), 1.52 (2 m, 1.35 (1H), 1.52 (35 (1H), 1.35 (2 z, 1H), 1.38, 1H)] ⁺ .

Example 60

(S) -4-amino-2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6- (2, 3-dichlorobenzyl) -5, 6-dihydro-7H-pyrrolo [3,4-d ] pyrimidin-7-one

Step 1:5- ((2, 3-dichlorobenzyl) amino) methyl) -2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidine-4-carboxylic acid

To a suspension of 2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidine-4-carboxylic acid (9.61 mmol,1.5 g) and formaldehyde (5.0 eq, 48.0mmol,1.443 g) in ethanol (100 mL) was added (2, 3-dichlorophenyl) carboxamide (2.0 eq, 19.22mmol,3.38 g). The reaction mixture was then stirred at 100 ℃ for 16 hours. After completion of the reaction, the resulting mixture was filtered to give 2.12g of a crude product as a white solid in a yield of 64% which was used directly in the next step. MS (ESI) m/z 344.14 and 346.10[ M+H ] ] ⁺ .

Step 2 6- (2, 3-dichlorobenzyl) -2, 4-dihydroxy-5, 6-dihydro-7H-pyrrolo [3,4-d ] pyrimidin-7-one

To a suspension of 5- ((2, 3-dichlorobenzylamino) methyl) -2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidine-4-carboxylic acid (6.16 mmol,2.12 g) in 2-methoxyethanol (50 mL) was added HCl (20.0 eq, 123.0mmol,4.49 g). The reaction mixture was then stirred at 130 ℃ for 16 hours. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ Washing the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to afford 835.0mg of product in 42% yield as a pale yellow solid.

MS (ESI) m/z 326.15 and 328.06[ M+H ]] ⁺ .

Step 32, 4-dichloro-6- (2, 3-dichlorobenzyl) -5, 6-dihydro-7H-pyrrolo [3,4-d ] pyrimidin-7-one

DIEA (3.0 eq, 7.68mmol,993.0 mg) was added to 6- (2, 3-dichlorobenzyl) -5, 6-dihydro-1H-pyrrolo [3, 4-d)]POCl of pyrimidine-2, 4,7 (3H) -trione (2.56 mmol,835.0 mg) ₃ (25 mL) in suspension. The reaction mixture was then stirred at 90℃for 3 hours. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to give 44.0mg of a pale yellow solid in 5% yield. (ESI) m/z 364.04 and 366.09[ M+H ] ] ⁺ .

Step 4 2-chloro-6- (2, 3-dichlorobenzyl) -4- ((3, 4-dimethylbenzyl) amino) -5, 6-dihydro-7H-pyrrolo [3,4-d ] pyrimidin-7-one

To 2, 4-dichloro-6- (2, 3-dichlorobenzyl) -5, 6-dihydro-7H-pyrrolo [3,4-d]Pyrimidin-7-one (0.12 mmol,44.0 mg) and DIEA (5.0 eq, 0.61 mmol)To a suspension of 78.0mg of DMSO (2 ml) was added (2, 4-dimethoxyphenyl) methylamine (1.2 eq, 0.15mmol,24.32 mg). The reaction mixture was then stirred at 120℃for 12 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO ₄ The above was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA ranging from 0 to 70%) to give 60.0mg of a pale yellow solid in 100% yield. MS (ESI) m/z 493.23 and 495.18[ M+H ]] ⁺ .

Step 5N- ((S) -1'- (6- (2, 3-dichlorobenzyl) -4- ((3, 4-dimethylbenzyl) amino) -7-oxo-6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 2-chloro-6- (2, 3-dichlorobenzyl) -4- ((2, 4-dimethoxybenzyl) amino) -5, 6-dihydro-7H-pyrrolo [3, 4-d)]To a solution of pyrimidin-7-one (0.12 mmol,60.0 mg) and DIEA (5.0 eq, 0.61mmol,79.0 mg) in N-BuOH (2 mL) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) ]-1-yl) -2-methylpropan-2-sulfinamide (1.5, 9mg eq). The reaction mixture was then stirred for 2 hours under microwaves at 140 ℃. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the crude product, which was purified by column chromatography (DCM and MeOH, meOH ranging from 0 to 10%) to give 80.0mg of a pale brown solid in 86% yield. MS (ESI) m/z 763.57 and 765.63[ M+H ]] ⁺ .

Step 6 (S) -4-amino-2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6- (2, 3-dichlorobenzyl) -5, 6-dihydro-7H-pyrrolo [3,4-d ] pyrimidin-7-one

To N- ((S) -1' - (6- (2, 3-dichlorobenzyl) -4- ((2, 4-dimethoxybenzyl)) Amino) -7-oxo-6, 7-dihydro-5H-pyrrolo [3,4-d]Pyrimidin-2-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (0.11 mmol,80.0 mg) was added TFA (2.0 mL). The reaction mixture was then stirred at 40 ℃ for 2 hours. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ Washing the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography to give 5.7mg of the product as a white solid in 11% yield.

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 7.61 (dd, j=8.0, 1.2hz, 1H), 7.37 (t, j=7.9 hz, 1H), 7.31-7.29 (m, 1H), 7.22 (dd, j=7.7, 1.0hz, 1H), 7.20-7.18 (m, 1H), 7.17-7.14 (m, 2H), 6.86 (s, 2H), 4.82 (s, 2H), 4.51 (t, j=13.2 hz, 1H), 4.04 (s, 2H), 3.82 (s, 1H), 3.15-3.05 (m, 4H), 2.62 (d, j=15.7 hz, 1H), 2.03-1.96 (m, 1H), 1.71-1.52 (m, 1H), 1.43 (d, j=13.4 hz, 1H), 1.30-1.23 (m, 2hz, 1H), 4.04 (s, 2H), 3.82 (s, 1H), 3.15-3.05 (m, 4H), 2.62 (d, 1H) and ESI (38 z)] ⁺ .

Example 61

(S) -2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6- (2, 3-dichlorophenyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-5-one

Reagents and conditions:(a)1-ethoxy vinyl tributyl stannan,Pd(PPh ₃ ) ₂ Cl ₂ ,DMF,100℃,12h；(b)ozone,10min,then Me ₂ S,DCM,-78℃,2h；(c)NBS,BPO,CCl ₄ ,80℃,18h；(d)2,3-dichloroaniline,Et ₃ N, meCN,60℃for 18h; (e) acetic acid,110 ℃,20h; (f) DIEA, DMF,90 ℃,3h step 1 2-chloro-4- (1-ethoxyvinyl) -5-methylpyrimidine

Pd (PPh under Ar ₃ ) ₂ Cl ₂ (1.06g0.05 eq) was added to a solution of 2, 4-dichloro-5-methylpyrimidine (4.5 g,1.0 eq) and 1-ethoxyvinyltributyltin (10.9 g,1.0 eq) in DMF (50 mL) and then reacted by heating at 100℃for 12h. After the reaction was cooled to room temperature, a saturated aqueous KF solution was added and stirred at room temperature for another 30 minutes. After the reaction was completed, the slurry was filtered through celite, and the filtrate was collected and concentrated under reduced pressure. The resulting residue is then purified by flash chromatography to afford the intermediate 2-chloro-4- (1-ethoxyvinyl) -5-methylpyrimidine in high yield. [ M+H ] ] ⁺ ＝199/201.

Step 2 2-chloro-5-methylpyrimidine-4-carboxylic acid ethyl ester

Ozone was pumped into a solution of 2-chloro-4- (1-ethoxyvinyl) -5-methylpyrimidine in DCM at-78℃for 30 minutes. After the reaction was completed, an excessive amount of dimethyl sulfide was added, and the reaction was stirred at the same temperature for another 2 hours. The volatiles were then removed under reduced pressure and the resulting residue was purified by flash chromatography to give the intermediate ethyl 2-chloro-5-methylpyrimidine-4-carboxylate. [ M+H ]] ⁺ ＝201/203. ¹ H NMR(400MHz,Chloroform-d)δ8.60(s,1H),4.46(q,J＝6.9Hz,2H),2.49(s,3H),1.42(t,J＝6.9Hz,3H).

Step 3 5- (bromomethyl) -2-chloropyrimidine-4-carboxylic acid ethyl ester

BPO (122 mg,0.05 eq) was added to CCl of ethyl 2-chloro-5-methylpyrimidine-4-carboxylate (2 g,1.0 eq) and NBS (1.97 g,1.1 eq) ₄ The reaction solution was heated in an argon atmosphere at 80℃for 18h. After cooling to room temperature, the mixture was poured into a separation funnel containing saturated aqueous NaCl solution and then extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. Volatiles were then removed under reduced pressure and the resulting residue was purified by flash chromatography to afford intermediate 5- (bromomethyl) -2-chloropyrimidine-4-carboxylic acid ethyl ester. [ M+H ]] ⁺ ＝279/281.

Step 4 2-chloro-5- ((2, 3-dichlorophenyl) amino) methyl) pyrimidine-4-carboxylic acid ethyl ester

Et is added to ₃ N (0.45 mL,3.0 eq) was added to a MeCN solution of ethyl 5- (bromomethyl) -2-chloropyrimidine-4-carboxylate (300 mg,1.0 eq) and 2, 3-dichloroaniline (209 mg,1.2 eq) and reacted at 60℃for 18h with heating, volatiles were removed under reduced pressure and the residue was purified by flash chromatography to give the intermediate ethyl 2-chloro-5- ((2, 3-dichlorophenyl) amino) methyl) pyrimidine-4-carboxylate. [ M+H ]] ⁺ ＝360/362. ¹ H NMR(600MHz,Chloroform-d)δ8.75(s,1H),7.01(t,J＝8.1Hz,1H),6.86(dd,J＝8.1,1.3Hz,1H),6.40(dd,J＝8.1,1.3Hz,1H),5.19(t,J＝6.2Hz,1H),4.73(d,J＝6.2Hz,2H),4.50(q,J＝7.1Hz,2H),1.44(t,J＝7.1Hz,3H).

Step 5 2-chloro-6- (2, 3-dichlorophenyl) -5, 6-dihydro-7H-pyrrolo [3,4-d ] pyrimidin-7-one

Ethyl 2-chloro-5- ((2, 3-dichlorophenyl) amino) methyl) pyrimidine-4-carboxylate was dissolved in acetic acid and the mixture was heated at 110 ℃ for 20 hours. After the reaction was completed, acetic acid was removed under reduced pressure, and the resultant residue was suspended in water. Then NaHCO is added ₃ And (3) an aqueous solution, and adjusting the pH value to 7-8. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure and the resulting residue was purified by flash chromatography to give the intermediate 2-chloro-6- (2, 3-dichlorophenyl) -5, 6-dihydro-7H-pyrrolo [3, 4-d)]Pyrimidin-7-one [ M+H ]] ⁺ ＝314/316. ¹ H NMR(400MHz,Chloroform-d)δ9.00(s,1H),7.62–7.55(m,1H),7.38–7.34(m,2H),4.91(s,2H).

Step 6 (S) -2- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6- (2, 3-dichlorophenyl) -5, 6-dihydro-7H-pyrrolo [3,4-d ] pyrimidin-7-one

To 2-chloro-6- (2, 3-dichlorophenyl) -5, 6-dihydro-7H-pyrrolo [3,4-d]Pyrimidin-7-one (50 mg,1.0 eq) and (S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]To a solution of 1-amine (52 mg,1.2 eq) in DMF was added DIEA (132. Mu.L, 5.0 eq) and the reaction was heated at 90℃for 3h. After cooling to room temperature, the mixture was poured into a separation funnel containing saturated brine and extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure and purified by prep HPLC at MeCN/H ₂ The resulting residue was purified with O as eluent and TFA as modifier to afford the title compound as a white solid.

Example 62:

(S) -1'- (2, 6-dichlorophenyl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1, 6-dichloro-N- (2, 4-dichloropyrimidin-5-yl) benzamide

To 2, 4-dichloropyrimidin-5-amine (2.46 mmol,404.0 mg), 2, 6-dichlorobenzoic acid (1.5 eq, 3.7mmol,706.0 mg) and Et ₃ To a suspension of N (5.0 eq, 12.32mmol,1.25 g) in THF (30 mL) was added 2,4, 6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2, 4, 6-trioxide (3.0 eq, 7.39mmol,2.35 g). The reaction mixture was then stirred at 90℃for 36 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO ₄ Drying, filtering and concentrating in vacuumThe crude product was concentrated and purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 487.0mg of product as a pale yellow solid in 59% yield. MS (ESI) m/z 336.06 and 338.05[ M+H ]] ⁺ .

Step 2 5-chloro-2- (2, 6-dichlorophenyl) oxazolo [5,4-d ] pyrimidine

To a suspension of 2, 6-dichloro-N- (2, 4-dichloropyrimidin-5-yl) benzamide (0.38 mmol,126.2 mg) in DMF (5 mL) was added Na ₂ CO ₃ (2.0 equivalents, 0.75mmol,79.0 mg). The reaction mixture was then stirred at 80℃for 2 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO ₄ The above was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 71.0mg of a pale yellow solid in 63% yield. MS (ESI) m/z 300.08 and 302.07[ M+H ]] ⁺ .

Step 3N- ((S) -1'- (2, 6-dichlorophenyl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 5-chloro-2- (2, 6-dichlorophenyl) oxazolo [5,4-d]To a solution of pyrimidine (0.24 mmol,71.0 mg) and DIEA (5.0 eq, 1.18mmol,153.0 mg) in N-BuOH (2 mL) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) ]-1-yl) -2-methylpropan-2-sulfinamide (1.5 eq, 0.35mmol,109.0 mg). The reaction mixture was then stirred under microwaves at 140 ℃ for 1 hour. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave 135.0mg of crude product as a pale brown solid, which was used directly in the next step, MS (ESI) m/z 570.56 and 572.67[ M+H ]] ⁺ .

Step 4: (S) -1'- (2, 6-dichlorophenyl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To N- ((S) -1' - (2, 6-dichlorophenyl) oxazolo [5, 4-d)]Pyrimidin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of-1-yl) -2-methylpropan-2-sulfinamide (0.24 mmol,135.0 mg) in THF (2 mL) was slowly added HCl/dioxane (1N, 1 mL). The reaction mixture was then stirred at rt for 1 hour. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography to give 9.4mg of the product as a white solid (9% yield in two steps).

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.96 (s, 1H), 7.76-7.68 (m, 3H), 7.31-7.29 (m, 1H), 7.21-7.15 (m, 3H), 4.53 (t, j=13.4 hz, 2H), 3.85 (s, 1H), 3.26-3.23 (m, 2H), 3.10 (d, j=15.7 hz, 1H), 2.65 (d, j=15.6 hz, 1H), 1.77 (td, j=12.7, 4.2hz, 1H), 1.65 (td, j=12.7, 4.1hz, 1H), 1.53 (d, j=13.0 hz, 1H), 1.13 (d, j=13.3 hz, 1H) MS (ESI) m/z 466.35 and 14[ m+h ] ⁺ .

The compounds of examples 63-80 were prepared as described in reference to example 62.

Example 63

(S) -1'- (2, 3-dichlorophenyl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS(ESI)m/z 465.11

Example 64

(S) -1'- (2- (2- (trifluoromethyl) pyridin-3-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.96(s,1H),8.95(d,J＝1.0Hz,1H),8.59(d,J＝7.3Hz,1H),7.96(dd,J＝8.0,4.7Hz,1H),7.31–7.29(m,1H),7.20–7.14(m,3H),4.53(t,J＝14.0Hz,2H),3.84(s,1H),3.29–3.23(m,2H),3.10(d,J＝15.7Hz,1H),2.64(d,J＝15.6Hz,1H),1.77(td,J＝12.7,4.3Hz,1H),1.65(td,J＝12.6,4.2Hz,1H),1.55–1.52(m,1H),1.13(d,J＝13.2Hz,1H).MS(ESI)m/z 467.44[M+H] ⁺ .

Example 65

(S) -1'- (2- (5-methylthiazol-4-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -5, 7-dihydrospiro [ b ] pyridin-6, 4' -piperidin ] -5-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.07(s,1H),8.85(s,1H),8.31(d,J＝4.4Hz,1H),7.65(d,J＝7.5Hz,1H),7.17(dd,J＝7.4,5.0Hz,1H),4.53(t,J＝12.5Hz,2H),3.89(s,1H),3.28–3.22(m,2H),3.13(d,J＝16.3Hz,1H),2.86(s,3H),2.76(d,J＝16.3Hz,1H),1.77(td,J＝12.7,4.3Hz,1H),1.68(td,J＝12.9,4.2Hz,1H),1.55(d,J＝12.5Hz,1H),1.14(d,J＝13.4Hz,1H).MS(ESI)m/z 420.31[M+H] ⁺ .

Example 66

(S) -1'- (2, 6-dimethylphenyl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.87(s,1H),7.40–7.37(m,1H),7.31–7.29(m,1H),7.23(d,J＝7.7Hz,2H),7.20(dd,J＝6.5,1.6Hz,1H),7.17–7.15(m,2H),4.53(t,J＝15.0Hz,2H),3.84(s,1H),3.28–3.20(m,2H),3.10(d,J＝15.7Hz,1H),2.64(d,J＝15.7Hz,1H),2.27(s,6H),1.76(td,J＝12.7,4.3Hz,1H),1.64(td,J＝12.7,4.2Hz,1H),1.52(d,J＝13.2Hz,1H),1.12 (d, J=13.1 Hz, 1H) MS (ESI) m/z 425.35 and 427.37[ M+H ]] ⁺ .

Example 67

(S) -1'- (2- (naphthalen-1-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 9.38 (d, j=8.6 hz, 1H), 8.90 (s, 1H), 8.35 (d, j=6.8 hz, 1H), 8.19 (d, j=8.2 hz, 1H), 8.08 (d, j=8.1 hz, 1H), 7.77-7.73 (m, 1H), 7.71-7.64 (m, 2H), 7.32-7.30 (m, 1H), 7.20-7.15 (m, 3H), 4.54 (t, j=14.3 hz, 2H), 3.85 (s, 1H), 3.23-3.20 (m, 2H), 3.09 (d, j=15.7 hz, 1H), 2.64 (d, j=15.7 hz, 1H), 1.77 (td, j=12.7, 4.3hz, 1H), 1.65 (td, 12.4.4, 4 hz, 2H), 3.85 (s, 1H), 3.23-3.20 (m, 2H), 3.09 (d, 1hz, 1H), 1.38 (d, 9hz, 1H) and 37 (d, 37 hz) ] ⁺ .

Example 68

(S) -1'- (2- (2-methylnaphthalen-1-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.97 (s, 1H), 8.12 (d, j=8.4 hz, 1H), 8.03 (dd, j=5.8, 3.0hz, 1H), 7.85-7.82 (m, 1H), 7.58 (t, j=7.7 hz, 3H), 7.34 (d, j=5.2 hz, 1H), 7.21-7.19 (m, 3H), 4.58 (t, j=13.0 hz, 2H), 3.89 (s, 1H), 3.26-3.19 (m, 2H), 3.13 (d, j=15.6 hz, 1H), 2.69 (d, j=15.7 hz, 1H), 2.52 (s, 3H), 1.80 (t, j=10.5 hz, 1H), 1.68 (t, j=10.7 hz, 1H), 1.55 (d, j=12.7 hz, 1H), 3.26-3.19 (m, 2H), 3.13 (d, 1.69) and (es) 38 m,1H (37 m, 1H)] ⁺ .

Example 69

(S) -1'- (2- (2-chloro-6- (trifluoromethyl) phenyl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.98 (s, 1H), 8.09 (d, j=8.1 hz, 1H), 8.02 (d, j=7.8 hz, 1H), 7.93 (t, j=8.1 hz, 1H), 7.30 (d, j=6.1 hz, 1H), 7.20-7.15 (m, 3H), 4.53 (s, 2H), 3.84 (s, 1H), 3.28-3.23 (m, 2H), 3.10 (d, j=15.6 hz, 1H), 2.64 (d, j=15.6 hz, 1H), 1.77 (td, j=12.7, 4.2hz, 1H), 1.65 (td, j=12.8, 4.2hz, 1H), 1.53 (d, j=13.0 hz, 1H), 1.12 (d, j=13.4 hz, 1H) [ ESI) and (500.57 +32 m/m.32H] ⁺ .

Example 70

(S) -1'- (2, 4-dimethylpyridin-3-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.90 (s, 1H), 8.49 (d, j=5.0 hz, 1H), 7.31 (d, j=5.0 hz, 2H), 7.19-7.16 (m, 3H), 4.54 (t, j=14.4 hz, 2H), 3.84 (s, 1H), 3.24 (d, j=12.1 hz, 2H), 3.11 (d, j=15.6 hz, 1H), 2.65 (d, j=15.6 hz, 1H), 2.50 (s, 3H), 2.34 (s, 3H), 1.76 (td, j=12.8, 4.0hz, 1H), 1.64 (td, j=13.0, 3.9hz, 1H), 1.53 (d, j=13.2 hz, 1H), 1.12 (d, j=13.7 hz, 1H) [ MS (ESI) m/426.45.46 m/z and 428+46H] ⁺ .

Example 71

(S) -1'- (2- (3, 5-dichloropyridin-4-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.02(s,1H),8.93(s,2H),7.30(d,J＝6.1Hz,1H),7.20–7.15(m,3H),4.53(s,2H),3.84(s,1H),3.26(d,J＝12.2Hz,2H),3.10(d,J＝15.6Hz,1H),2.64(d,J＝15.6Hz,1H),1.77(td,J＝12.7,4.2Hz,1H),1.65(td,J＝12.7,3.8Hz,1H),1.54(d,J＝12.9Hz,1H),1.12(d,J＝13.6Hz,1H).MS (ESI) m/z 467.29 and 469.08[ M+H ]] ⁺ .

Example 72

(S) -1'- (2, 4-dichloropyridin-3-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 9.00 (s, 1H), 8.67 (d, j=5.4 hz, 1H), 7.93 (d, j=5.4 hz, 1H), 7.33-7.31 (m, 1H), 7.23-7.15 (m, 3H), 4.54 (s, 2H), 3.90 (s, 1H), 3.25-3.17 (m, 2H), 3.12 (d, j=15.7 hz, 1H), 2.69 (d, j=15.6 hz, 1H), 1.75 (td, j=12.7, 4.2hz, 1H), 1.65 (td, j=12.7, 3.8hz, 1H), 1.54 (d, j=12.3 hz, 1H), 1.17 (d, j=14.1 hz, 1H) MS (ESI) m/z467.17 and 469.35 m+h] ⁺ .

Example 73

(S) -1'- (2- (1, 4-dimethyl-1H-pyrazol-3-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.77 (s, 1H), 7.71 (s, 1H), 7.30 (d, j=6.1 hz, 1H), 7.20-7.15 (m, 3H), 4.50 (t, j=14.6 hz, 2H), 3.90 (s, 3H), 3.83 (s, 1H), 3.22 (dd, j=21.3, 11.0hz, 2H), 3.08 (d, j=15.6 hz, 1H), 2.63 (d, j=15.6 hz, 1H), 2.32 (s, 3H), 1.75 (td, j=12.7, 4.1hz, 1H), 1.63 (td, j=12.6, 4.0hz, 1H), 1.51 (d, j=13.2 hz, 1H), 1.11 (d, j=13.2 hz, 1H) [ MS (ESI) m/z 415.21 and 30+m+3H ] ⁺ .

Example 74

(S) -1'- (2- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.70 (s, 1H), 7.29 (d, j=6.1 hz, 1H), 7.20-7.13 (m, 3H), 4.49 (t, j=15.2 hz, 2H), 3.82 (s, 1H), 3.74 (s, 3H), 3.28-3.16 (m, 2H), 3.09 (d, j=15.6 hz, 1H), 2.63 (d, j=15.7 hz, 1H), 2.58 (s, 3H), 2.42 (s, 3H), 1.75 (td, j=12.7, 4.2hz, 1H), 1.62 (td, j=12.7, 4.1hz, 1H), 1.50 (d, j=13.0 hz, 1H), 1.09 (d, j=13.3 hz, 1H) MS (ESI) m/z 428.34 and 430.45 m+h] ⁺ .

Example 75

(S) -1'- (2- (3, 5-dimethylisoxazol-4-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.82 (s, 1H), 7.29 (d, j=6.1 hz, 1H), 7.20-7.15 (m, 3H), 4.51 (t, j=15.4 hz, 2H), 3.83 (s, 1H), 3.28-3.19 (m, 2H), 3.09 (d, j=15.6 hz, 1H), 2.77 (s, 3H), 2.63 (d, j=15.7 hz, 1H), 2.52 (s, 3H), 1.75 (td, j=12.7, 4.2hz, 1H), 1.63 (td, j=12.6, 4.1hz, 1H), 1.52 (d, j=13.0 hz, 1H), 1.11 (d, j=13.1 hz, 1H). MS (ESI) m/z 415.35 and 58[ m+h ]] ⁺ .

Example 76

(S) -1'- (2, 5-dimethylthiazol-4-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.81 (s, 1H), 7.31 (d, j=5.4 hz, 1H), 7.18 (dt, j=6.6, 5.8hz, 3H), 4.52 (t, j=13.0 hz, 2H), 3.87 (s, 1H), 3.25-3.20 (m, 2H), 3.10 (d, j=15.7 hz, 1H), 2.78 (s, 3H), 2.66 (d, j=15.4 hz, 1H), 1.76 (td, j=12.7, 4.0hz, 1H), 1.64 (dt, j=17.6, 5.3hz, 1H), 1.52 (d, j=13.2 hz, 1H), 1.14 (d, j=13.8 hz, 1H) [ MS (ESI) m/z 432.38 and 434.35 m+m ] ⁺ .

Example 77

(S) -1'- (2, 6-dichlorophenyl) oxazolo [5,4-d ] pyrimidin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.98 (s, 1H), 8.34 (d, j=4.5 hz, 1H), 7.77-7.70 (m, 2H), 7.68 (d, j=7.4 hz, 1H), 7.19 (dd, j=7.2, 5.1hz, 2H), 4.56 (s, 2H), 3.97 (s, 1H), 3.27-3.24 (m, 2H), 3.16 (d, j=16.3 hz, 1H), 2.81 (d, j=16.2 hz, 1H), 1.77 (td, j=12.7, 4.0hz, 1H), 1.68 (td, j=12.9, 4.1hz, 1H), 1.56 (d, j=13.4 hz, 1H), 1.21 (d, j=13.3 hz, 1H). MS (ESI) m/z 467.29 and 469.04 m+9.m+] ⁺ .

Example 78

(S) -1'- (2, 4-dimethylpyridin-3-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.91(s,1H),8.49(d,J＝5.1Hz,1H),8.31(d,J＝4.6Hz,1H),7.65(d,J＝7.4Hz,1H),7.31(d,J＝5.0Hz,1H),7.17(dd,J＝7.3,5.1Hz,1H),4.55(t,J＝12.0Hz,2H),3.89(s,1H),3.26(d,J＝13.5Hz,2H),3.14(d,J＝16.3Hz,1H),2.77(d,J＝16.3Hz,1H),2.50(s,3H),2.34(s,3H),1.76(td,J＝12.7,4.2Hz,1H),1.68(td,J＝12.9,4.1Hz,1H),1.55(d,J＝12.9Hz,1H),1.14(d,J＝13.3Hz,1H).MS(ESI)m/z 428.38[M+H] ⁺ .

Example 79

(S) -1'- (2- (2-chloro-6-methylphenyl) oxazolo [5,4-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.92(s,1H),7.56–7.51(m2H), 7.42 (dd, j=6.9, 1.4hz, 1H), 7.31-7.29 (m, 1H), 7.21-7.15 (m, 3H), 4.53 (t, j=14.2 hz, 2H), 3.84 (s, 1H), 3.27-3.22 (m, 2H), 3.10 (d, j=15.6 hz, 1H), 2.65 (d, j=15.6 hz, 1H), 2.28 (s, 3H), 1.76 (td, j=12.7, 4.3hz, 1H), 1.64 (td, j=12.7, 4.1hz, 1H), 1.53 (d, j=12.8 hz, 1H), 1.12 (d, j=13.2 hz, 1H) MS (ESI) m/z 446.41 and 448.63 m+h] ⁺ .

Example 80

(S) -1'- (2- (5-methylthiazol-4-yl) oxazolo [5,4-d ] pyrimidin-5-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-amine

Example 81

(S) -1'- (2, 3-dichlorophenyl) - [1,2,4] triazolo [1,5-c ] pyrimidin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Reagents and conditions:(a)hydrazine hydrate,EtOH,60℃,12h,90％；(b)2,3-dichlorobenzaldehyde,EtOH,r.t.,5h；(c)IBD,DCM,r.t.,18h；(d)1N HCl,1h；(e)Et3N/MeCN,90℃,1h.

Step 1 4-chloro-6-hydrazinopyrimidine

Hydrazine hydrate (3.25 ml,2.0 eq) was added to 4, 6-dichloropyrimidine (5 g,1.0 eq) at a temperature of 0℃and then heating the mixture at 60℃for 12h. After the reaction was completed, 50% of volatiles were removed under reduced pressure, and solids were added. The slurry was filtered, the filter cake was washed with cold ethanol and dried under vacuum to give the intermediate 4-chloro-6-hydrazinopyrimidine, [ M+H ] in high yield] ⁺ ＝144.90/146.66. ¹ H NMR(400MHz,Chloroform-d)δ8.35(s,1H),6.84(s,1H),6.43(s,1H),3.83(s,2H).

Step 2 (E) -4-chloro-6- (2, 3-dichlorobenzylidene) hydrazino) pyrimidine

2, 3-dichlorobenzaldehyde (2.66 g,1.1 eq) dissolved in EtOH was added dropwise to a solution of 4-chloro-6-hydrazinopyrimidine (2 g,1.0 eq) in EtOH and reacted at room temperature with stirring for 5h. After the reaction was completed, 50% of volatiles were removed under reduced pressure. The resulting slurry was filtered, the filter cake was washed with cold ethanol and dried under vacuum to give intermediate (E) -4-chloro-6- (2, 3-dichlorobenzylidene) hydrazino) pyrimidine in high yield. [ M+H ]] ⁺ ＝301.04/302.84/304.94/306.96. ¹ H NMR(400MHz,DMSO-d ₆ )δ12.09(s,1H),8.57(s,1H),8.49(d,J＝0.9Hz,1H),8.15(dd,J＝7.9,1.6Hz,1H),7.69(dd,J＝7.9,1.6Hz,1H),7.43(t,J＝7.9Hz,1H),7.33(s,1H).

Step 3 7-chloro-2- (2, 3-dichlorophenyl) - [1,2,4] triazolo [1,5-c ] pyrimidine

IBD (1.39 g,1.3 eq) was added in portions to a DCM suspension of (E) -4-chloro-6- (2, 3-dichlorobenzylidene) hydrazino) pyrimidine (1 g,1.0 eq) and the reaction stirred at room temperature for 18 hours. After the reaction was completed, volatiles were removed under reduced pressure and the resulting residue was redissolved in a mixture of EtOH/1N hydrochloric acid (30 mL/10 mL). The reaction was stirred at room temperature for a further 2 hours. Volatiles were removed and the resulting slurry was poured into a separation funnel containing saturated brine and extracted three times with ethyl acetate . The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure and the resulting residue was purified by flash chromatography to give intermediate 7-chloro-2- (2, 3-dichlorophenyl) - [1,2,4]]Triazolo [1,5-c ]]Pyrimidine. [ M+H ]] ⁺ ＝298.97/300.96/302.91. ¹ H NMR(400MHz,Chloroform-d)δ9.33(d,J＝1.2Hz,1H),7.89(dd,J＝7.9,1.6Hz,1H),7.76(d,J＝1.2Hz,1H),7.63(dd,J＝7.9,1.6Hz,1H),7.36(t,J＝7.9Hz,1H).

Step 4 (S) -1'- (2, 3-dichlorophenyl) - [1,2,4] triazolyl [1,5-c ] pyrimidin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To 7-chloro-2- (2, 3-dichlorophenyl) - [1,2,4]]Triazolo [1,5-c ]]Pyrimidine (100 mg,1.0 eq) and (S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]To a suspension of 1-amine (110 mg,1.0 eq) in MeCN was added Et ₃ N (2 mL) and heated at 90℃for 1h. Thereafter, volatiles were removed and purified by prep HPLC at MeCN/H ₂ Purifying the resulting residue with O as eluent and TFA as modifier to provide the target compound, thereby providing the target compound in the form of a white solid, [ M+H ]] ⁺ ＝465.18/467.09/469.15；[M-NH ₂ ] ⁺ ＝448.15/450.03/451.90. ¹ H NMR(400MHz,Methanol-d ₄ )δ9.22(s,1H),7.76(dd,J＝7.9,1.6Hz,1H),7.72(dd,J＝7.9,1.6Hz,1H),7.51–7.41(m,2H),7.40–7.28(m,3H),6.69(s,1H),4.46–4.36(m,1H),4.36–4.24(m,2H),3.45–3.26(m,2H),3.25–3.06(m,2H),1.94–1.77(m,2H),1.75–1.56(m,2H).

Example 82

(S) -1'- (2- ((2, 3-dichlorophenyl) thio) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 5-Chlorothiazolo [4,5-d ] pyrimidine-2-thiol

To a suspension of 5-bromo-2-chloropyrimidin-4-amine (4.8 mmol,1.0 g) in DMF (50 mL) was added potassium O-ethyldithiocarbonate (3.0 eq, 14.39mmol,2.31 g). The reaction mixture was then stirred at 130℃for 10 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with 1N HCl solution. The separated organic layer was dried over MgSO ₄ The upper was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 909.0mg of a yellow solid in 93% yield. MS (ESI) m/z 204.05 and 206.04[ M+H ]] ⁺ .

Step 2:

5-chloro-2- ((2, 3-dichlorophenyl) thio) thiazolo [4,5-d ] pyrimidine

Under Ar, to 5-chlorothiazolo [4,5-d ]]Pyrimidine-2-thiol (0.97 mmol,198.0 mg), pd ₂ (dba) ₃ To a suspension of dioxane (10 ml) of (10 mol%,0.01mmol,89.0 mg), xantphos (20 mol%,0.19mmol,113.0 mg) and DIEA (3.0 eq, 2.92mmol,377.0 mg) was added 1, 2-dichloro-3-iodobenzene (1.5 eq, 1.46mmol,398.0 mg). The reaction mixture was then stirred at 100℃for 10 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO ₄ The above was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA ranging from 0 to 60%) to give the product as a pale yellow solid in 259.0 mg. MS (ESI) m/z 348.00 and 350.03[ M+H ]] ⁺ .

Step 3

N- ((S) -1'- (2- ((2, 3-dichlorophenyl) thio) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 5-chloro-2- ((2, 3-dichlorophenyl) thio) thiazolo [4,5-d]To a solution of pyrimidine (0.17 mmol,60.0 mg) and DIEA (3.0 eq, 0.52mmol,66.7 mg) in N-BuOH (2 mL) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (1.5 eq, 0.26mmol,79.0 mg). The reaction mixture was then stirred under microwaves at 140 ℃ for 1 hour. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the crude product which was purified by column chromatography (DCM and MeOH, meOH ranging from 0 to 10%) to give 72.4mg of a pale brown solid in 68% yield. MS (ESI) m/z 618.43 and 620.42[ M+H ]] ⁺ .

Step 4

To N- ((S) -1' - (2- ((2, 3-dichlorophenyl) thio) thiazolo [4, 5-d)]Pyrimidin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To THF (2 mL) of-1-yl) -2-methylpropan-2-sulfinamide (0.12 mmol,72.4 mg) was slowly added HCl/dioxane solution (1 n,1 mL). The reaction mixture was then stirred at rt for 1 hour. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the crude product, which was purified by column chromatography to give 3.0mg of a white solid in 5% yield,

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.75(s,1H),7.79–7.77(m,2H),7.45(t,J＝7.9Hz,1H),7.31(d,J＝5.2Hz,1H),7.21–7.14(m,4H),3.90(s,1H),3.08(d,J＝15.7Hz,1H),2.66(d,J＝15.7Hz,1H),2.03–1.96(m,1H),1.77(dt,J＝27.4,12.1Hz,1H),1.60(d,J＝12.8Hz,1H),1.48–1.38(m,1H),1.30–1.17(m,5H),0.93–0.77(m,1H).MS(ESI) m/z 514.30 and 516.10[ M+H ]] ⁺ .

Example 83

(S) -1'- (2, 3-dichlorophenyl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1, 5-Dichlorothiazolo [4,5-d ] pyrimidine

To 5-chlorothiazolo [4,5-d ]]To a suspension of pyrimidine-2-thiol (3.49 mmol,710.0 mg) in DCM (30 mL) was slowly added dropwise sulfonyl chloride (10.0 equivalents, 34.9mmol,4.71 g). The reaction mixture was then stirred at rt for 2 hours. After completion of the reaction, the resulting mixture was diluted with DCM and washed with brine. The separated organic layer was dried over MgSO ₄ The above was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 50%) to afford 538.0mg of yellow solid in 75% yield. MS (ESI) m/z 206.00 and 207.95[ M+H ]] ⁺ .

Step 2 5-chloro-2- (2, 3-dichlorophenyl) thiazolo [4,5-d ] pyrimidine

Under Ar, to 2, 5-dichloro-thiazolo [4,5-d ]]Pyrimidine (1.07 mmol,220.0 mg), pdCl ₂ (dppf) (10 mol%,0.11mmol,78.0 mg) and K ₂ CO ₃ To a suspension of (3.0 eq, 3.2mmol,443.0 mg) dioxane (10 mL) and water (1 mL) was added (2, 3-dichlorophenyl) boronic acid (1.5 eq, 1.6mmol,306.0 mg). The reaction mixture was then stirred at 100℃for 10 hours. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO ₄ Drying, filtering and concentrating in vacuum to obtain crude productPurification by column chromatography (PE and EA, EA ranging from 0 to 60%) gave the product as a pale yellow solid in a yield of 224.0mg. MS (ESI) m/z 316.01 and 318.23[ M+H ]] ⁺ .

Step 3

N- ((S) -1'- (2, 3-dichlorophenyl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 5-chloro-2- (2, 3-dichlorophenyl) thiazolo [4,5-d]To a solution of pyrimidine (0.19 mmol,60.0 mg) and DIEA (3.0 eq, 0.57mmol,73.5 mg) in N-BuOH (2 mL) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (1.5 eq, 0.28mmol,87.0 mg). The reaction mixture was then stirred under microwaves at 140 ℃ for 1 hour. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography (DCM and MeOH, meOH ranging from 0 to 10%) to afford 79.0mg of product in 71% yield as a light brown solid. MS (ESI) m/z586.48 and 588.70[ M+H ]] ⁺ .

Step 4

To N- ((S) -1' - (2, 3-dichlorophenyl) thiazolo [4, 5-d)]Pyrimidin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (0.14 mmol,79.0 mg) in THF (2 mL) was slowly added HCl/dioxane solution (1N, 1 mL). The reaction mixture was then stirred at rt for 1 hour. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtering and concentrating in vacuum to obtain crude productPurification by column chromatography gave 3.0mg of the product as a yellow solid in 5% yield.

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 9.25 (s, 1H), 8.17 (d, j=7.0 hz, 1H), 7.92 (d, j=7.1 hz, 1H), 7.60 (t, j=8.0 hz, 1H), 7.31 (d, j=5.3 hz, 1H), 7.19 (dt, j=6.9, 4.4hz, 3H), 4.59 (t, j=13.7 hz, 2H), 3.88 (s, 1H), 3.12 (d, j=15.7 hz, 1H), 2.68 (d, j=15.5 hz, 1H), 2.00 (q, j=7.7 hz, 1H), 1.81-1.61 (m, 1H), 1.55-1.42 (m, 1H), 1.32-1.23 (m, 3H), 1.15 (d, j=13.2 hz, 1H), 0.86-0.83 (m, 1H), and (e.484 m+30/m/v)] ⁺ .

See example 83 for the preparation of the compounds of examples 84-89.

Example 84

(S) -1' - (2, 3-dichlorophenyl) -7-methylthiazolo [4, 5-d)]Pyrimidin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.20 (dd, j=8.0, 1.4hz, 1H), 7.92 (dd, j=8.0, 1.4hz, 1H), 7.60 (t, j=8.0 hz, 1H), 7.32-7.30 (m, 1H), 7.22-7.16 (m, 3H), 4.60 (t, j=14.0 hz, 2H), 3.85 (s, 1H), 3.28-3.20 (m, 2H), 3.12 (d, j=15.6 hz, 1H), 2.68 (d, j=4.1 hz, 1H), 2.65 (s, 3H), 1.76 (td, j=12.7, 4.3hz, 1H), 1.64 (td, j=12.7, 4.0hz, 1H), 1.52 (d, j=13.8 hz, 1H), 1.13 (d, j=15.6 hz, 1H), 2.68 (d, j=4.38 hz, 1H), 2.68 (d, 1.38H) and (MS/38 z/1H) ] ⁺ .

Example 85

(S) -1'- (2- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.04(s,1H),7.36–7.34(m,1H),7.22(td,J＝8.8,5.1Hz,3H),4.58(td,J＝8.1,3.7Hz,2H),3.94(s,1H),3.77(s,3H),3.21(dd,J＝20.2,8.2Hz,2H),3.13(d,J＝15.8Hz,1H),2.73(d,J＝15.8Hz,1H),2.66(s,3H),2.47(s,3H),1.79–1.61(m,1H),1.47(dt,J＝13.8,10.5Hz,3H).MS(ESI)m/z 446.57[M+H] ⁺ .

Example 86

(S) -1'- (2- (3, 5-dimethylisoxazol-4-yl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.88(s,1H),7.32–7.31(m,1H),7.22–7.16(m,3H),4.55(t,J＝12.8Hz,2H),3.87(s,1H),3.19(dd,J＝27.7,12.7Hz,2H),3.10(d,J＝15.7Hz,1H),2.67(d,J＝15.7Hz,1H),2.39(s,6H),1.74(td,J＝12.7,4.3Hz,1H),1.62(td,J＝12.8,3.8Hz,1H),1.49(d,J＝13.1Hz,1H),1.12(d,J＝11.8Hz,1H).MS(ESI)m/z 433.38[M+H] ⁺ .

Example 87

(S) -1'- (2- (3, 4-dihydroquinolin-1 (2H) -yl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.60 (s, 1H), 7.93 (d, j=8.0 hz, 1H), 7.33-7.31 (m, 1H), 7.28 (d, j=8.0 hz, 2H), 7.21-7.16 (m, 4H), 4.54-4.45 (m, 2H), 4.00 (t, j=6.1 hz, 1H), 3.88 (s, 1H), 3.21-3.14 (m, 3H), 3.10 (d, j=15.6 hz, 1H), 2.80 (t, j=6.4 hz, 1H), 2.68 (d, j=15.3 hz, 1H), 2.03-1.95 (m, 4H), 1.75-1.68 (m, 1H), 1.66-1.54 (m, 1H), 1.48-1.45 (m, 1H), 1.40-1.29 (m, 1.29), 1.471 (m, 12.62, 1hz, 1H), 2.80 (t, 1H), 2.03-1.95 (m, 1H) and (e.38 z/v)] ⁺ .

Example 88

(S) -1'- (2- (indolin-1-yl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.71 (s, 1H), 7.34-7.30 (m, 3H), 7.19 (dt, j=6.9, 4.5hz, 4H), 7.08 (t, j=7.4 hz, 1H), 4.54 (t, j=13.1 hz, 2H), 4.17 (t, j=8.3 hz, 2H), 3.86 (s, 1H), 3.23-3.16 (m, 3H), 3.10 (d, j=15.8 hz, 1H), 2.66 (d, j=15.6 hz, 1H), 2.00 (q, j=7.6 hz, 1H), 1.74 (td, j=12.6, 4.1hz, 1H), 1.49 (d, j=13.4 hz, 1H), 1.32-1.23 (m, 12.6 hz, 1H), 2.66 (d, j=15.6 hz, 1H), 2.00 (d, j=12.6 hz, 1H), 2.00 (d, 3.4hz, 1H) 2.00 (d, 1H) and (e.38 z/v) ] ⁺ .

Example 89

(S) -1'- (2- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS(ESI)m/z 470.48[M+H] ⁺ .

See example 82 for the preparation of the compounds of examples 90-93.

Example 90

(S) -5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -N- (2, 3-dichlorophenyl) thiazolo [4,5-d ] pyrimidin-2-amine

MS (ESI) m/z 498.27 and 500.33[ M+H ]] ⁺ .

Example 91

(S) -1'- (2, 3-dichlorophenoxy) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.73(s,1H),7.58(dd,J＝8.0,1.3Hz,1H),7.45(t,J＝8.1Hz,1H),7.38(dd,J＝8.1,1.3Hz,1H),7.31(dJ=5.5 hz, 1H), 7.20-7.15 (m, 3H), 3.89 (s, 1H), 3.08 (d, j=15.7 hz, 1H), 2.66 (d, j=15.7 hz, 1H), 1.78 (dt, j=22.7, 10.0hz, 1H), 1.60 (d, j=13.6 hz, 1H), 1.56 (d, j=11.7 hz, 1H), 1.49-1.37 (m, 1H), 1.30-1.15 (m, 4H) MS (ESI) m/z 498.38 and 500.57[ m+h ]] ⁺ .

Example 92

(S) -1'- (2- (cyclohexylalkynyl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS(ESI)m/z 444.50[M+H] ⁺ .

Example 93

(S) -1'- (2- ((2, 3-dichlorophenyl) ethynyl) thiazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

MS (ESI) m/z 506.30 and 508.18[ M+H ]] ⁺ .

Example 94

(S) -1'- (2, 3-dichlorophenyl) benzo [ d ] thiazol-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 15-bromo-2-iodobenzo [ d ] thiazole

To a suspension of 5-bromobenzothiazole (3.26 mmol,698.0 mg) and sodium t-butoxide (1.0 eq, 3.26mmol,313.0 mg) in DMF (30 mL) was added 1,2, 3, 4-nonafluoro-4-iodobutane (1.1 eq, 3.59mmol,1.24 g). The reaction mixture was then stirred at rt for 1 hour. After completion of the reaction, EA was usedThe resulting mixture was diluted and washed with brine. The separated organic layer was dried over MgSO ₄ The above was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 50%) to give 1.0g of the product as a pale yellow solid with a yield of 90%.

MS (ESI) m/z 339.93 and 341.92[ M+H ]] ⁺ .

Step 25-bromo-2- (2, 3-dichlorophenyl) benzo [ d ] thiazole

To 5-bromo-2-iodobenzothiazole (0.41 mmol,138.0 mg), pdCl under Ar ₂ (dppf) (10 mol%,0.04mmol,29.7 mg) and K ₂ CO ₃ To a suspension of (3.0 eq, 1.22mmol,168.0 mg) dioxane (5 mL) and water (0.5 mL) was added (2, 3-dichlorophenyl) boronic acid (1.5 eq, 0.61mmol,116.0 mg). The reaction mixture was then stirred under microwaves at 80 ℃ for 1 hour. After completion of the reaction, the resulting mixture was diluted with EA and washed with brine. The separated organic layer was dried over MgSO ₄ The above was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 60%) to give 103.0mg of the product as a pale yellow solid, 71% yield. MS (ESI) m/z 358.07 and 360.06[ M+H ] ] ⁺ .

Step 3N- ((S) -1'- (2, 3-dichlorophenyl) benzo [ d ] thiazol-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 5-bromo-2- (2, 3-dichlorophenyl) benzo [ d ] under Ar]Thiazole (0.29 mmol,103.0 mg), pd ₂ (dba) ₃ (10 mol%,0.03mmol,26.3 mg), xantphos (20 mol%,0.06mmol,33.2 mg) and Cs ₂ CO ₃ (3.0 eq., 0.86mmol,280.0 mg) in dioxane (5 ml) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropanAlkane-2-sulfinamide (1.5 eq, 0.43mmol,132.0 mg) and then the reaction mixture was stirred at 100 ℃ for 12h. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ Washing the solution. Separating the organic layer, na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography (DCM and MeOH, meOH ranging from 0 to 10%) to give 138.0mg of product as a pale brown solid in 82% yield, MS (ESI) m/z 584.49 and 586.40[ M+H ]] ⁺ .

Step 4

To N- ((S) -1' - (2, 3-dichlorophenyl) benzo [ d)]Thiazol-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (0.18 mmol,103.0 mg) in THF (2 mL) was slowly added HCl/dioxane solution (1N, 1 mL). The reaction mixture was then stirred at rt for 1 hour. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography to afford 14.5mg of the product as a yellow solid in 17% yield.

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.09 (dd, j=7.9, 1.2hz, 1H), 7.97 (d, j=9.0 hz, 1H), 7.85 (dd, j=8.0, 1.3hz, 1H), 7.58-7.54 (m, 2H), 7.31 (dd, j=8.8, 2.4hz, 2H), 7.21-7.14 (m, 3H), 3.89 (s, 1H), 3.69 (t, j=13.3 hz, 2H), 3.01 (ddd, j=27.4, 10.9,3.5hz, 3H), 2.62 (d, j=15.7 hz, 1H), 2.03-1.79 (m, 2H), 1.55 (d, j=12.3 hz, 1H), 1.29-1.18 (m, 3H) [ MS (ESI) m/z 480.36 and 482+m.31H] ⁺ .

The compounds of examples 95-98 were prepared with reference to example 94.

Example 95

(S) -1'- (2- ((2, 3-dichlorophenyl) thio) thiazolo [5,4-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.75 (s, 1H), 7.68 (dd, j=8.0, 1.0hz, 1H), 7.47-7.45 (m, 1H), 7.39 (t, j=7.9 hz, 1H), 7.32 (d, j=5.0 hz, 1H), 7.19 (t, j=6.8 hz, 3H), 7.10 (s, 1H), 3.92 (s, 1H), 3.46 (dd, j=25.6, 11.8hz, 2H), 3.08 (d, j=15.7 hz, 1H), 2.67 (d, j=15.8 hz, 1H), 2.03-1.96 (m, 2H), 1.87-1.69 (m, 1H), 1.58 (d, j=13.2 hz, 1H), 1.47 (dd, 1.8, 6.7 hz), 1.34-1.34 (m, 24 hz), 2.7 hz, 1H) 2.38 (m, 1H) 2.03-1.96 (m, 2H) and 38 (m, 1H) ] ⁺ .

Example 96

(S) -1'- (2, 3-dichlorophenyl) thiazolo [5,4-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.98 (s, 1H), 8.08 (dd, j=7.8, 1.2hz, 1H), 7.91 (dd, j=8.0, 1.3hz, 1H), 7.59 (t, j=8.0 hz, 1H), 7.44 (s, 1H), 7.35 (t, j=4.0 hz, 1H), 7.24-7.18 (m, 2H), 6.63 (s, 1H), 4.24 (d, j=13.1 hz, 1H), 3.97 (s, 1H), 3.17-3.09 (m, 1H), 2.75-2.67 (m, 1H), 2.34-2.31 (m, 1H), 1.84-1.69 (m, 1H), 1.49-1.42 (m, 2H), 1.31-1.24 (m, 5H) [ MS (ESI) m/481.29 and 4840+3.m.40] ⁺ .

Example 97

(S) -1'- (2- ((2, 3-dichlorophenyl) thio) thiazolo [4,5-b ] pyridin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.11(d,J＝8.0Hz,1H),7.68(dd,J＝8.0,1.3Hz,1H),7.50(dd,J＝7.8,1.3Hz,1H),7.39(t,J＝7.9Hz,1H),7.33–7.32(m,1H),7.22–7.16(m,3H) 6.95 (d, j=8.0 hz, 1H), 3.93 (s, 2H), 3.47-3.41 (m, 1H), 3.09 (d, j=15.8 hz, 1H), 2.68 (d, j=15.7 hz, 1H), 1.99 (dt, j=13.3, 6.8hz, 1H), 1.87-1.65 (m, 2H), 1.58 (d, j=13.3 hz, 1H), 1.49-1.43 (m, 1H), 1.30-1.19 (m, 3H) MS (ESI) m/z 513.33 and 515.28[ m+h ]] ⁺ .

Example 98

(S) -1'- (2, 3-dichlorophenyl) thiazolo [4,5-b ] pyridin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.32 (d, j=9.0 hz, 1H), 8.16 (dd, j=7.9, 1.2hz, 1H), 7.86 (dd, j=8.0, 1.1hz, 1H), 7.57 (t, j=8.0 hz, 1H), 7.45-7.34 (m, 1H), 7.25-7.15 (m, 4H), 4.32-4.28 (m, 1H), 3.97 (s, 1H), 3.12 (d, j=15.8 hz, 1H), 2.75 (d, j=15.7 hz, 1H), 2.03-1.95 (m, 2H), 1.82-1.66 (m, 2H), 1.54-1.44 (m, 1H), 1.35 (d, j=4.5 hz, 1H), 1.29-1.23 (m, 3H) [ ESI ] (m, 3H) and 48z/481.33 +3.36H ] ⁺ .

Example 99

(S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 4-amino-2-chloropyrimidin-5-ol

To a suspension of 2-chloro-5-methoxypyrimidin-4-amine (7.5 mmol,1.2 g) in DCM (40 mL) was slowly added BBr ₃ .Et ₂ O (5.0 equivalents, 37.5 mmol). The reaction mixture was then stirred at room temperature for 20 hours. After the reaction was completed, the resulting mixture was diluted with methanol and washed with brine. The separated organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo,the crude product was obtained as a pale yellow solid. MS (ESI) m/z 146.05 and 148.08[ M+H ]] ⁺ .

Step 25-chloro-2- (2, 3-dichlorophenyl) oxazolo [4,5-d ] pyrimidine

2, 3-Dichlorobenzoic acid (1.5 eq, 10.31mmol,1.97 g) was added to POCl of 4-amino-2-chloropyrimidin-5-ol (6.87 mmol,1.0 g) ₃ (50 mL) in suspension. The reaction mixture was then stirred at 110℃for 48 hours. After completion of the reaction, the resulting mixture was diluted with EA and saturated NaHCO ₃ Washing the solution. The separated organic layer was dried over MgSO ₄ The upper was dried, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 70%) to give 242.0mg of product as a pale yellow solid in 12% yield. MS (ESI) m/z300.12 and 302.17[ M+H ] ] ⁺ 。

Step 3N- ((S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To 5-chloro-2- (2, 3-dichlorophenyl) oxazolo [4,5-d]To a solution of pyrimidine (0.27 mmol,80.0 mg) and DIEA (5.0 eq, 1.33mmol,172.0 mg) in N-BuOH (3 mL) was added N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (1.5 eq, 0.4mmol,122.0 mg). The reaction mixture was then stirred under microwaves at 140 ℃ for 1 hour. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give 152.0mg of crude product as a pale brown solid, which was used directly in the next step. MS (ESI) m/z 570.56 and 572.67[ M+H ]] ⁺ .

Step 4 (S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-d ] pyrimidin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To N- ((S) -1' - (2, 3-dichlorophenyl) oxazolo [4, 5-d)]Pyrimidin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (0.27 mmol,152.0 mg) in THF (3 mL) was slowly added HCl/dioxane solution (1N, 1 mL). The reaction mixture was then stirred at rt for 1 hour. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the crude product, which was purified by column chromatography to give 13.2mg of the product as a yellow solid (11% yield in two steps)

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.99 (s, 1H), 8.27 (s, 2H), 8.16 (dd, j=7.9, 1.5hz, 1H), 7.99 (dd, j=8.1, 1.5hz, 1H), 7.64 (t, j=8.0 hz, 1H), 7.51 (d, j=7.3 hz, 1H), 7.37-7.29 (m, 3H), 4.57 (dd, j=24.6, 13.7hz, 2H), 4.37 (d, j=4.8 hz, 1H), 3.33-3.26 (m, 2H), 3.20 (d, j=16.2 hz, 1H), 3.04 (d, j=16.2 hz, 1H), 1.77-1.68 (m, 2H), 1.55-1.49 (m, 2H) [ MS (ESI) m/z 466.35 and m+468] ⁺ .

Example 100

(S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-d ] thiazol-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1N- ((S) -1'- (4-chloro-5-formylthiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To a solution of 2, 4-dichlorothiazole-5-carbaldehyde (1.37 mmol,250.0 mg) and DIEA (5.0 eq, 6.87mmol,888.0 mg) in MeCN (15 mL) was added N- ((S) -1,3-Dihydro spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (1.5 eq, 2.06mmol,631.0 mg). The reaction mixture was then stirred at rt for 2 hours. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 100%) to afford 615.0mg of the product as a pale yellow solid in 99% yield. MS (ESI) m/z 452.46 and 454.21[ M+H ]] ⁺ .

Step 2

N- ((S) -1'- (4-azido-5-formylthiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To N- ((S) -1'- (4-chloro-5-formylthiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (0.33 mmol,150.0 mg) and TMSN ₃ To a solution of (5.0 eq, 1.66mmol,191.0 mg) in DCM (5 mL) was added TBAF (5 eq, 1.66mmol,434.0 mg). The reaction mixture was then stirred at 35 ℃ for 48 hours. After removal of the solvent, the residue was diluted with DCM and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 80%) to afford 142.0mg of product in 93% yield as a yellow solid. MS (ESI) m/z 459.56[ M+H ]] ⁺ .

Step 3:

n- ((S) -1'- (4-azido-5- ((E) - (2, 3-dichlorophenyl) imino) methyl) thiazol-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To N- ((S) -1'- (4-chloro-5-formylthiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-ylideneSulfonamide (0.31 mmol,142.0 mg), 2, 3-dichloroaniline (1.5 eq, 0.47mmol,76.0 mg) and Et ₃ To a solution of N (3.0 equivalents, 0.94mmol,95.0 mg) in DCM (5 mL) was added TiCl ₄ (0.5 eq, 0.16mmol,29.8 mg). The reaction mixture was then stirred at 25 ℃ for 12 hours. After removal of the solvent, the residue was diluted with toluene and concentrated in vacuo to give 189.0mg of crude product as a brown solid, which was used directly in the next step. MS (ESI) m/z 602.44 and 604.35[ M+H ]] ⁺ .

Step 4

N- ((S) -1'- (2, 3-dichlorophenyl) -2H-pyrazolo [3,4-d ] thiazol-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

Addition of N- ((S) -1'- (4-azido-5- ((E) -2, 3-dichlorostyryl) thiazol-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) to the vial]-1-yl) -2-methylpropan-2-sulfinamide (0.31 mmol,189.0 mg) and toluene (5 mL). The reaction mixture was then stirred at 120℃for 5 hours. After removal of the solvent, the residue was diluted with EA and washed with brine. Separating the organic layer, na ₂ SO ₄ Drying, filtration and concentration in vacuo gave the crude product, which was purified by column chromatography (PE and EA, EA ranging from 0 to 80%) to yield 47.3mg of the product as a yellow solid in 26% yield. MS (ESI) m/z 574.34 and 576.46[ M+H ] ] ⁺ .

Step 5

To N- ((S) -1' - (2, 3-dichlorophenyl) -2H-pyrazolo [3, 4-d)]Thiazol-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]To a solution of-1-yl) -2-methylpropan-2-sulfinamide (0.08 mmol,47.2 mg) in THF (2 mL) was slowly added HCl/dioxane (1N, 1 mL). Then at rthe reaction mixture was stirred at t for 1 hour. After removal of the solvent, the residue was diluted with EA and saturated NaHCO ₃ And (5) cleaning the solution. Separating the organic layer, na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography to give 2.6mg of a pale yellow solid in 7% yield.

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.14 (s, 1H), 7.73 (dd, j=8.0, 1.5hz, 1H), 7.59 (dd, j=8.0, 1.5hz, 1H), 7.52 (t, j=8.0 hz, 1H), 7.32-7.30 (m, 1H), 7.20-7.15 (m, 3H), 3.96-3.92 (m, 2H), 3.87 (s, 1H), 3.46-3.42 (m, 2H), 3.08 (d, j=15.7 hz, 1H), 2.65 (d, j=15.7 hz, 1H), 1.85 (td, j=12.8, 4.4hz, 1H), 1.57 (d, j=13.4 hz, 1H), 1.17 (d, j=12.8, 4.4hz, 1H), 1.38 (d, j=13.7 hz, 1H) and (es) 3.46-3.42 (d, j=15.7 hz, 1H) 1.472 (d, j+2H)] ⁺ .

The compound of example 101 was prepared with reference to example 100.

Example 101

(S) -1'- (2, 3-dichlorobenzyl) -2H-pyrazolo [3,4-d ] thiazol-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 7.86 (s, 1H), 7.60 (dd, j=8.0, 1.0hz, 1H), 7.32 (dd, j=15.6, 7.6hz, 2H), 7.20-7.15 (m, 3H), 6.87 (d, j=7.5 hz, 1H), 5.46 (s, 2H), 3.89-3.81 (m, 3H), 3.27 (d, j=2.7 hz, 2H), 3.06 (d, j=15.7 hz, 1H), 2.63 (d, j=15.7 hz, 1H), 1.82 (td, j=12.7, 4.4hz, 1H), 1.71 (td, j=12.7, 4.3hz, 1H), 1.54 (d, j=12.9 hz, 1H), 1.15 (d, j=13.5 hz, 1H) [ ESI ] (484.34 +m/v and 36.m+36.v/v.f.] ⁺ .

Example 102

(S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyridin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 7-bromo-2- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyridine

4-bromopyridin-2-amine (0.5 g,2.89mmol,1.0 eq), 2-bromo-1- (2, 3-dichlorophenyl) ethan-1-one (1.549 g,5.78mmol,2 eq) and NaHCO under Ar ₃ (0.4816 g,5.78mmol,2 eq) was dissolved in ethanol (20 mL) to give a yellow suspension. The reaction mixture was stirred at 85 ℃ for 12 hours. Addition of H to the reaction mixture ₂ O (30 mL) and then extracted with ethyl acetate (50 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 15% ethyl acetate in hexanes to give the product as a yellow solid (0.36 g, 36.4%). MS (ESI) m/z 341.14[ M+H ] ] ⁺ .

Step 2 (R) -N- ((S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyridin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

Under Ar, 7-bromo-2- (2, 3-dichlorophenyl) imidazo [1,2-a]Pyridine (0.1 g,0.292mmol,1.000 eq), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (0.108 g,0.351mmol,1.2 eq), pd ₂ (dba) ₃ (0.027g，0.029mmol，0.1eq)，Cs ₂ CO ₃ (0.284 g,0.877mmol,3 eq) Xantphos (0.034 g,0.058mmol,0.2 eq) was dissolved in 1, 4-dioxane (8 ml) to give a brown suspension. The reaction mixture was stirred at 100℃for 12 hours. Addition of H to the reaction mixture ₂ O (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol in dichloromethane to give the product as a yellow solid (0.086 g, 51.8%). MS (ESI) m/z 567.38[ M+H ]] ⁺ .

Step 3 (S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyridin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

(R) -N- ((S) -1' - (2, 3-dichlorophenyl) imidazo [1, 2-a) under argon]Pyridin-7-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (0.086 g,0.152mmol,1.0 eq) and HCl (0.0554 g,1.520mmol,10.03 eq) were dissolved in 1, 4-dioxane (3 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Addition of saturated NaHCO to the reaction mixture ₃ (20 mL) and then extracted with ethyl acetate (30 mL. Times.3). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column chromatography to give the product as a white solid (17.4 mg, 24.8%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.35(d,J＝9.3Hz,2H),8.21(dd,J＝7.9,1.6Hz,1H),7.57(dd,J＝7.9,1.6Hz,1H),7.43(t,J＝7.9Hz,1H),7.31(d,J＝6.0Hz,1H),7.23–7.12(m,3H),6.90(dd,J＝7.7,2.3Hz,1H),6.70(d,J＝1.8Hz,1H),3.86(s,1H),3.70(dd,J＝16.8,13.0Hz,2H),3.08–2.91(m,3H),2.61(d,J＝15.6Hz,1H),1.91–1.71(m,2H),1.53(d,J＝12.0Hz,1H),1.15(d,J＝13.2Hz,1H).MS(ESI)m/z 463.38[M+H] ⁺ .

The compound of example 103 was prepared with reference to example 102.

Example 103

(S) -1'- (2, 3-dichlorophenyl) -5-methylimidazo [1,2-a ] pyridin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.18(dd,J＝7.9,1.4Hz,1H),8.09(s,1H),7.59(dd,J＝7.9,1.4Hz,1H),7.44(t,J＝7.9Hz,1H),7.38–7.30(m,1H),7.23–7.15(m,3H),6.83(s,1H),6.65(s,1H),3.92(s,1H),3.72(td,J＝10.7,4.6Hz,2H),3.08–2.92(m,3H),2.70–2.62(m,1H),2.58(s,3H),1.92–1.72(m,2H),1.59–1.39(m,2H).MS(ESI)m/z 477.26[M+H] ⁺ .

Example 104

(S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 6-bromo-2- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazine

5-bromopyrazin-2-amine (0.2 g,1.149mmol,1.0 eq) and 2-bromo-1- (2, 3-dichlorophenyl) ethan-1-one (0.616 g,2.299mmol,2 eq) were dissolved in ethanol (15 mL) under Ar to give a yellow solution. The reaction mixture was stirred at 85 ℃ for 24 hours. Addition of H to the reaction mixture ₂ O (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 20% ethyl acetate in hexanes to give the product as a yellow solid (0.073 g, 18.52%). MS (ESI) m/z 341.92[ M+H ]] ⁺ 。

Step 2 (R) -N- ((S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

Under Ar, 6-bromo-2- (2, 3-dichlorophenyl) imidazo [1,2-a]Pyrazine (0.05 g,0.146mmol, 1.000), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (0.067 g,0.219mmol, 1.5), BINAP (0.018 g,0.029mmol, 0.2), sodium tert-butoxide (0.042 g, 0.433 mmol, 3), pd ₂ (dba) ₃ (0.013 g,0.015mmol, 0.1) was dissolved in 1, 4-dioxane (4 ml) to give a brown suspension. The reaction mixture was stirred at 90℃for 1 hour under microwave. Adding H to the reaction mixture ₂ O (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was applied to a silica gel column and eluted with 0% to 3% methanol in dichloromethane to give the product as a yellow oil (0.02 g, 24.13%) MS (ESI) M/z568.26[ M+H)] ⁺ .

Step 3 (S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-a ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

(R) -N- ((S) -1' - (2, 3-dichlorophenyl) imidazo [1, 2-a) under Ar]Pyrazin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (0.02 g,0.035mmol,1.0 eq) and HCl (1.282 mg,0.035mmol,1.0 eq) were dissolved in 1, 4-dioxane (4 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Addition of saturated NaHCO to the reaction mixture ₃ (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column chromatography to give the product as a white solid (2.3 mg, 14.1%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.90(s,1H),8.58(s,1H),8.14(dd,J＝7.9,1.4Hz,1H),8.02(s,1H),7.67(dd,J＝8.0,1.5Hz,1H),7.49(t,J＝7.9Hz,1H),7.34(d,J＝5.3Hz,1H),7.19(dd,J＝7.3,4.1Hz,3H),3.93(s,1H),3.86(d,J＝12.8Hz,2H),3.06(d,J＝15.7Hz,1H),2.98(dd,J＝21.8,10.4Hz,2H),2.72–2.62(m,1H),1.93–1.84(m,1H),1.84–1.73(m,1H),1.54(d,J＝13.7Hz,1H),1.34(s,1H).MS(ESI)m/z 464.33[M+H] ⁺ .

Example 105

(S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 (R) -N- ((S) -1'- (6-aminopyrimidin-4-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

6-bromopyrimidin-4-amine (0.114 g,0.653mmol,2 eq), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) was reacted under Ar]-1-yl) -2-methylpropan-2-sulfinamide (0.1 g,0.326mmol,1.0 eq) and DIEA (0.127 g,0.979mmol,3 eq) were dissolved in n-butanol (4 mL) to give a yellow solution. The reaction mixture was stirred at 140℃for 1.5 hours under microwave. The crude product was added to a silica gel column and eluted with 0% to 6% methanol in dichloromethane to give the product as a colourless oil (0.09 g, 69.0%). MS (ESI) m/z 400.34[ M+H ]] ⁺ .

Step 2 (R) -N- ((S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

Under Ar, (R) -N- ((S) -1'- (6-aminopyrimidin-4-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]-1-yl) -2-methylpropan-2-sulfinamide (0.063 g,0.158mmol,1.0 eq), 2-bromo-1- (2, 3-dichlorophenyl) ethan-1-one (0.127 g,0.473mmol, 3), naHCO ₃ (0.040 g,0.473mmol,3 eq) was dissolved in ethanol (15 ml) to give a yellow solution. The reaction mixture was stirred at 85 ℃ for 12 hours. Addition of H to the reaction mixture ₂ O (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product is added to a silica gel column and 0% to 3% of alpha-methyl acetate is usedAlcohol/dichloromethane elution afforded the product as a yellow oil (0.038 g, 42.4%). MS (ESI) m/z 568.26[ M+H ]] ⁺ .

Step 3 (S) -1'- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

(R) -N- ((S) -1' - (2, 3-dichlorophenyl) imidazo [1,2-c ] under Ar]Pyrimidin-7-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (0.038 g,0.067mmol,1.0 eq) and HCl (0.024 g,0.668mmol,10 eq) were dissolved in 1, 4-dioxane (3 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Addition of saturated NaHCO to the reaction mixture ₃ (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column chromatography to give the product as a white solid (10.0 mg, 32.2%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.16(d,J＝1.0Hz,1H),8.41(s,1H),8.20(dd,J＝7.9,1.6Hz,1H),7.63(dd,J＝7.9,1.6Hz,1H),7.46(t,J＝7.9Hz,1H),7.36–7.30(m,1H),7.23–7.16(m,3H),6.57(s,1H),4.16–4.06(m,2H),3.91(s,1H),3.11(dd,J＝24.1,14.0Hz,3H),2.68(d,J＝15.7Hz,1H),1.86–1.75(m,1H),1.70(d,J＝3.7Hz,1H),1.51(d,J＝12.7Hz,1H),1.17(d,J＝12.4Hz,1H).MS(ESI)m/z 464.38[M+H] ⁺ .

The compounds of examples 106-107 were prepared as described in reference to example 105.

Example 106

(S) -1'- (2, 3-dichlorophenyl) -5-methylimidazo [1,2-c ] pyrimidin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.18(s,1H),8.15(dd,J＝7.9,1.6Hz,1H),7.63(dd,J＝7.9,1.6Hz,1H),7.46(t,J＝7.9Hz,1H),7.34–7.30(m,1H),7.21–7.16(m,3H),6.48(s,1H),4.19–4.06(m,2H),3.88(s,1H),3.13–3.00(m,3H),2.76(s,3H),2.65(d,J＝15.6Hz,1H),1.80(td,J＝12.8,4.3Hz,1H),1.75–1.63(m,1H),1.51(d,J＝13.0Hz,1H),1.14(dd,J＝12.4,5.1Hz,1H).MS(ESI)m/z 478.28[M+H] ⁺ .

Example 107

(S) -1'- (2, 3-dichlorophenyl) -8-fluoroimidazo [1,2-c ] pyrimidin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.08(s,1H),8.55(d,J＝3.0Hz,1H),8.22(dd,J＝8.0,1.6Hz,1H),7.67(dd,J＝8.0,1.6Hz,1H),7.49(t,J＝8.0Hz,1H),7.36–7.31(m,1H),7.20(dt,J＝8.4,4.1Hz,3H),4.04–3.96(m,2H),3.94(s,1H),3.23(d,J＝6.6Hz,2H),3.10(d,J＝15.8Hz,1H),2.74–2.67(m,1H),1.87(d,J＝3.3Hz,1H),1.78(d,J＝3.6Hz,1H),1.53(d,J＝12.3Hz,1H),1.18(s,1H).MS(ESI)m/z 482.32[M+H] ⁺ .

Example 108

(S) -7- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -2- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidine-8-carbonitrile

MS(ESI)m/z 489.33[M+H] ⁺ .

Example 109

(S) - (7- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -2- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-8-yl) methanol

Step 14- ((S) -1- ((R) -tert-Butylsulfoxide) amino) -1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6-chloropyrimidine-5-carboxylic acid methyl ester

4, 6-dichloropyrimidine-5-carboxylic acid methyl ester (0.2 g,0.966mmol,1.0 eq), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) under Ar]-1-yl) -2-methylpropan-2-sulfinamide (0.298 g,0.966mmol,1.0 eq) and CsF (0.440 g,2.90mmol,3 eq) were dissolved in DMF (2 ml) to give a yellow suspension. The reaction mixture was stirred at 60 ℃ for 2 hours. Addition of H to the reaction mixture ₂ O (20 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% methanol in dichloromethane to give the product as a yellow oil (0.46 g, 100%). MS (ESI) m/z 477.19[ M+H ]] ⁺ .

Step 2 4-amino-6- ((S) -1- ((R) -tert-butyl sulfoxide) amino) -1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrimidine-5-carboxylic acid methyl ester

4- ((S) -1- ((R) -tert-butyl sulfoxide) amino) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1' -yl) -6-chloropyrimidine-5-carboxylic acid methyl ester (0.46 g,0.964mmol,1.0 eq) and 25% aqueous ammonia (3.28 g,48.2mmol,50 eq) were dissolved in 1, 4-dioxane (3 ml). The reaction mixture was stirred at 90℃for 1.5 hours under microwave. The crude product was added to a silica gel column and eluted with 0% to 6% methanol in dichloromethane to give the product as a white solid (0.223 g, 50.5%). MS (ESI) m/z 458.26[ M+H ]] ⁺ .

Step 3

(R) -N- ((S) -1'- (6-amino-5- (hydroxymethyl) pyrimidin-4-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfamide

4-amino-6- ((S) -1- ((R) -tert-butylsulfoxide) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]Methyl-1' -yl-pyrimidine-5-carboxylate (0.223 g,0.487mmol,1.0 eq) was dissolved in THF (10 ml) to obtain a solution. The reaction mixture was cooled to 0 ℃ with an ice/water bath. LiAlH is prepared ₄ (0.092 g, 2.433 mmol,5 eq) was added in one portion to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. Addition of H to the reaction mixture ₂ O (10 mL) and then extracted with dichloromethane (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ g dried, filtered and concentrated to give the product as a yellow oil (0.2 g, 96%), MS (ESI) m/z 430.38[ M+H ]] ⁺ .

Step 4 (R) -N- ((S) -1'- (2, 3-dichlorophenyl) -8- (hydroxymethyl) imidazo [1,2-c ] pyrimidin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

Under Ar, the reaction mixture was purified by distillation under the conditions of Ar, followed by (R) -N- ((S) -1'- (6-amino-5- (hydroxymethyl) pyrimidin-4-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (0.2 g, 0.463 mmol,1.0 eq), 2-bromo-1- (2, 3-dichlorophenyl) ethan-1-one (0.374 g,1.397mmol,3 eq), and NaHCO ₃ (0.196 g,2.328mmol,5 eq) was dissolved in ethanol (10 ml) and the reaction mixture was stirred at 85℃for 16 hours. The crude product was added to a silica gel column and eluted with 0% to 6% methanol in dichloromethane to give the product as a yellow oil (0.063 g, 22.61%).

MS(ESI)m/z 598.34[M+H] ⁺ .

Step 5

(R) -N- ((S) -1' - (2, 3-dichlorophenyl) -8- (hydroxymethyl) imidazo [1, 2-c) under Ar]Pyrimidin-7-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (0.063 g,0.105mmol,1.0 eq) and HCl (0.038 g,1.052mmol,10 eq) were dissolved in 1, 4-dioxane (3 ml) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 hour. Addition of saturated NaHCO to the reaction mixture ₃ (20 mL) and then extracted with ethyl acetate (30 mL. Times.2). The combined organic layers Na ₂ SO ₄ Dried, filtered and concentrated. The crude product was purified by column chromatography to give the product as a white solid (0.6 mg, 1.1%). MS (ESI) m/z 494.35[ M+H ]] ⁺ .

Example 110

(S) -1'- (2, 3-dichlorophenyl) oxazolo [5,4-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1, 6-dibromo-3-fluoropyridin-4-amine

To a mixture of 2, 6-dibromopyridin-4-amine (3 g,11.91mmol,1.0 eq) in anhydrous DMF (20 mL) and anhydrous acetonitrile (20 mL) was added 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo [2.2.2]Octanedi (tetrafluoroborate) (5.06 g,14.29mmol,1.2 eq). The reaction was stirred at 80℃for 0.5 h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography, eluting first with DCM, to give the crude product, which was further purified by 0% to 30% hexane/ethyl acetate to give compound 2, 6-dibromo-3-fluoropyridin-4-amine (850 mg, 26.4%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ6.93(br,2H),6.84–6.80(m,1H).MS:268.9(M+H ⁺ ).

Step 2, 3-dichloro-N- (2, 6-dibromo-3-fluoropyridin-4-yl) benzamide

A solution of 2, 6-dibromo-3-fluoropyridin-4-amine (600 mg,2.22mmol,1.0 eq), 2, 3-dichlorobenzoic acid (425 mg,2.22mmol,1.0 eq), EDC (850 mg,4.45mmol,2.0 eq) and DMAP (407 mg,3.33mmol,1.5 eq) in anhydrous DCM (20 mL) was stirred at 35℃for 18 h under Ar. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0 to 35% hexane/ethyl acetate to give the compound 2, 3-dichloro-N- (2, 6-dibromo-3-fluoropyridin-4-yl) benzamide (550 mg, 55.9%) as a white solid,

MS:440.9(M+H ⁺ ).

step 3 6-bromo-2- (2, 3-dichlorophenyl) oxazolo [5,4-c ] pyridine

A mixture of 2, 3-dichloro-N- (2, 6-dibromo-3-fluoropyridin-4-yl) benzamide (22 mg,0.05mmol,1.0 eq) and NaH (2 mg,0.05mmol,1.0 eq) in NMP (3 mL) was subjected to microwaves at 200℃for 2 hours. Pouring the solution into H ₂ O. The precipitate was filtered and collected, purified by silica gel chromatography eluting with 0-15% hexane/ethyl acetate to give the compound 6-bromo-2- (2, 3-dichlorophenyl) oxazolo [5,4-c ] as a white solid]Pyridine (5 mg, 29.3%). ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.06(d,J＝0.5Hz,1H),8.29(d,J＝0.5Hz,1H),8.19(dd,J＝7.9,1.5Hz,1H),8.01(dd,J＝8.1,1.5Hz,1H),7.65(t,J＝8.0Hz,1H).MS:343.1(M+H ⁺ ).

Step 4N- ((S) -1'- (2, 3-dichlorophenyl) oxazolo [5,4-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

By reacting 6-bromo-2- (2, 3)-dichlorophenyl) oxazolo [5,4-c]Pyridine (5 mg,0.015mmol,1.0 eq), N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (11.14 mg,0.036mmol,2.5 eq), pd ₂ dba ₃ (2.66 mg, 2.91. Mu. Mol,0.2 eq) BINAP (3.62 mg, 5.81. Mu. Mol,0.4 eq) and potassium tert-butoxide (6.52 mg,0.058mmol,4.0 eq) in dry dioxane (3 mL) were subjected to microwaves at 120℃for 2 hours. The volatiles were removed under reduced pressure to give a crude product which was purified by silica gel chromatography eluting with 0% to 9% DCM/MeOH to give the compound N- ((S) -1' - (2, 3-dichlorophenyl) oxazolo [5, 4-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (10 mg, crude). MS 570.9 (M+H) ⁺ ).

Step 5 (S) -1'- (2, 3-dichlorophenyl) oxazolo [5,4-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Addition of HCl/dioxane solution to N- ((S) -1' - (2, 3-dichlorophenyl) oxazolo [5, 4-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]A solution of (E) -1-yl) -2-methylpropan-2-sulfinamide (40 mg,0.07mmol,1.0 eq) in dioxane (4 mL) was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 7 using saturated sodium carbonate solution, then at ethyl acetate/H ₂ O. Collecting organic matters, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give the crude product, which is purified by preparative HPLC to give the compound-1' - (2, 3-dichlorophenyl) oxazolo [5,4-c]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]1-amine (2 mg, 6.12%) as a yellow solid, MS:465.3 (M+H) ⁺ ) Purity of: 98.8%.

Example 111

(S) -1'- (2, 3-dichlorophenyl) -4-methylbenzo [ d ] oxazol-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 2-amino-4-bromo-3-methylphenol

A mixture of 4-bromo-3-methyl-2-nitrophenol (500 mg,2.155mmol,1.0 eq) and tin (II) chloride dihydrate) (1.23 g,6.46mmol,3.0 eq) in ethanol (10 mL) was refluxed for 3 hours. Adding additional SnCl ₂ (4.5 equivalents). The reaction was refluxed for 2 hours. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0 to 15% hexane/ethyl acetate to give the compound 2-amino-4-bromo-3-methylphenol (418 mg, 96%). MS 202.2 (M+H) ⁺ ).

Step 2 5-bromo-2- (2, 3-dichlorophenyl) -4-toluo [ d ] oxazole

A solution of 2-amino-4-bromo-3-methylphenol (418 mg,2.07mmol,1.0 eq), 2, 3-dichlorobenzoyl chloride (433 mg,2.07mmol,1.0 eq) and methanesulfonic acid (596 mg,6.21mmol,3.0 eq) in anhydrous dioxane (20 mL) was stirred at 100deg.C for 6 hours. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0 to 10% hexane/ethyl acetate to give the compound 5-bromo-2- (2, 3-dichlorophenyl) -4-methylbenzo [ d ] ]Oxazole (400 mg, 54.2%). MS:357.1 (M+H) ⁺ ).

Step 3N- ((S) -1'- (2, 3-dichlorophenyl) -4-methylbenzo [ d ] oxazol-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

N- ((S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (129 mg,0.42mmol,1.5 eq), 5-bromo-2- (2, 3-dichlorophenyl) -4-methylBenzo [ d ] radicals]Oxazole (100 mg,0.28mmol,1.0 eq), pd ₂ (dba) ₃ (51.3 mg,0.056mmol,0.2 eq), xantphos (48.6 mg,0.084mmol,0.3 eq) and sodium tert-butoxide (81 mg,0.84mmol,3.0 eq) in anhydrous dioxane (5 mL) were stirred at 90℃for 2 hours, volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0% to 5% DCM/MeOH to give the product N- ((S) -1' - (2, 3-dichlorophenyl) -4-methylbenzo [ d)]Oxazol-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (12 mg, 7.35%)

MS:582.5(M+H ⁺ ).

Step 4 (S) -1'- (2, 3-dichlorophenyl) -4-methylbenzo [ d ] oxazol-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To N- ((S) -1' - (2, 3-dichlorophenyl) -4-methylbenzo [ d) at room temperature]Oxazol-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (12 mg,0.021mmol,1.0 eq) in dioxane (3 ml). The reaction solution was stirred for 0.5h. Dilute the solution with ethyl acetate, use saturated NaHCO ₃ The solution was adjusted to pH 7. Solution in ethyl acetate/H ₂ O. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give the crude product, which is purified by preparative HPLC to afford the product (S) -1' - (2, 3-dichlorophenyl) -4-methylbenzo [ d) as a white solid]Oxazol-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-amine (2.6 mg, 26.4%). MS 478.4 (M+H) ⁺ ) The purity is 89.6%.

Example 112

(S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-b ] pyridin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 5-Bromooxazolo [4,5-b ] pyridine-2-thiol

A mixture of 2-amino-6-bromopyridin-3-ol (1 g,5.29mmol,1.0 eq) and potassium O-ethyldithiocarbonate (1.02 g,6.35mmol,1.2 eq) in absolute ethanol (15 mL) was stirred at 100deg.C for 16 hours. Removing volatiles under reduced pressure using H ₂ The residue was diluted with O and the pH was adjusted to 7 with aqueous hydrochloric acid. Collecting the precipitate and drying to obtain crude compound 5-bromooxazolo [4,5-b ]]Pyridine-2-thiol (750 mg, 61.3%). MS 231.1 (M+H) ⁺ ).

Step 2 5-bromo-2-chlorooxazolo [4,5-b ] pyridine

To 5-bromooxazolo [4,5-b ]]To a solution of pyridine-2-thiol (750 mg,3.25mmol,1.0 eq) in anhydrous DMF (5 mL) was added dropwise oxalyl chloride (618 mg,4.87mmol,1.5 eq) at 0deg.C. The reaction was slowly warmed to room temperature and stirred for 2 hours. The solution was taken up in ethyl acetate/NaHCO ₃ Separating in aqueous solution, collecting organic matter, washing with brine, anhydrous Na ₂ SO ₄ Drying, filtering and concentrating to obtain crude product, purifying by silica gel chromatography, eluting with 0% to 5% hexane/ethyl acetate to obtain product 5-bromo-2-chlorooxazolo [4,5-b ]]Pyridine (450 mg, 59.4%). MS 233.4 (M+H) ⁺ ).

Step 3 5-bromo-2- (2, 3-dichlorophenyl) oxazolo [4,5-b ] pyridine

Under Ar, 5-bromo-2-chlorooxazolo [4,5-b]Pyridine (210 mg,0.90mmol,1.0 eq), (2, 3-dichlorophenyl) boronic acid (206 mg,1.08mmol,1.2 eq), pdCl ₂ (dppf)-CH ₂ Cl ₂ adduct(147mg，0.18mmol,0.2 eq) and K ₂ CO ₃ (373 mg,2.70mmol,3 eq) in dioxane (5 mL) and H ₂ The mixture in O (0.5 mL) was stirred at 70℃for 70 min. Volatiles were removed under reduced pressure and purified by silica gel chromatography eluting with 0% to 10% hexane/ethyl acetate to give the product 5-bromo-2- (2, 3-dichlorophenyl) oxazolo [4, 5-b)]Pyridine (130 mg, 42%), MS:343.4 (M+H) ⁺ ).

Step 4N- ((S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-b ] pyridin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

5-bromo-2- (2, 3-dichlorophenyl) oxazolo [4,5-b under Ar]Pyridine (110 mg,0.32mmol,1.0 eq), N- ((S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine) ]-1-yl) -2-methylpropan-2-sulfinamide (147 mg,0.48mmol,1.5 eq), pd ₂ (dba) ₃ A mixture of (58.6 mg,0.064mmol,0.2 eq), BINAP (59.7 mg,0.096mmol,0.3 eq) and sodium tert-butoxide (92 mg,0.96mmol,3.0 eq) in dry toluene (7 ml) was microwaved at 90℃for 50 minutes. Volatiles were removed under reduced pressure and purified by silica gel chromatography eluting with 0% to 5% DCM/MeOH to give the product N- ((S) -1' - (2, 3-dichlorophenyl) oxazolo [4, 5-b)]Pyridin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (50 mg, 27.5%). MS 569.5 (M+H) ⁺ ).

Step 5 (S) -1'- (2, 3-dichlorophenyl) oxazolo [4,5-b ] pyridin-5-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

At room temperature, to N- ((S) -1' - (2, 3-dichlorophenyl) oxazolo [4, 5-b)]Pyridin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]A solution of HCl/dioxane (6N) added to a solution of-1-yl) -2-methylpropan-2-sulfinamide (50 mg,0.088mmol,1.0 eq) in dioxane (2 mL). The reaction was stirred for 0.5h. With acetic acidEthyl ester dilution of the solution with saturated NaHCO ₃ The solution was adjusted to pH 7. Solution in ethyl acetate/H ₂ O. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by preparative HPLC to afford the product (S) -1' - (2, 3-dichlorophenyl) oxazolo [4, 5-b) as a yellow solid ]Pyridin-5-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-amine (2.4 mg, 5.87%). MS 465.2 (M+H) ⁺ ) The purity is 85.8%.

Example 113

(S) -1'- (5-amino-3- (2, 3-dichlorophenyl) -1, 6-naphthyridin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1, 7-dichloro-3-iodo-1, 6-naphthyridine

A solution of 5, 7-dichloro-1, 6-naphthyridine (2 g,10.05mmol,1.0 eq) and 1-iodopyrrolidine-2, 5-dione (4.52 g,20.10mmol,2.0 eq) in acetic acid (25 mL) was stirred under Ar for 17 hours at 110 ℃. The volatiles were removed under reduced pressure, the residue diluted with DCM and purified by silica gel chromatography eluting with hexane/ethyl acetate from 0% to 10% to give the compound 5, 7-dichloro-3-iodo-1, 6-naphthyridine (1.0 g, 30.6%) as a grey solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.39(d,J＝2.0Hz,1H),9.01(dd,J＝1.9,0.9Hz,1H),8.14(d,J＝0.7Hz,1H).MS:324.9(M+H ⁺ ).

Step 2, 7-dichloro-3- (2, 3-dichlorophenyl) -1, 6-naphthyridine

5, 7-dichloro-3-iodo-1, 6-naphthyridine (600 mg,1.85 mm)ol,1.0 eq), (2, 3-dichlorophenyl) boronic acid (423 mg,2.22mmol,1.2 eq), pdCl ₂ (dppf) (270 mg,0.37mmol,0.2 eq) and sodium carbonate (399mg, 3.69mmol,2.0 eq) were microwaved at 80℃for 45 minutes. The crude compound 5, 7-dichloro-3- (2, 3-dichlorophenyl) -1, 6-naphthyridine (1.6 g, crude product) was collected as a grey solid by precipitation and used directly in the next step. MS 345.2 (M+H) ⁺ ).

Step 3 7-chloro-3- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -1, 6-naphthyridin-5-amine

To a solution of 5, 7-dichloro-3- (2, 3-dichlorophenyl) -1, 6-naphthyridine (1.6 g,4.65mmol,1.0 eq) in dioxane (10 mL) was added (2, 4-dimethoxyphenyl) methylamine (1.4 g,8.37mmol,1.8 eq) at room temperature. The reaction was stirred at 100℃for 3 hours. The volatiles were removed under reduced pressure and the residue diluted with DCM. The solid was filtered, the filtrate was concentrated and purified by silica gel chromatography eluting with DCM to give the compound 7-chloro-3- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -1, 6-naphthyridin-5-amine (815 mg, 36.9%) as a yellow solid. MS 474.5 (M+H) ⁺ ).

Step 4N- ((S) -1'- (3- (2, 3-dichlorophenyl) -5- ((2, 4-dimethoxybenzyl) amino) -1, 6-naphthyridin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

7-chloro-3- (2, 3-dichlorophenyl) -N- (2, 4-dimethoxybenzyl) -1, 6-naphthyridin-5-amine (700 mg,1.47mmol,1.0 eq), N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) was reacted under Ar]-1-yl) -2-methylpropan-2-sulfinamide (678 mg,2.21mmol,1.5 eq), sodium tert-butoxide (425 mg,4.42mmol,3.0 eq), xantphos (256 mg,0.44mmol,0.3 eq) and Pd ₂ (dba) ₃ (270 mg,0.30mmol,0.2 eq) of anhydrous dioxane (10 mL) was subjected to microwave at 110℃for 1 hour. Removing volatile substances under reduced pressure, and removing residue Purification by silica gel chromatography eluting with DCM/MeOH from 0% to 9% afforded the compound N- ((S) -1'- (3- (2, 3-dichlorophenyl) -5- ((2, 4-dimethoxybenzyl) amino) -1, 6-naphthyridin-7-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (100 mg, 9.11%). MS 744.5 (M+H) ⁺ ).

Step 5N- ((S) -1'- (5-amino-3- (2, 3-dichlorophenyl) -1, 6-naphthyridin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

TFA (2 mL) was added dropwise to N- ((S) -1'- (3- (2, 3-dichlorophenyl) -5- ((2, 4-dimethoxybenzyl) amino) -1, 6-naphthyridin-7-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) under Ar at room temperature]In a solution of (1-yl) -2-methylpropan-2-sulfinamide (100 mg,0.13mmol,1.0 eq) in DCM (6 mL). The solution was stirred for 0.5 hours. The volatiles were removed under reduced pressure and the compound N- ((S) -1'- (5-amino-3- (2, 3-dichlorophenyl) -1, 6-naphthyridin-7-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) was used directly in the next step]-1-yl) -2-methylpropan-2-sulfinamide (80 mg, crude) MS:594.3 (M+H) ⁺ ).

Step 6 (S) -1'- (5-amino-3- (2, 3-dichlorophenyl) -1, 6-naphthyridin-7-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Dropwise addition of HCl/dioxane solution to N- ((S) -1'- (5-amino-3- (2, 3-dichlorophenyl) -1, 6-naphthyridin-7-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) under Ar at room temperature ]-1-yl) -2-methylpropan-2-sulfinamide (80 mg,0.14mmol,1.0 eq) in anhydrous dioxane (5 mL). The solution was stirred for 0.5 h using saturated NaHCO ₃ The solution was adjusted to pH 7. Solution in ethyl acetate/H ₂ O. The organics were collected and concentrated to give the crude product which was purified by preparative HPLC to afford the compound (S) -1' - (5-amino-3- (2, 3-dichlorophenyl) -1, 6-naphthalene as a white solidPyridin-7-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-amine (6 mg, 9.09%).

MS:490.3(M+H ⁺ ) Purity of: 86.8%.

Example 114

(S) -1'- (4-amino-6- (2, 3-dichlorophenyl) pyridin [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 6-bromopyridine [2,3-d ] pyrimidine-2, 4-diol

A mixture of 2-amino-5-bromonicotinic acid (1 g,4.61mmol,1.0 eq) and urea (2.77 g,46.1mmol,10 eq) was heated at 180deg.C (oil bath) for 5 hours. The reaction was cooled and diluted with 2N NaOH solution. The pH of the solution was adjusted to 8 using 6N HCl solution. The precipitate was filtered and dried to give the compound 6-bromopyridine [2,3-d ] as a grey solid]Pyrimidine-2, 4-diol (0.6 g, 53.8%). MS 242.3 (M+H) ⁺ ).

Step 2 6-bromo-2, 4-dichloropyridine [2,3-d ] pyrimidine

6-bromopyridine [2,3-d ]]Pyrimidine-2, 4-diol (600 mg,2.48mmol,1.0 eq), DIPEA (740 mg,5.73mmol,2.31 eq) and POCl ₃ The mixture of (8 mL) was reacted at 120℃for 48 hours. Volatiles were removed under reduced pressure and the pH of the residue was adjusted to 7. Solution in DCM/H ₂ O. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Drying, filtering and concentrating to obtain crude 6-bromo-2, 4-dichloropyridine [2,3-d ]]Pyrimidine (500 mg, 72.3%) was used directly in the next step. MS 278.8 (M+H) ⁺ ).

Step 3 6-bromo-2-chloro-N- (2, 4-dimethoxybenzyl) pyridin [2,3-d ] pyrimidin-4-amine

A solution of 6-bromo-2, 4-dichloropyridine [2,3-d ] pyrimidine (500 mg,1.79mmol,1.0 eq), DIPEA (695 mg,5.38mmol,3.0 eq) and (2, 4-dimethoxyphenyl) methylamine (2910 mg,2.15mmol,1.2 eq) in butanol (5 mL) and tetrahydrofuran (5 mL) was stirred at 40℃for 1h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-10% hexane/ethyl acetate to give the compound 6-bromo-2-chloro-N- (2, 4-dimethoxybenzyl) pyridin [2,3-d ] pyrimidin-4-amine (200 mg, 29.5%).

MS:377.6(M+H ⁺ ).

Step 4N- ((S) -1'- (6-bromo-4- ((2, 4-dimethoxybenzyl) amino) pyridin [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

A solution of 6-bromo-2-chloro-N- (2, 4-dimethoxybenzyl) pyridin [2,3-d ] pyrimidin-4-amine (200 mg,0.49mmol,1.0 eq), DIPEA (126 mg,0.98mmol,2.0 eq) and N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide (180 mg,0.59mmol,1.2 eq) in butanol (5 ml) was stirred at 140℃for 1h, volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography eluting with hexane/ethyl acetate to give the compound N- ((S) -4- (6-bromo-4- ((2, 4-dimethoxybenzyl) amino) pyridin [2,3-d ] pyrimidin-2-yl) -1',3' -dihydrospiro [ cyclohexane-1, 2' -indene ] -1' -yl) -2-methylpropan-2-sulfinamide (245 mg, 73.9%).

MS:679.7(M+H ⁺ ).

Step 5N- ((S) -1'- (6- (2, 3-dichlorophenyl) -4- ((2, 4-dimethoxybenzyl) amino) pyridin [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

PdCl is added to ₂ (dppf) (6.47 mg, 8.84. Mu. Mol,0.1 eq), potassium carbonate (36.7 mg,0.27mmol,3.0 eq), (2, 3-dichlorophenyl) boronic acid (33.7 mg,0.18mmol,2.0 eq) and N- ((S) -4- (6-bromo-4- ((2, 4-dimethoxybenzyl) amino) pyridine [2,3-d]Pyrimidin-2-yl) -1',3' -dihydrospiro [ cyclohexane-1, 2' -indene]-1' -yl) -2-methylpropane-2-sulfinamide (60 mg,0.09mmol,1.0 eq) in dioxane (2 mL) and H ₂ O (0.5 mL) was microwaved at 115℃for 0.5h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with DCM/MeOH from 0% to 8% to give the compound N- ((S) -4- (6- (2, 3-dichlorophenyl) -4- ((2, 4-dimethoxybenzyl) amino) pyridine [2, 3-d)]Pyrimidin-2-yl) -1',3' -dihydrospiro [ cyclohexane-1, 2' -indene]-1' -yl) -2-methylpropane-2-sulfinamide (50 mg, 76%). MS 744.6 (M+H) ⁺ ).

Step 6N- ((S) -1'- (4-amino-6- (2, 3-dichlorophenyl) pyridin [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

To N- ((S) -4- (6- (2, 3-dichlorophenyl) -4- ((2, 4-dimethoxybenzyl) amino) pyridine [2,3-d ] at room temperature ]Pyrimidin-2-yl) -1',3' -dihydrospiro [1,2' -indenes]To a solution of (1' -yl) -2-methylpropane-2-sulfinamide (50 mg,0.067mmol,1.0 eq) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred for 18 hours. The volatiles were removed under reduced pressure and the crude product N- ((S) -4- (4-amino-6- (2, 3-dichlorophenyl) pyridine [2, 3-d) was used directly in the next step]Pyrimidin-2-yl) -1',3' -dihydrospiro [ cyclohexane-1, 2' -indene]-1' -yl) -2-methylpropan-2-sulfinamide (40 mg, 100%), MS:595.2 (M+H) ⁺ ).

Step 7 (S) -1'- (4-amino-6- (2, 3-dichlorophenyl) pyridin [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To N- ((S) -4- (4-amino-6- (2, 3-dichlorophenyl) pyridine [2, 3-d) at room temperature]Pyrimidin-2-yl) -1',3' -dihydrospiro [ cyclohexane-1, 2' -indene]To a solution of (1' -yl) -2-methylpropane-2-sulfonamide (40 mg,0.067mmol,1.0 eq) in dioxane (4 mL) was added dropwise HCl/dioxane solution. The reaction was stirred for 20 minutes. Using NaHCO ₃ The aqueous solution adjusts the pH of the solution to 7. Collecting organic matters, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give a crude product which is further purified by preparative HPLC to provide the compound-2- (1 '-amino-1', 3 '-dihydrospiro [ cyclohexane-1, 2' -indene]-4-yl) -6- (2, 3-dichlorophenyl) pyridine [2,3-d ]Pyrimidin-4-amine (6.8 mg, 20.61%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.69(d,J＝2.3Hz,1H),8.49(d,J＝2.4Hz,1H),7.80–7.60(m,3H),7.52–7.46(m,2H),7.37–7.27(m,1H),7.24–7.14(m,3H),4.75–4.60(m,2H),3.86(s,1H),3.26–3.07(m,3H),2.72–2.62(m,1H),1.78–1.68(m,1H),1.68–1.57(m,1H),1.54–1.44(m,1H),1.14–1.06(m,1H).MS:490.2(M+H ⁺ ) The purity is 93.3%.

The compound of example 115 was prepared as described in reference to example 114.

Example 115

(S) -1'- (4-amino-6- ((2, 3-dichlorophenyl) thio) pyridin [2,3-d ] pyrimidin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.69–8.64(m,2H),7.83–7.72(m,1H),7.45(dd,J＝8.0,1.2Hz,1H),7.36–7.31(m,1H),7.27–7.14(m,4H),6.67(dd,J＝8.1,1.2Hz,1H),4.74–4.60(m,2H),3.89(s,1H),3.25–3.05(m,3H),2.73–2.65(m,1H),1.79–1.66(m,1H),1.66–1.56(m,1H),1.53–1.43(m,1H),1.18–1.08(m,1H).MS:523.2(M+H ⁺ ) The purity is 91.9%.

Example 116

(S) -1'- (8- (2, 3-dichlorophenyl) -7H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine

Step 1 2-chloro-8- (2, 3-dichlorophenyl) -9H-purine

POCl of 2-chloropyrimidine-4, 5-diamine (378 mg,2.62mmol,1.0 eq) and 2, 3-dichlorobenzoic acid (500 mg,2.62mmol,1.0 eq) were reacted under Ar ₃ (10 mL) the mixture was stirred at 100deg.C for 5 hours. The volatiles were removed under reduced pressure and the residue was taken up in ethyl acetate/saturated NaHCO ₃ Dispensing in solution. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give a crude product, which was eluted from 0% to 20% hexane/ethyl acetate by silica gel chromatography to give the product 2-chloro-8- (2, 3-dichlorophenyl) -9H-purine (130 mg, 16.58%). MS 299.2 (M+H) ⁺ ).

Step 2N- ((S) -1'- (8- (2, 3-dichlorophenyl) -7H-purin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

A solution of 2-chloro-8- (2, 3-dichlorophenyl) -9H-purine (110 mg,0.367mmol,1.0 eq.) was reacted with N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]A mixture of (1-yl) -2-methylpropan-2-sulfinamide (113 mg,0.367mmol,1.0 eq) and DIPEA (47.5 mg,0.367mmol,1.0 eq) in n-butanol (5 mL) was microwaved at 150℃for 1 hour. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with DCM/ethyl acetate to give the product N- ((S) -1'- (8- (2, 3-dichlorophenyl) -7H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (50 mg, 23.91%). MS 569.6 (M+H) ⁺ )

Step 3 (S) -1'- (8- (2, 3-dichlorophenyl) -7H-purin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

N- ((S) -1'- (8- (2, 3-dichlorophenyl) -7H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) in dioxane (4 mL)]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (50 mg,0.088mmol,1.0 eq) was added a solution of HCl/dioxane (6N) at room temperature. The reaction was stirred for 0.5h. Dilute the solution with ethyl acetate, use saturated NaHCO ₃ The solution was adjusted to pH 7. Solution in ethyl acetate/H ₂ O. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give the crude product which is purified by preparative HPLC to give the product ((S) -1'- (8- (2, 3-dichlorophenyl) -7H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) as a white solid ]-1-amine (10 mg, 24.48%). ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.77(s,1H),7.83(dd,J＝8.1,0.7Hz,1H),7.75(d,J＝7.4Hz,1H),7.58–7.51(m,1H),7.47–7.31(m,1H),7.30–7.20(m,3H),4.61–4.50(m,2H),4.11–3.90(m,1H),3.31–3.11(m,3H),2.84–2.76(m,1H),1.82–1.61(m,2H),1.55–1.45(m,1H),1.34–1.27(m,1H).MS:465.2(M+H ⁺ ) The purity is 95.6%.

Example 117

(S) -1'- (4-amino-2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1 6-chloro-N ² ,N ² -bis (4-methoxybenzyl) -3-nitropyridine-2, 4-diamine

A solution of 2, 6-dichloro-3-nitropyridin-4-amine (2 g,9.62mmol,1.0 eq), bis (4-methoxybenzyl) amine (2.55 g,9.90mmol,1.03 eq) and triethylamine (1.46 g,14.42mmol,1.5 eq) in anhydrous DCM (40 mL) was stirred at room temperature for 18 hours. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with DCM to give compound 6-chloro-N ² ,N ² Bis (4-methoxybenzyl) -3-nitropyridine-2, 4-diamine (4 g, 97%) as foam,

MS:429.2(M+H ⁺ ).

step 2N- ((S) -1'- (4-amino-6- (bis (4-methoxybenzyl) amino) -5-nitropyridin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

6-chloro-N ² ,N ² Mixtures of bis (4-methoxybenzyl) -3-nitropyridine-2, 4-diamine (1.4 g,3.26mmol,1.0 eq), N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (1.0 g,3.26mmol,1.0 eq) and N-ethyl-N-isopropyl-propan-2-amine (844 mg,6.53mmol,2.0 eq) were subjected to microwaves at 133℃for 135 minutes. Pouring the solution into H ₂ In O, a precipitate formed, was filtered and dissolved in DCM, and was first purified by chromatography on silica gel with DCM to recover the unreacted starting material. The compound N- ((S) -1'- (4-amino-6- (bis (4-methoxybenzyl) amino) -5-nitropyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) was then provided as a brown foam, eluting with DCM/MeOH from 0% to 9%]-1-yl) -2-methylpropan-2-sulfinamide (1.5 g, 65.7%). MS 699.3 (M+H) ⁺ ).

Step 3N- ((S) -1'- (4, 5-diamino-6- (bis (4-methoxybenzyl) amino) pyridin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

N- ((S) -1'- (4-amino-6- (bis (4-methoxybenzyl) amino) -5-nitropyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]A mixture of (1-yl) -2-methylpropan-2-sulfinamide (700 mg,1.002mmol,1.0 eq) and Raney Nickel in ethanol (50 mL) and H ₂ 3 substitutions. The reaction was stirred at room temperature for 16 hours. The solution was filtered. The filtrate was concentrated to provide the compound N- ((S) -1'- (4, 5-diamino-6- (bis (4-methoxybenzyl) amino) pyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (670 mg, crude) was used directly in the next step, MS:669.3 (M+H) ⁺ ).

Step 4N- ((S) -1'- (4- (bis (4-methoxybenzyl) amino) -2-mercapto-3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

N- ((S) -1'- (4, 5-diamino-6- (bis (4-methoxybenzyl) amino) pyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]A mixture of (1-yl) -2-methylpropan-2-sulfinamide (640 mg,1.002mmol,1.0 eq) and potassium O-ethyldithiocarbonate (193 mg,1.202mmol,1.2 eq) in ethanol (5 mL) and pyridine (3 mL) was stirred at 100deg.C for 16 hours. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with DCM/ethyl acetate from 0% to 30% to give the compound N- ((S) -1' - (4- (bis (4-methoxybenzyl) amino) -2-mercapto-3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (110 mg, 15.45%). MS 711.2 (M+H) ⁺ ).

Step 5N- ((S) -1'- (4- (bis (4-methoxybenzyl) amino) -2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide

N- ((S) is-1' - (4- (bis (4-methoxybenzyl) amino) -2-mercapto-3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines ]-1-yl) -2-methylpropan-2-sulfinamide (83 mg,0.117mmol,1.0 eq), 1, 2-dichloro-3-iodobenzene (38.2 mg,0.14mmol,1.2 eq), pd ₂ (dba) ₃ (21.38 mg,0.023mmol, eq) and a mixture of BINAP (21.81 mg,0.035mmol,0.3 eq) and DIPEA (45.3 mg,0.350mmol,3.0 eq) in dioxane (5 mL) were microwaved at 90℃for 50 minutes. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with DCM/ethyl acetate from 0% to 30% to give the compound N- ((S) -1' - (4- (bis (4-methoxybenzyl) amino) -2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (80 mg, 80%). MS 855.9 (M+H) ⁺ ).

Step 6N- ((S) -1'- (4-amino-2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

A solution of N- ((S) -1'- (4- (bis (4-methoxybenzyl) amino) -2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide (80 mg,0.093mmol,1.0 eq) in TFA (3 mL) and DCM (3 mL) was stirred at 35℃for 1 hour. Using saturation

NaHCO ₃ The pH of the solution was adjusted to 7. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Drying, filtering and concentrating to give the compound N- ((S) -1' - (4-amino-2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (57 mg, 99%) was used directly in the next step. MS 615.6 (M+H) ⁺ ).

Step 7 (S) -1'- (4-amino-2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

N- ((S) -1' - (4-amino-2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] into dioxane (4 ml) at room temperature]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (57 mg,0.093mmol,1.0 eq) was added HCl/dioxane (6N, 1.5 ml). The reaction was stirred for 0.5h. Using saturated NaHCO ₃ The pH of the solution was adjusted to 7. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give a crude product which is purified by preparative HPLC to provide the compound (S) -1' - (4-amino-2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]1-amine (3 mg, 6.34%) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.55–7.50(m,1H),7.37–7.26(m,2H),7.24–7.15(m,3H),6.84–6.76(m,1H),6.18–6.06(m,2H),5.87(s,1H),4.05–3.96(m,2H),3.90(s,1H),3.09–3.00(m,1H),2.99–2.87(m,2H),2.69–2.61(m,1H),1.85–1.73(m,1H),1.72–1.62(m,1H),1.50–1.42(m,1H),1.20–1.11(m,1H).MS:511.4(M+H ⁺ ).

Example 118

(S) -1'- (2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1N- ((S) -1'- (4-amino-5-nitropyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

2-chloro-5-nitropyridin-4-amine (850 mg,4.90mmol,1.0 eq) was reacted under Ar,N- ((S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]A solution of-1-yl) -2-methylpropan-2-sulfinamide (1.65 g,5.39mmol,1.1 eq) and DIPEA (1.9 g,14.69mmol,3.0 eq) in butanol (10 mL) was stirred at 135℃for 18 hours. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0 to 30% hexane/ethyl acetate to give the compound N- ((S) -1'- (4-amino-5-nitropyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (1.7 g, 78%). MS 444.6 (M+H) ⁺ ).

Step 2N- ((S) -1'- (4, 5-diaminopyridin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

N- ((S) -1'- (4-amino-5-nitropyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]Mixtures of-1-yl) -2-methylpropan-2-sulfinamide (200 mg, 0.457 mmol,1.0 eq) and Raney Nickel in ethanol (10 mL) and using H ₂ 3 substitutions. The reaction was stirred at room temperature for 16 hours. Filtration and concentration of the filtrate to provide the compound N- ((S) -1'- (4, 5-diaminopyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropan-2-sulfinamide (186 mg, 100%) which is used directly in the next step. MS 414.5 (M+H) ⁺ ).

Step 3N- ((S) -1'- (2-mercapto-3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

N- ((S) -1'- (4, 5-diaminopyridin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]A solution of-1-yl) -2-methylpropan-2-sulfinamide (60 mg,0.145mmol,1.0 eq) and potassium O-ethyldithiocarbonate (27.9 mg,0.174mmol,1.2 eq) in ethanol (5 mL) and pyridine (3 mL) was stirred at 100deg.C for 10 hours. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography with DCM/ethyl acetate from 0% to 30% elution to give the compound N- ((S) -1' - (2-mercapto-3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (50 mg, 76%). MS 456.2 (M+H) ⁺ ).

Step 4N- ((S) -1'- (2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfonamide

N- ((S) -1' - (2-mercapto-3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (50 mg,0.11mmol,1.0 eq), 1, 2-dichloro-3-iodobenzene (35.9 mg,0.132mmol,1.2 eq), pd ₂ (dba) ₃ (20.10 mg,0.022mmol,0.2 eq), BINAP (20.50 mg,0.033mmol,0.3 eq) and DIPEA (42.5 mg,0.329mmol,3.0 eq) in dioxane (5 mL) were subjected to microwaves at 90℃for 70 minutes. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with DCM/ethyl acetate from 0% to 30% to give the compound N- ((S) -1' - (2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]-1-yl) -2-methylpropan-2-sulfinamide (20 mg, 30.3%), MS:600.2 (M+H) ⁺ ).

Step 5 (S) -1'- (2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] pyridin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

N- ((S) -1' - (2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4,5-c ] into dioxane (3 ml) at room temperature]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]To a solution of (1-yl) -2-methylpropan-2-sulfinamide (20 mg,0.033mmol,1.0 eq) was added a 6N HCl/dioxane solution. The reaction was stirred for 1 hour. Using saturated NaHCO ₃ The solution was adjusted to pH 7. Collecting organic matters, and flushing with brineWashing, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give a crude product which is purified by preparative HPLC to provide the compound (S) -1' - (2- ((2, 3-dichlorophenyl) thio) -3H-imidazo [4, 5-c)]Pyridin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidines]1-amine (1.0 mg, 6.05%) as a white solid, MS:496.4 (M+H) ⁺ ).

Examples 119 and 120

(S) -1'- (8- (2, 3-dichlorophenyl) -9-methyl-9H-purin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

(S) -1'- (8- (2, 3-dichlorophenyl) -7-methyl-7H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine

Step 1 2-chloro-8- (2, 3-dichlorophenyl) -9-methyl-9H-purine and 2-chloro-8- (2, 3-dichlorophenyl) -7-methyl-7H-purine

A mixture of 2-chloro-8- (2, 3-dichlorophenyl) -9H-purine (200 mg,0.668mmol,1.0 eq) and NaH (16.02 mg,0.668mmol,1.0 eq) in anhydrous DMF (3 mL) was stirred under Ar for 15 min at 0deg.C. MeI (95 mg,0.668mmol,1.0 eq) was then added dropwise. The solution was gently warmed to room temperature and stirred for 1 hour. With saturated NH ₄ The Cl solution stopped the reaction. Solution in ethyl acetate/H ₂ O. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by silica gel chromatography eluting hexane/ethyl acetate from 0% to 40% to give the product 119-A (relatively low polarity, 38mg, 18.15%) and 120-A (relatively high polarity, 13mg, 6.21%). MS 313.5 (M+H) ⁺ ).

Step 2N- ((S) -1'- (8- (2, 3-dichlorophenyl) -9-methyl-9H-purin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide and N- ((S) -1'- (8- (2, 3-dichlorophenyl) -7-methyl-7H-purin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-yl) -2-methylpropan-2-sulfinamide

119-A (38 mg,0.121mmol,1.0 eq.) N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]A solution of (1-yl) -2-methylpropan-2-sulfinamide (37.1 mg,0.121mmol,1.0 eq) and DIPEA (31.3 mg,0.242mmol,2.0 eq) in BuOH (5 mL) was subjected to microwaves at 150℃for 1h. The volatiles were removed under reduced pressure, the residue was purified by silica gel chromatography eluting with DCM/ethyl acetate to give compound 119-B (50 mg, 70.7%). MS 583.5 (M+H) ⁺ ).

120-A (13 mg,0.041mmol,1.0 eq.) N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]A solution of-1-yl) -2-methylpropan-2-sulfinamide (12.71 mg,0.041mmol,1.0 eq) and DIPEA (10.72 mg,0.083mmol,2.0eq of BuOH (5 mL) was subjected to microwaves at 150℃for 1 hour. The volatiles were removed under reduced pressure, the residue was purified by silica gel chromatography eluting with DCM/ethyl acetate to give compound 120-B (15 mg, 62.0%). MS 583.5 (M+H) ⁺ ).

Step 3 (S) -1'- (8- (2, 3-dichlorophenyl) -9-methyl-9H-purin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine and (S) -1'- (8- (2, 3-dichlorophenyl) -7-methyl-7H-purin-2-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

To a solution of 119-B (50 mg,0.086mmol,1.0 eq) in dioxane (2 ml) was added 6N HCl/dioxane at room temperature. The reaction was stirred for 1 hour. Using saturated NaHCO ₃ The solution was adjusted to pH 7. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give the crude product, which was purified by preparative HPLC to afford compound 119 as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.80(s,1H),8.26–8.16(m,2H),7.91(d,J＝7.6Hz,1H),7.66–7.62(m,1H),7.61–7.56(m,1H),7.51(d,J＝7.2Hz,1H),7.39–7.35(m,2H),7.34–7.28(m,1H),4.72–4.56(m,2H),4.42–4.34(m,1H),3.47(s,3H),3.25–4.16(m,3H),3.08–3.01(m,1H),2.07–1.91(m,1H),1.82–1.63(m,2H),1.49–1.40(m,1H).MS:479.2(M+H ⁺ ) The purity is 90.5%.

To a solution of 120-B (15 mg,0.026mmol,1.0 eq) in dioxane (2 ml) was added 6N HCl/dioxane at room temperature. The reaction was stirred for 1 hour. Using saturated NaHCO ₃ The solution was adjusted to pH 7. The organics were collected, washed with brine, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give the crude product, which was purified by preparative HPLC to afford compound 120 (1.0 mg, 8.12%) as a white solid, MS:479.2 (M+H) ⁺ ) The purity is 88.1%.

The compounds of examples 121-124 were prepared as described in reference to examples 119 and 120.

Examples 121 and 122

(S) -1'- (8- (2, 3-dichlorophenyl) -7-ethyl-7H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine and (S) -1'- (8- (2, 3-dichlorophenyl) -9-ethyl-9H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine

Example 121: ¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.76 (s, 1H), 7.90 (dd, j=8.0, 1.3hz, 1H), 7.65 (dd, j=7.6, 1.3hz, 1H), 7.58 (t, j=7.8 hz, 1H), 7.33-7.31 (m, 1H), 7.22-7.14 (m, 3H), 4.58 (t, j=12.6 hz, 2H), 3.92 (q, j=7.1 hz, 2H), 3.87 (s, 1H), 3.25-3.17 (m, 2H), 3.11 (d, j=15.7 hz, 1H), 2.67 (d, j=15.7 hz, 1H), 1.81-1.61 (m, 1H), 1.51 (d, j=13.2 hz, 1H), 1.28-1.23 (m, 2H), 1.18 (t, j=7.2 hz, 2H), 3.25-3.17 (m, 2H), 3.11 (d, j=15.7 hz, 1H) and 495.38 m/3.34 z (v/v)] ⁺

Example 122: MS (ESI) m/z 493.42 and 495.73[ M+H ]] ⁺ .

Examples 123 and 124

(S) -1'- (8- (2, 3-dichlorophenyl) -7-isopropyl-7H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine and (S) -1'- (8- (2, 3-dichlorophenyl) -9-isopropyl-9H-purin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine

Example 123: ¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 8.74 (s, 1H), 7.89 (dd, j=7.9, 1.6hz, 1H), 7.63 (dd, j=7.6, 1.7hz, 1H), 7.56 (t, j=7.8 hz, 1H), 7.31-7.29 (m, 1H), 7.17 (dtd, j=8.2, 5.5,2.5hz, 3H), 4.53 (t, j=12.6 hz, 2H), 4.11-4.04 (m, 1H), 3.84 (s, 1H), 3.26-3.18 (m, 2H), 3.10 (d, j=15.7 hz, 1H), 2.65 (d, j=15.6 hz, 1H), 1.99 (dt, j=12.3, 6.9hz, 1H), 1.78 (td, j=12.6, 4.4.hz), 69-1.46 (m, 1H), 3.84 (s, 1H), 3.26-3.18 (m, 2H), 3.10 (d, j=15.7 hz, 1H), 1.78 (d, 1H), 1.9 (j=12.9 hz, 1H) and (m, 35H) ] ⁺ .

Example 124: ¹ H NMR(400MHz,DMSO-d ₆ ) Delta (ppm) 9.05 (s, 1H), 7.90 (dd, j=7.7, 1.8hz, 1H), 7.62 (dd, j=7.7, 1.8hz, 1H), 7.59 (d, j=7.7 hz, 1H), 7.34-7.32 (m, 1H), 7.21 (dt, j=8.5, 4.8hz, 3H), 4.54 (td, j=9.5, 4.8hz, 2H), 4.20-4.14 (m, 1H), 3.90 (s, 1H), 3.20 (dd, j=27.3, 13.7hz, 2H), 3.12 (d, j=15.8 hz, 1H), 2.71 (d, j=15.8 hz, 1.71 (m, 1H), 1.67-1.56 (m, 3H), 1.49-1.49 (m, 3H), 1.31.90 (s, 1H), 3.20 (dd, 27.3.7 hz, 2H), 3.12 (d, 1.79-1.38 hz, 1H) and (38 (v/v)] ⁺ .

Example 125

(S) -1'- (2, 3-dichlorophenyl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

Step 1:

5-chloropyrazin-2-amine (3.0 g,1.0 eq) was added in portions to a solution of ethoxycarbonyl isothiocyanate (4.56 g,1.5 eq) in dioxane. The reaction solution was stirred at room temperature for 24 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate three times. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure and the resulting residue was purified by flash chromatography to give the title compound.

Step 2: 6-chloro- [1,2,4] triazolo [1,5-a ] pyrazin-2-amine

DIEA (2.86 ml,1.5 eq) was added dropwise to a solution of hydroxylamine hydrochloride (1.20 g,1.5 eq) in EtOH at 0 ℃ and the mixture was stirred at 0 ℃ for 10min. Then, the intermediate (3 g,1.0 eq) obtained in step 1 was added and the reaction solution was heated at 90℃for 12h. The volatiles were removed under reduced pressure and the resulting residue was purified by flash chromatography to give the title compound. [ M+H ] ] ⁺ ＝232.95/234.94/236.89。

Step 3: 2-bromo-6-chloro- [1,2,4] triazolo [1,5-a ] pyrazines

CuBr (3.38 g,2.0 eq) was added to 6-chloro- [1,2,4]]Triazolo [1,5-a ]]In a solution of pyrazin-2-amine (2.0 g,1.0 eq) and isoamyl nitrite (2.76 g,2.0 eq) in MeCN, the mixture was then heated at 60 ℃ for 1 hour under argon atmosphere. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography to give the title compound. [ M+H ]] ⁺ ＝232.95/234.94/236.89。

Step 4: 6-chloro-2- (2, 3-dichlorophenyl) - [1,2,4] triazolo [1,5-a ] pyrazine

Pd (PPh) ₃ ) ₄ (124 mg,0.05 eq) to 2-bromo-6-chloro- [1,2,4]]Triazolo [1,5-a ]]Pyrazine (500 mg,1.0 eq), 2, 3-dichlorophenyl boronic acid (450 mg,1.1 eq) and K ₂ CO ₃ (887 mg,3.0 eq) MeCN/H ₂ O (30 mL/3 mL). The reaction solution was heated at 110℃for 3 hours under an argon atmosphere. After cooling to room temperature, the mixture was poured into a separating funnel containing a saturated aqueous NaCl solution and extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure and the resulting residue was purified by flash chromatography to give the title compound. [ M+H ]] ⁺ ＝299.01/301.00/302.95。

Step 5: (S) -N- ((S) -1'- (2, 3-dichlorophenyl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide

RuPhos Pd G2 (CAS: 2361069-97-6) (146 mg,0.2 eq) was added to 6-chloro-2- (2, 3-dichlorophenyl) - [1,2,4]]Triazolo [1,5-a ]]Pyrazine (300 mg,1.0 eq), (S) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropan-2-sulfinamide (4816 mg,1.2 eq), sodium tert-butoxide (961 mg,10.0 eq) in anhydrous toluene, and then heating the reaction solution at 115℃for 3 hours under argon atmosphere. The reaction solution was cooled to room temperature, poured into a separating funnel containing a saturated aqueous NaCl solution, and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The volatiles were then removed under reduced pressure and the resulting residue was purified by flash chromatography to give the title compound. [ M+H ]] ⁺ ＝569.27/571.18/573.13。

Step 6: (S) -1'- (2, 3-dichlorophenyl) - [1,2,4] triazolo [1,5-a ] pyrazin-6-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine

4M HCl/dioxane (5 mL) was added to (S) -N- ((S) -1' - (2, 3-dichlorophenyl) - [1,2, 4)]Triazolo [1,5-a ]]Pyrazin-6-yl) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine]In a methanol (5 mL) solution of-1-yl) -2-methylpropan-2-sulfinamide, and the reaction solution was stirred at room temperature for 3 hours. Volatiles were removed and purified by prep-HPLC (MeCN/H ₂ O as the eluting page, TFA as the modifier) to give the title compound as a white solid. [ M-NH ] ₂ ] ⁺ ＝448.15/450.07/451.98。 ¹ H NMR(400MHz,Methanol-d ₄ )δ(ppm)9.03(s,1H),8.30(s,1H),7.83(dd,J＝7.9,1.5Hz,1H),7.71(dd,J＝7.9,1.5Hz,1H),7.52(d,J＝7.5Hz,1H),7.45(t,J＝7.9Hz,1H),7.42–7.31(m,3H),4.43(s,1H),4.26–4.13(m,1H),4.10–3.94(m,1H),3.28–3.10(m,4H),2.07–1.74(m,3H),1.74–1.63(m,1H)。

Test example 1 measurement of the inhibitory Effect of the Compounds of the invention on SHP-2 kinase Activity

The purpose of the experiment is as follows:

the purpose of this test is to measure the ability of a compound to inhibit the allosteric activity of the SHP-2 full-length protein.

Experimental instrument: centrifuge (5810R) was purchased from Eppendorf corporation, pipettor from Eppendorf or Rainin corporation, and microplate reader from BioTek corporation, U.S.A., model number SynergyH1 full function microplate reader.

The experimental method comprises the following steps: 50 μl of Master Mix was first added to a 96-well black low adsorption microplate (Corning, # 3915), i.e., 25nM SHP-2Enzyme (RD, #1894-SH-100 UG), 0.5 μM IRS1 Peptide (gold Style, # Sequence: LN { pTYR } IDLDLV { PEG8} LST { pTYR } ASINFQK-NH 2) and 5mM DTT were contained in a reaction buffer having a final concentration of 1 Xand then 1 μl of test compound was added to each well (test compound was dissolved in DMSO to a 10mM mother solution, followed by three-fold serial dilutions, 9 concentrations and 1 DMSO control well to give a final concentration of the reaction ranging from 10 μM to 0.5 nM) and reacted at room temperature for 30 minutes after gentle shaking. After the reaction was completed, 50ul of Substrate Solution per well was added, and the reaction system contained 200uM of DiFMUP and 5mM of DTT, and after gentle shaking, the reaction was carried out at room temperature for 30 minutes. After the reaction, the excitation wavelength was set to 340nm, the emission wavelength was 450nm, and the gain value was 100 on a full-function microplate reader (Biotek, synergy H1).

The experimental data processing method comprises the following steps:

percentage inhibition ratio data {% inhibition ratio = 100- [ (test compound-Min mean)/(Max mean-Min mean) for wells treated with compound was calculated from positive control wells (DMSO control wells) and negative control wells (no kinase added wells) on reaction plates based on the values of total active control and total inhibitory control as Max and Min]x100}. Calculation of IC for test compounds using GraphPad prism fit percent inhibition and 9-point concentration data to 4-parameter nonlinear logistic equation ₅₀ Values.

Test example 2 determination of proliferation inhibitory Activity of Compounds of the invention against MV-4-11 and HCC827 cells

The purpose of the experiment is as follows:

the purpose of this test example is to determine the inhibition of tumor cell proliferation activity by the compounds of the present invention.

The experimental method comprises the following steps: 1000 cells were seeded per well in 96-well cell culture plates (Corning, # 3917), 95. Mu.l of cell suspension, and the plates were placed at 37℃with 5% CO ₂ The incubator was cultured overnight. The next day a gradient of diluted test compound solution (test compound dissolved in DMSO to 10mM stock solution, then 3-fold gradient diluted, 9 concentrations with 1 DMSO control well to final concentration ranging from 10uM to 0.5 nM) was added to the plate cells while full active control (compound with DMSO only) and full inhibited control (without cells) were set up on the plate and the plates were incubated in the incubator for 5 days. After the incubation was completed, 50. Mu.l of Cell Titer-Glo reagent (Promega, #G7573) was added to each well of the Cell culture plate, and the plate was shaken at room temperature for 2 minutes, and then allowed to stand for 10 minutes. Chemiluminescent signal values were read on a Synergy H1 full-function microplate reader (Biotek).

Experimental data processing: according to the total activity control and the total inhibition control as the numerical values of Max and Min, the calculation and the use are carried outPercent inhibition ratio data for compound treated wells {% inhibition = 100- [ (test compound-Min mean)/(Max mean-Min mean)]x100}. Calculation of IC for test compounds using GraphPad prism fit percent inhibition and 9-point concentration data to 4-parameter nonlinear logistic equation ₅₀ Values.

The activity test data for some of the compounds of the present invention are shown in table 1 below:

while particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein X is CH or N;

b is

B ₁ o, S, NH or NR _b1 ；R _b1 Is C ₁ -C ₄ An alkyl group;

B ₃ h, NH of a shape of H, NH ₂ Or C ₁ -C ₄ An alkyl group;

B ₅ is N or CR _b5 ；R _b5 Is H or C ₁ -C ₄ An alkyl group;

B ₆ H, NH of a shape of H, NH ₂ Or C ₁ -C ₄ An alkyl group;

B ₉ h, OH or C ₁ -C ₄ An alkyl group;

B ₁₀ h, NH of a shape of H, NH ₂ Halogen or C ₁ -C ₄ An alkyl group;

B ₁₃ is H or halogen;

B ₁₅ is H or C ₁ -C ₄ An alkyl group;

B ₁₇ is H, halogen, CN, C ₁ -C ₄ Alkyl or-C ₁ -C ₄ An alkylene-OH;

B ₁₉ is H or NH ₂ ；

B ₂₁ O, NH or NR _b21 ；R _b21 Is C ₁ -C ₄ An alkyl group;

Each R ₁ And R is ₂ Each independently is C ₁ -C ₄ An alkyl group;

n is 1, 2, 3, 4 or 5;

each m is independently 1, 2, 3, 4, or 5;

each R _3a And R is _3b Each independently F, cl, br, I, NH ₂ OH or cyano;

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula I meets one or more of the following conditions,

(1) B is

(2) L is a single bond, -O-, -S-, -NH-, -N (R) ₁ )-、-CH ₂ -、-CH(R ₁ )-、-C(R ₁ )(R ₂ ) -or

(3) A is a saturated or partially unsaturated 3-10 membered cycloalkyl, a saturated or partially unsaturated 3-10 membered heterocyclyl, phenyl, naphthyl, 5-6 membered heteroaryl, 8-10 membered fused heteroaryl, which saturated or partially unsaturated 3-10 membered cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, phenyl, naphthyl, 5-6 membered heteroaryl, a hydrogen atom on the 8-10 membered fused heteroaryl is unsubstituted or substituted by n R ₃ Substitution;

(4) n is 1, 2 or 3;

(5) Each R ₃ Each independently F, cl, br, NH ₂ OH, cyano, methyl, ethyl, isopropyl, methoxy, trifluoromethyl or hydroxymethyl;

(6) X is CH or N.

3. A compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I satisfies one of the following conditions:

(1)is->

(2)Is->

(3)Is->

(4)Is->

(5)Is->

4. A compound of formula I according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has a structure according to any one of formulae I-1 to I-34:

5. A compound of formula I according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I satisfies one of the following conditions:

(1) In the formula I-3, R _b5 Is H or methyl;

(2) In the formula I-4, B ₃ Is H or methyl;

(3) In the formula I-9, B ₃ Is NH ₂ ；

(4) In the formula I-10, R _b1 Methyl, ethyl or isopropyl;

(5) In the formula I-12, B ₆ Is NH ₂ ；

(6) In the formula I-13, B ₆ Is H or NH ₂ ；

(7) In the formula I-15, B ₁₀ H, NH of a shape of H, NH ₂ Or methyl;

(8) In formula I-16, B ₁₀ Is H or Cl;

(9) In the formula I-17, B ₉ Is H;

(10)B ₁₅ is H or methyl; and/or B ₁₇ Is H, F, CN, methyl or-CH ₂ OH；

(11)B ₁₃ Is H or F;

(12)B ₁₉ is NH ₂ ；

(13)R _b21 Is methyl, ethyl or isopropyl.

6. A compound of formula I according to claim 5, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I satisfies one of the following conditions:

(1) In the formula I-15, B ₁₀ Is H;

(2) In formula I-16, B ₁₀ Is H;

(3) In the formula I-17, B ₉ Is H;

(4)B ₁₅ is H or methyl; and/or B ₁₇ H.

7. A compound of formula I according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I satisfies one of the following conditions:

(1) In the definition of A, the saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

(2) In the definition of A, the saturated or partially unsaturated 3-10 membered heterocyclic group is

(3) In the definition of A, the 5-6 membered heteroaryl is pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine or pyrazine;

(4) In the definition of A, the 8-10 membered ring is thickHeteroaryl is

8. A compound of formula I according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I satisfies one of the following conditions:

(3) In the definition of A, the 5-6 membered heteroaryl is pyrrole, furan, thiophene, oxazole, Isothiazole, pyrazole, imidazole,/->Pyrimidine or pyrazine;

(4) In the definition of A, the naphthyl is

(5) In the definition of A, the 8-10 membered fused heteroaryl is

9. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 wherein the compound of formula I meets one of the following conditions:

(1) A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

(2) A-L-is

10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula I is any one of the following:

11. a process for the preparation of a compound of formula I comprising the steps of: removing tert-butylsulfinyl from a compound shown in a formula II in a solvent in the presence of acid to obtain the compound shown in the formula I;

wherein A, L, B and X are as defined in any one of claims 1 to 9.

12. A compound of formula II:

wherein A, L, B and X are as defined in any one of claims 1 to 9.

13. A pharmaceutical composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

14. Use of a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the manufacture of an inhibitor of SHP2 or a medicament for the treatment of SHP 2-related diseases.

15. The use of claim 14, wherein the SHP 2-associated disease is noonan syndrome, leopard syndrome, diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, acute myelogenous leukemia, HER 2-positive breast cancer, triple-negative breast cancer, ductal carcinoma, invasive ductal carcinoma, non-small cell lung cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, neutropenia, or systemic lupus erythematosus.