CN116924976A - Diaryl heterocyclic amine compound, preparation method, pharmaceutical composition and application thereof - Google Patents

Diaryl heterocyclic amine compound, preparation method, pharmaceutical composition and application thereof Download PDF

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CN116924976A
CN116924976A CN202210321485.9A CN202210321485A CN116924976A CN 116924976 A CN116924976 A CN 116924976A CN 202210321485 A CN202210321485 A CN 202210321485A CN 116924976 A CN116924976 A CN 116924976A
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amino
substituted
nicotinamide
pyridin
methylpiperazin
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冯志强
黄旭鹏
夏亮
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Institute of Materia Medica of CAMS
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Abstract

The invention belongs to the technical field of medicines, and discloses a diaryl heterocyclic amine compound, a preparation method thereof, a pharmaceutical composition and application thereof.

Description

Diaryl heterocyclic amine compound, preparation method, pharmaceutical composition and application thereof
Technical Field
The invention discloses a diaryl heterocyclic amine compound, a preparation method, a pharmaceutical composition and application thereof. In particular to a diarylheterocyclic amine compound shown in a general formula I, a medicinal salt, a stereoisomer and a preparation method thereof, a composition containing one or more compounds, and application of the compounds in treating diseases related to HPK1 signaling pathway such as cancers, infectious diseases and autoimmune diseases, and belongs to the technical field of medicines.
Background
Cancer immunotherapy has become a major tool in cancer therapy, supplementing surgery, chemotherapy, targeted therapy, and radiation therapy. Regeneration of depleted cytotoxic T Cells (CTLs) by immune checkpoint inhibitors (CPIs) of the PD-1 and CTLA-4 pathways alters the therapeutic outcome for various tumor types. Immunotherapy is expected to be the most effective form of treatment for patients with tumor metastasis. Despite encouraging success in CPI, about 60% -70% of tumors are ineffective in single CPI treatments, while those responsive tumors develop resistance over time. Determining an effective method to return the immune system to combat cancer and overcome various immune evasion mechanisms remains a significant challenge. In the Tumor Microenvironment (TME), tumor cells inhibit CTL activity by recruiting immunoregulatory cells and inducing inhibitory signals, thereby impeding T cell infiltration, function, proliferation, and survival. Tumor cells release the normal immune regulation mechanism, and there is an inhibitory immune cell population and associated immunosuppressive factors including PGE2, adenosine and transforming growth factor beta (TGF- β) in TME, which are major sources of therapeutic resistance or drug tolerance, and therefore, there is an urgent need to develop novel therapeutic agents that act synergistically with the discovery of CPI.
Hematopoietic progenitor kinase 1 (HPK 1), also known as MAP4K1, is thought to be involved in several important steps that limit T cell activity, particularly in cancer. HPK1 is expressed predominantly in hematopoietic cell lines, is highly expressed in T cells, B cells and Dendritic Cells (DCs), and is lowly expressed in monocytes/macrophages (human protein profile). HPK1 has been shown to be a negative regulator in T cells, B cells and DCs. The signaling pathway of HPK1 is studied and understood in T cells. HPK1 plays a key role in negatively regulating T cell activation, mediating the Linker (LAT) and related downstream signaling molecules of activated T cells, including the Src homology 2 domain of adaptor protein containing 76kDa albumin (SLP 76), phospholipase cγ1 and extracellular signaling kinase signaling pathways. Studies have shown that Knockout (KO) of HPK1 reduces the threshold of T Cell Receptor (TCR) signaling and renders T cells resistant to the inhibitory effects of PGE 2. HPK1 activity is critical for its mediated down-regulation of T cell function. In antiviral and antitumor immunotherapy, inhibition of T cell failure by drug inhibition of HPK1, enhancement of T cell function, may provide a better balance of efficacy and safety. The development of small molecule HPK1 inhibitors is an optimal solution for elucidating the role of HPK1 in human diseases, and has potential clinical application value.
Disclosure of Invention
The invention solves the technical problem of providing a diarylheterocycle amine compound with a structural formula I for inhibiting HPK1 interaction, a stereoisomer and a medicinal salt thereof, a preparation method, a medicinal composition and application thereof in preparing medicaments for preventing or treating diseases related to HPK1 signal paths.
In order to solve the technical problems of the invention, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides a diaryl heterocyclic amine compound shown in a general formula I and pharmaceutically acceptable salts thereof,
R 1 selected from:wherein R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituents independently include mono-, methylamino-, dimethylaminoSubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted;
wherein n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Or two R 31 Or two R 32 Or two R 33 Can be linked to form a heterocycle, forming a C6-C9 benzo heterocycle or a C4-C8 heterocyclo heterocycle, the heterocycle being an aromatic or alicyclic heterocycle selected from nitrogen, oxygen, sulfur heteroatoms;
X 1 、X 2 、X 3 Can be selected from: CH. N, CR 3 Wherein R is 3 Halogen, methyl; y may be selected from: o, S, NH, CO, N (C1-C6 alkyl);
R 2 selected from:-NHR 5 、-N(R 5 ) 2 、-CH 2 OR 5 、-CF 2 OR 5 、-CH 2 NHR 5 、-CF 2 NHR 5 、-CH 2 NR 5 、-CF 2 NR 5 、-CH 2 N(R 5 ) 2 、-CF 2 N(R 5 ) 2 、-CON(R 5 ) 2 、-CONHR 5 the method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 5 Can be selected from hydrogen, hydroxy, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituents are each independently selected from fluorine, chlorine, hydroxy, O= =, C1-5 alkyl, amino, and each independently comprises mono-, di-, tri-substitution; wherein D may be selected from CH 2 、CO、O、S、SO、SO 2 、NO、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 When R is 4 Selected from the group consisting of substituted or unsubstituted C3-C6 alkanediyl, substituted or unsubstituted N, O, S-containing heterogensC1-C6 heterochain diradical of the child; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IA):
in the middle of
R 30 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Can be connected to form a heterocycle to form a C6-C9 benzo heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, and/or amino, and each substituent is independently selected from the group consisting of mono-substituted alkyl, amino, and/or chloro, and/or hydroxy, = O, C1-5 alkyl Di-substituted, tri-substituted.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IB):
in the middle of
R 30 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Can be connected to form a heterocycle to form a C6-C9 benzo heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, and/or an amino group of the formula (O, C) 1-5 alkyl, and each substituent independently comprises a single substituent, a double substituent and a triple substituent.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IC):
in the middle of
R 30 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Can be connected to form a heterocycle to form a C6-C9 benzo heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (ID):
in the middle of
R 30 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Can be connected to form a heterocycle to form a C6-C9 benzo heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IE):
in the middle of
R 31 Can be selected from H,F、Cl、Br、CN、NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 31 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are of formula (IF):
in the middle of
R 31 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 nitrogenHeterocycloalkyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 31 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IG):
in the middle of
R 31 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 31 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are of formula (IH):
in the middle of
R 31 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups independently comprise monosubstituted, disubstituted, trisubstituted and tetrasubstitutedPenta-substitution;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 31 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (II):
in the middle of
R 33 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 33 Can be linked to form a heterocycle to form a C6-C9 pyridoHeterocyclic ring means aromatic or alicyclic ring selected from nitrogen, oxygen, sulfur hetero atoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IJ):
in the middle of
R 33 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 33 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are of formula (IK):
in the middle of
R 32 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 32 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from hydrogen, halogen, hydroxyCyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are of formula (IL):
in the middle of
R 32 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 32 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 ringAn alkyl group; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IM):
in the middle of
R 34 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted and tetrasubstituted independently; n is selected from 0, 1, 2;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, and/or an amino group of the formula (O, C) 1-5 alkyl, and each substituent independently comprises a single substituent, a double substituent and a triple substituent.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IN):
in the middle of
X 1 Can be selected from: CH. N, CR 3 Wherein R is 3 Halogen, methyl; y may be selected from: o, S, NH, CO, N (C1-C6 alkyl);
R 36 can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are represented by formula (IN):
in the middle of
X 1 Can be selected from: CH. N, CR 3 Wherein R is 3 Halogen, methyl; y may be selected from: o, S, NH, CO, N (C1-C6 alkyl);
R 35 can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
Preferred diarylamines and pharmaceutically acceptable salts thereof, wherein the compounds are of formula (IN):
in the middle of
X 1 Can be selected from: CH. N, CR 3 Wherein R is 3 Halogen, methyl; y may be selected from: o, S, NH, CO, N (C1-C6 alkyl);
R 37 can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、＝＝O、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein each substituent is independently selected from fluorine, chlorine, hydroxyl, O= =, C1-5 alkyl and amino, and each substituent independently comprises mono-substitution, di-substitution and tri-substitution.
In the above general formula, the preferred diarylamines and pharmaceutically acceptable salts thereof are characterized in that:
said R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, and nitrogenA heterocycloalkylene group, an azetidinyl group, a piperidinyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, an isopropoxy group, a methoxymethyl group, a methoxyethyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, a fluoro-substituted methyl group, a fluoro-substituted ethyl group, a fluoro-substituted isopropyl group, a fluoro-substituted butyl group, a fluoro-substituted isobutyl group, a chloro-substituted methyl group, a chloro-substituted ethyl group, a chloro-substituted propyl group, a chloro-substituted isopropyl group, a chloro-substituted isobutyl group, a fluoro-substituted methoxy group, a fluoro-substituted ethoxy group, a fluoro-substituted propoxy group, a fluoro-substituted isopropoxy group, a methylamino group, a butylamino group, an isobutylamino group, a dimethylamino group, an ethoxydiyl group, an isopropoxydryl group, an ethanamidino group, an isopropylamine diradiyl group, an ethylenediamine diradiyl group;
D is CR 4 R at the time 4 Except for the rest of said R 4 Any one selected from the group consisting of hydrogen, methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminomethyl, aminoethyl, aminopropyl, methoxy, ethoxy, methoxyethyl, methoxyethoxy, methylamino, dimethylamino, ethylamino, methoxyethylamino, methylethoxy, dimethylaminoethoxy, methoxyethylamino, carbamoyl, hydroxyethyl carbamoyl, carbamoyl methyl, methoxyethylcarbamoylmethyl, carbamoyl ethyl, methoxyethylcarbamoethyl, hydroxyethyl carbamoyl methyl, carbamoyl ethyl, dimethylcarbamoyl ethyl, hydroxyethyl amino, dihydroxyethylamino, hydroxyacetamino, acetamido, methoxyacetamido, fluoro, chloro, bromo, hydroxy, amino, cyano, methanesulfonyl.
D is CR 4 When R is 2 Is of spiro structure selected from:
most preferred are diarylamines and stereoisomers thereof, and pharmaceutically acceptable salts thereof, which may be selected from, but are not limited to, the following:
4- (phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2, 5-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2, 4-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2, 3-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxy-6-fluoroanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-propoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropoxy-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-cyclopropylmethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (1-fluoroethoxy) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2, 3-dihydrobenzo [ b ] [1,4] -dioxane-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (benzofuranan-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methylbenzofuran-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methylbenzofuran-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-trifluoromethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (1, 1-difluoroethyl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-propylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (1, 1-difluoropropyl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isobutylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-tert-butylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-cyclopropylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-vinylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethynylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-hydroxymethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methoxymethyl-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-ethylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-isopropylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-cyclopropylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-acetylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (piperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-ethylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-carbamoyl piperidin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-oxopiperidin-1-yl) pyridin-2-amino) nicotinamide
4- (2-fluorophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-Chloroamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-fluoro-6-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethylamino-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-Methylaminophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (aziridin-1-yl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
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4- (2- (azetidin-1-yl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (pyrrolidin-1-yl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-cyanophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-isopropylpyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-dimethylaminopyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-Methylaminopyridine-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-isopropylpyrimidin-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-isopropylpyrimidin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminopyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylpyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-isopropylpyridin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-dimethylaminopyridin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-dimethylaminopyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-isopropylpyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylpyrazin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminopyrazin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-ethoxypyrimidin-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-chloro-pyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-dimethylaminoisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-dimethylamino-1-methylpyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-isopropylisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylthiophen-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-ethylisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-isopropylisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-ethylisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-acetamidoisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (1-methyl-5-ethoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (1-isopropyl-5-ethoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (1-methyl-5-propoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-isopropylthiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (1-methyl-3-trifluoromethylpyrazole-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-isopropylthiazol-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxypyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminophenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-Methylaminophenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (4-dimethylaminopyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (4-isopropylpyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminopyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylpyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
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4- (2-dimethylaminopyrazin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylpyrazin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (6-methyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (6-isopropyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (6-acetyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (7-methyl-2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (7-isopropyl-2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2-methyl-2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2-isopropyl-2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (9-methyl-3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (9-isopropyl-3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2-oxo-7-azaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (3-oxo-2, 8-diazaspiro [4,5] nonan-8-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (7-oxo-2, 6-diazaspiro [3,4] oct-2-yl) pyridin-2-amino) nicotinamide
4- (2-acetamidophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
4- (2-isopropylphenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
4- (2-dimethylaminophenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
4- (2-isopropylphenylamino) -6- (6- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridazin-3-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyrimidin-2-amino) nicotinamide
4- (2-hydroxymethyl-phenylamino) -6- (5-carbamoyl-pyridin-2-amino) -nicotinamide
4- (2-ethoxyphenylamino) -6- (5-carbamoylpyridin-2-amino) -nicotinamide
4- (2-ethyl-phenylamino) -6- (5-carbamoyl-pyridin-2-amino) -nicotinamide
4- (2-propylphenylamino) -6- (5-carbamoyl-pyridin-2-amino) -nicotinamide
4- (2, 3-dimethoxy) phenylamino) -6- (5-carbamoylpyridin-2-amino) nicotinamide
4- (2, 4-dimethoxy) phenylamino) -6- (5-carbamoylpyridin-2-amino) nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5-carbamoyl pyridin-2-amino) -nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5-hydroxymethylpyridine-2-amino) -nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5-aminomethylpyridin-2-amino) -nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5-hydroxydifluoromethylpyridin-2-amino) -nicotinamide
4- (2-ethoxyphenylamino) -6- (5-hydroxymethylpyridin-2-amino) -nicotinamide
4- (2-ethoxyphenylamino) -6- (5-hydroxydifluoromethylpyridin-2-amino) -nicotinamide
The diarylamines and stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts comprise salts formed by combination with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases capable of providing physiologically acceptable cations, and ammonium salts.
The diarylheterocyclic amine compound, the stereoisomer and the medicinal salt thereof are further characterized in that the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, matrimony vine acid, maleic acid tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions and potassium ions; the alkaline earth metal ions are selected from calcium ions and magnesium ions; the organic base capable of providing a physiologically acceptable cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine.
According to a second aspect of the technical scheme of the invention, the preparation method of the compound in the first aspect is provided:
the synthetic route is as follows:
in order to prepare the compounds of the general formula I according to the invention, the synthetic route for preparing the compounds of the general formula I according to the structure of the general formula I:
(a) Halogenated nicotinamide compound 1 is taken as a raw material and is reacted with R containing nucleophilic groups under alkaline conditions 1 Carrying out nucleophilic substitution reaction on the H compound 2 to obtain a compound 3;
(b) Reacting the compound 3 with an amino-substituted azaaromatic ring compound 4 under the condition of a palladium catalyst to generate a target compound I; said R is 1 、R 2 、X 1 、X 2 、X 3 Is as defined in any one of claims 1 to 18.
In addition, the starting materials and intermediates in the above reactions are readily available, and each step of the reaction can be readily synthesized according to the reported literature or by conventional methods in organic synthesis to those skilled in the art. The compounds of the general formula I may exist in the form of solvates or non-solvates, and crystallization using different solvents may give different solvates. Pharmaceutically acceptable salts of formula I include the different acid addition salts, such as the acid addition salts of inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, matrimony vine acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid. Pharmaceutically acceptable salts of formula I also include the various alkali metal (lithium, sodium, potassium), alkaline earth metal (calcium, magnesium) and ammonium salts, and salts of organic bases which provide a physiologically acceptable cation, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris (2-hydroxyethyl) amine. All such salts within the scope of the present invention may be prepared by conventional methods. During the preparation of the compounds of the general formula I and solvates and salts thereof, polycrystal or eutectic crystals may occur under different crystallization conditions.
According to a third aspect of the technical scheme, the invention provides a pharmaceutical composition, which comprises the diarylheterocyclic amine compound and the stereoisomer thereof, the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier or excipient as the effective components.
The invention also relates to a pharmaceutical composition containing the compound as an active ingredient. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be made by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are typically present in the pharmaceutical compositions thereof in an amount of 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, cutaneous, vaginal, rectal, etc.
The dosage form may be a liquid, solid or semi-solid dosage form. The liquid preparation can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including injection solution, powder injection and transfusion), eye drop, nasal drop, lotion, liniment, etc.; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays; the semisolid dosage form may be an ointment, gel, paste, or the like.
The compound of the invention can be prepared into common preparations, slow release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the preparation of the compounds of the present invention into tablets, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
In order to make the administration unit into a capsule, the compound of the present invention as an active ingredient may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient of the compound can be prepared into particles or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used to prepare the tablets of the compounds of the invention may also be used to prepare capsules of the compounds of the invention.
For the preparation of the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture may be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator may be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol, glucose, etc. can be added as propping agent for preparing lyophilized powder for injection.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the pharmaceutical composition of the present invention may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. Generally, the suitable daily dosage of the compounds of the invention will range from 0.001 to 150mg/Kg of body weight, preferably from 0.01 to 100mg/Kg of body weight. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
The fourth aspect of the technical scheme of the invention provides application of a diaryl heterocyclic amine compound, a stereoisomer and a pharmaceutically acceptable salt thereof in preparing medicaments for preventing and/or treating diseases related to HPK1 signal paths. The diseases related to HPK1 signal path are selected from cancer, infectious diseases and autoimmune diseases. The cancer is selected from skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, and head and neck cancer. The infectious disease is selected from bacterial infection and virus infection. The autoimmune disease is selected from organ specific autoimmune diseases and systemic autoimmune diseases, wherein the organ specific autoimmune diseases comprise chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia accompanied by chronic atrophic gastritis, lung hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebral spinal sclerosis, acute idiopathic polyneuritis, and the systemic autoimmune diseases comprise rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue diseases and autoimmune hemolytic anemia.
The beneficial technical effects are as follows:
the compound has a unique skeleton structure, has high inhibition activity on HPK1, and is far higher than the reported compound; has strong binding capacity with HPK1 protein; in-vivo pharmacodynamic researches show that the compound can obviously inhibit the growth of subcutaneous tumors from the aspects of tumor volume and weight, and can obviously increase the number of each lymphocyte in blood and spleen of mice.
Detailed Description
The invention will be further illustrated with reference to examples, which are not intended to limit the scope of the invention.
Measuring instrument: nuclear magnetic resonance spectroscopy was performed using a vaarian Mercury model 300 nmr. Mass spectrometry was performed using ZAD-2F and VG300 mass spectrometers.
Example 1:4- (phenylamino) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) nicotinamide
4-anilino-6-chloronicotinamide
Aniline (513 mg,6 mmol) was dissolved in 5mL anhydrous tetrahydrofuran and argon shielded, and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4,6-Dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added dropwise to the reaction mixture, and the reaction mixture was allowed to warm to room temperature and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 510mg of a white solid in 68.6% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.66(s,1H),8.57(s,1H),8.30(s,1H),7.75(s,1H),7.45(t,J＝7.8Hz,2H),7.30(d,J＝7.8Hz,2H),7.24(t,J＝7.4Hz,1H),6.83(s,1H).MS(ESI)m/z:248.0591[M+H] + .
4- (phenylamino) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) nicotinamide
4-anilino-6-chloronicotinamide (123 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL anhydrous dioxane was added to the flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the white solid was separated by silica gel column chromatography to give 34mg in 16.9% yield. mp 140.2-142.0 ℃. 1 H NMR(400MHz,Methanol-d 4 )δ：8.42(s,1H),7.86(d,J＝3.0Hz,1H),7.47–7.37(m,4H),7.37–7.26(m,3H),7.20–7.11(m,1H),3.22–3.11(m,4H),2.69–2.55(m,4H),2.36(s,3H).MS(ESI)m/z:404.2211[M+H] + .
Example 2:4- (2-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-Methoxyanilino) -6-chloronicotinamide
2-Methoxyaniline (738 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran and protected with argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4, 6-Dichloronicotinamide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, added dropwise to the reaction solution, and allowed to react overnight at room temperature. Adding 50mL of water, precipitating solid, stirring for 2 hours, filtering, leaching the filter residue with 10mL of ethyl acetate to obtain324mg brown solid, yield 38.9%. 1 H NMR(400MHz,DMSO-d 6 )δ：10.50(s,1H),8.55(s,1H),8.27(s,1H),7.69(s,1H),7.38(dd,J＝7.8,1.6Hz,1H),7.27–7.18(m,1H),7.15(dd,J＝8.3,1.4Hz,1H),7.01(td,J＝7.6,1.4Hz,1H),6.72(s,1H),3.82(s,3H).MS(ESI)m/z:278.0697[M+H] + .
4- (2-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-methoxyphenyl) amino) nicotinamide (139 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (34 mg) in 15.7% yield. 1 H NMR(400MHz,Methanol-d 4 )δ：8.38(s,1H),7.89–7.81(m,1H),7.48(dd,J＝7.8,1.9Hz,1H),7.45–7.33(m,2H),7.26(dd,J＝9.0,2.1Hz,1H),7.17–7.02(m,2H),7.02–6.91(m,1H),3.86(s,3H),3.23–3.06(m,4H),2.67–2.49(m,4H),2.33(s,3H).MS(ESI)m/z:434.1957.[M+H] + .
Example 3:4- (4-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (4-methoxyphenylamino) nicotinamide
4-Methoxyaniline (738 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran and protected with argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, added dropwise to the reaction solution, and the mixture was allowed to stand at room temperature to react overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 453mg of a brown solid in 54.5% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.41(s,1H),8.53(s,1H),8.25(s,1H),7.69(s,1H),7.32–7.18(m,2H),7.09–6.96(m,2H),6.58(s,1H),3.78(s,3H).MS(ESI)m/z:278.0699[M+H] + .
4- (4-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (4-methoxyphenylamino) nicotinamide (114 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd, in this order 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL anhydrous dioxane, argon substitution, and microwave heating at 120deg.C for 2 hours. Filtration through celite and column chromatography on silica gel gave 47mg of pale yellow solid in 21.7% yield. 1 H NMR(400MHz,Methanol-d 4 )δ：8.37(s,1H),7.82(dd,J＝3.0,0.7Hz,1H),7.38(dd,J＝9.0,3.0Hz,1H),7.27(dd,J＝9.0,0.7Hz,1H),7.21(d,J＝2.2Hz,1H),7.20(d,J＝2.3Hz,1H),7.05(s,1H),6.98(d,J＝2.2Hz,1H),6.96(d,J＝2.3Hz,1H),3.81(s,3H),3.19–3.08(m,4H),2.68–2.57(m,4H),2.34(s,3H).MS(ESI)m/z:434.2344[M+H] + .
Example 4:4- (3-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (3-methoxyphenylamino) nicotinamide
3-Methoxyaniline (738 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran and protected with argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, added dropwise to the reaction solution, and the mixture was allowed to stand at room temperature to react overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 344mg of a brown solid in 41.4% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.62(s,1H),8.57(s,1H),8.30(s,1H),7.75(s,1H),7.35(t,J＝8.0Hz,1H),6.92–6.87(m,2H),6.87(s,2H),3.77(s,3H).MS(ESI)m/z:278.0706[M+H] + .
4- (3-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- ((3-methoxyphenyl) amino) nicotinamide (114 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (28 mg) in 11.5% yield. 1 H NMR(400MHz,Methanol-d 4 )δ：8.37(s,1H),7.85(d,J＝2.9Hz,1H),7.51(s,1H),7.37(dd,J＝9.0,3.0Hz,1H),7.29–7.21(m,2H),6.89(t,J＝2.2Hz,1H),6.85–6.79(m,1H),6.73–6.65(m,1H),3.78(s,3H),3.16–3.10(m,4H),2.63–2.57(m,4H),2.33(s,3H).MS(ESI)m/z:434.2319[M+H] + .
Example 5:4- (2, 4-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2, 4-dimethoxyphenylamino) nicotinamide
2, 4-Dimethoxyaniline (918 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon atmosphere, and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 246mg of a gray solid in 26.7% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.14(s,1H),8.46(s,1H),8.17(s,1H),7.59(s,1H),7.18(d,J＝8.6Hz,1H),6.66(d,J＝2.6Hz,1H),6.53(dd,J＝8.6,2.7Hz,1H),6.38(s,1H),3.74(s,3H),3.73(s,3H).MS(ESI)m/z:308.0821[M+H] + .
4- (2, 4-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
In turn6-chloro-4- (2, 4-dimethoxyphenylamino) nicotinamide (154 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (15 mg) in a yield of 6.5%. 1 H NMR(500MHz,Methanol-d 4 )δ：8.41–8.32(m,1H),7.84(d,J＝3.4Hz,1H),7.39(d,J＝8.7Hz,1H),7.28(dt,J＝10.0,5.1Hz,2H),6.98(s,1H),6.65(t,J＝2.5Hz,1H),6.57(d,J＝8.6Hz,1H),3.82(d,J＝2.2Hz,6H),3.15(s,4H),2.63(d,J＝4.5Hz,4H),2.39–2.32(m,3H).MS(ESI)m/z:464.2453[M+H] + .
Example 6:4- (2, 5-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2, 5-dimethoxyphenylamino) nicotinamide
2, 5-Dimethoxyaniline (918 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon atmosphere, and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 657mg of a brown solid in 69.2% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.50(s,1H),8.56(s,1H),8.27(s,1H),7.70(s,1H),7.07(d,J＝9.0Hz,1H),6.96(d,J＝3.0Hz,1H),6.79(dd,J＝9.0,3.0Hz,1H),6.76(s,1H),3.76(s,3H),3.73(s,3H).MS(ESI)m/z:308.0804[M+H] + 。
4- (2, 5-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2, 5-dimethoxyphenylamino) nicotinamide (154 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piper-ide are successively addedOxazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (22 mg) in 9.5% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.42(s,1H),7.95(d,J＝3.0Hz,1H),7.73(s,1H),7.43(dd,J＝9.0,3.0Hz,1H),7.26–7.18(m,2H),6.99(d,J＝8.9Hz,1H),6.67(dd,J＝8.9,2.9Hz,1H),3.85(s,3H),3.81(s,3H),3.25–3.17(m,4H),2.70–2.63(m,4H),2.38(s,3H).MS(ESI)m/z:464.2398[M+H] + 。
Example 7:4- (2-allyloxyanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-allyloxyaniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-allyloxyanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.6% yield. MS (ESI) m/z 460.25[ M+H ]] + 。
Example 8:4- (2, 3-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2, 3-dimethoxyphenylamino) nicotinamide
2, 3-Dimethoxyaniline (918 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon atmosphere, and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 183mg of a white solid in 19.9% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.74(s,1H),8.57(s,1H),8.30(s,1H),7.73(s,1H),7.12(t,J＝8.2Hz,1H),7.02(dd,J＝8.1,1.5Hz,1H),6.92(dd,J＝8.3,1.4Hz,1H),6.89(s,1H),3.84(s,3H),3.68(s,3H).MS(ESI)m/z:308.0820[M+H] + 。
4- (2, 3-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2, 3-dimethoxyphenylamino) nicotinamide (154 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (18 mg) in 7.8% yield. 1 H NMR(400MHz,Methanol-d 4 )δ：8.40(s,1H),7.88(d,J＝2.9Hz,1H),7.51(s,1H),7.40(dd,J＝9.0,3.0Hz,1H),7.30(d,J＝9.0Hz,1H),7.17(dd,J＝8.2,1.5Hz,1H),7.09(t,J＝8.2Hz,1H),6.79(dd,J＝8.2,1.4Hz,1H),3.87(s,3H),3.79(s,3H),3.16(t,J＝5.0Hz,4H),2.63(t,J＝5.0Hz,4H),2.35(s,3H).MS(ESI)m/z:464.2442[M+H] + 。
Example 9:4- (2-isopropoxy-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-hydroxyphenylamino) nicotinamide
6-chloro-4- (2-methoxyphenylamino) nicotinamide (277 mg,1 mmol) was dissolved in 5mL of anhydrous dichloromethane, and boron tribromide (660 mg,5 mmol) was added under an ice bath and reacted at room temperature under argon atmosphere for 5 hours. After the reaction, 5mL of methanol was added under ice bath, then saturated sodium bicarbonate solution was added to adjust pH to 7, 20mL of water was added, extraction was performed 3 times with 20mL of ethyl acetate, the organic phases were combined and washed 3 times with saturated brine in sequence, and dried over anhydrous sodium sulfate. Evaporating to dryness under reduced pressure, and performing silica gel column chromatography to obtain 235mg of pale yellow solid with the yield of 89.4%. 1 H NMR(400MHz,DMSO-d 6 )δ：10.36(s,1H),9.88(s,1H),8.53(s,1H),8.24(s,1H),7.66(s,1H),7.27(dd,J＝7.9,1.6Hz,1H),7.08(td,J＝7.7,1.6Hz,1H),6.97(dd,J＝8.0,1.5Hz,1H),6.86(td,J＝7.5,1.4Hz,1H),6.63(s,1H).MS(ESI)m/z:264.0536[M+H] + 。
6-chloro-4- (2-isopropoxy-phenylamino) nicotinamide
6-chloro-4- (2-hydroxyphenylamino) nicotinamide (200 mg,0.76 mmol), potassium carbonate (210 mg,1.52 mmol) and 2-iodopropane (142 mg,0.84 mmol) were successively dissolved in 10mL of acetonitrile and reacted at 80℃for 12 hours. After the reaction, 20mL of water was added, extracted 3 times with 20mL of ethyl acetate, respectively, and the organic phases were combined and washed 3 times with saturated sodium bicarbonate solution, saturated brine, and dried over anhydrous sodium sulfate. Evaporated to dryness under reduced pressure and chromatographed on silica gel to give 192mg of white solid in 82.8% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.67(s,1H),8.56(s,1H),8.29–8.24(m,1H),7.72(s,1H),7.40(dd,J＝7.5,1.3Hz,1H),7.21–7.11(m,2H),7.00(ddd,J＝7.8,6.0,2.8Hz,1H),6.84(s,1H),4.61(hept,J＝6.0Hz,1H),1.25(s,3H),1.24(s,3H).MS(ESI)m/z:306.1019[M+H] + 。
4- (2-isopropoxy-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-isopropoxy-phenylamino) nicotinamide (153 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (50 mg) in 21.7% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.39(s,1H),7.87(d,J＝2.9Hz,1H),7.55–7.49(m,1H),7.46–7.38(m,2H),7.28(d,J＝8.9Hz,1H),7.09–7.04(m,2H),7.03–6.94(m,1H),4.57(p,J＝6.1Hz,1H),3.16(t,J＝5.0Hz,4H),2.66–2.61(m,4H),2.36(s,3H),1.33(s,3H),1.31(s,3H).MS(ESI)m/z:462.2807[M+H] + 。
Example 10:4- (2-cyclopropylmethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-cyclopropylmethoxy-phenylamino) nicotinamide
2-Cyclopropylmethoxyaniline (978 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran under argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 625mg of a white solid in 65.7% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),8.50(s,1H),8.21(s,1H),7.73–7.56(m,1H),7.32(dd,J＝7.8,1.6Hz,1H),7.13(ddd,J＝8.8,7.2,1.6Hz,1H),7.07(dd,J＝8.2,1.6Hz,1H),6.94(td,J＝7.5,1.6Hz,1H),6.70(s,1H),3.85(d,J＝6.6Hz,2H),1.16–1.04(m,1H),0.48–0.40(m,2H),0.28–0.20(m,2H).MS(ESI)m/z:318.1028[M+H] + 。
4- (2- (cyclopropylmethoxy) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2- (cyclopropylmethoxy) phenylamino) nicotinamide (158 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (33 mg) in 14.0% yield. 1 H NMR(400MHz,Methanol-d 4 )δ：8.39(s,1H),7.85(dd,J＝3.0,0.7Hz,1H),7.48(dd,J＝7.9,1.6Hz,1H),7.42–7.35(m,2H),7.27(dd,J＝9.1,0.7Hz,1H),7.11–6.95(m,3H),3.89(d,J＝6.7Hz,2H),3.20–3.11(m,4H),2.67–2.57(m,4H),2.35(s,3H),1.32–1.18(m,1H),0.63–0.45(m,2H),0.38–0.24(m,2H).MS(ESI)m/z:474.2612[M+H] + 。
Example 11:4- (2-ethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethoxyanilino) nicotinamide
2-ethoxyaniline (82 mg,6 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon, and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water is added to precipitate a solid, the mixture is stirred for 2 hours, the filtration residue is leached by 10mL of ethyl acetate, and 720mg of light yellow solid is obtained, and the yield is 82.5%. 1 H NMR(400MHz,DMSO-d 6 )δ10.64(s,1H),8.55(s,1H),8.26(s,1H),7.70(s,1H),7.39(dd,J＝7.9,1.6Hz,1H),7.18(ddd,J＝8.7,7.2,1.6Hz,1H),7.12(dd,J＝8.3,1.6Hz,1H),7.00(td,J＝7.5,1.6Hz,1H),6.81(s,1H),4.08(q,J＝7.0Hz,2H),1.29(t,J＝7.0Hz,3H).MS(ESI)m/z:292.0870[M+H] + 。
4- (2-ethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethoxyphenylamino) nicotinamide (146 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (43 mg) in 19.2% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.39(s,1H),7.86(d,J＝3.0Hz,1H),7.49(dd,J＝7.8,1.6Hz,1H),7.44(s,1H),7.39(dd,J＝9.0,3.0Hz,1H),7.27(d,J＝9.0Hz,1H),7.11–7.01(m,2H),6.98(td,J＝7.4,1.7Hz,1H),4.09(q,J＝7.0Hz,2H),3.21–3.09(m,4H),2.62(t,J＝5.0Hz,4H),2.34(s,3H),1.40(t,J＝7.0Hz,3H).MS(ESI)m/z:448.2444[M+H] + 。
Example 12:4- (2-ethoxyphenylamino) -6- (5- (4-ethylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The same procedures used in example 11 were repeated except for using 1-ethyl-4- (6-aminopyridin-3-yl) piperazine instead of 1-methyl-4- (6-aminopyridin-3-yl) piperazine to give 4- (2-ethoxyphenylamino) -6- (5- (4-ethylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in a yield of 32.8%. MS (ESI) m/z 462.26[ M+H ]] + 。
Example 13:4- (2-ethoxyphenylamino) -6- (5- (4-isopropylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The same procedures used in example 11 were repeated except for using 1-isopropyl-4- (6-aminopyridin-3-yl) piperazine instead of 1-methyl-4- (6-aminopyridin-3-yl) piperazine to give 4- (2-ethoxyphenylamino) -6- (5- (4-isopropylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 31.1% yield. MS (ESI) m/z 476.27[ M+H ] ] + 。
Example 14:4- (2-ethoxyphenylamino) -6- (5- (4-cyclopropylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The same procedures used in example 11 were repeated except for using 1-cyclopropyl-4- (6-aminopyridin-3-yl) piperazine instead of 1-methyl-4- (6-aminopyridin-3-yl) piperazine to give 4- (2-ethoxyphenylamino) -6- (5- (4-cyclopropylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 30.9% yield. MS (ESI) m/z 474.26[ M+H ]] + 。
Example 15:4- (2-ethoxyphenylamino) -6- (5- (4-acetylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The same procedures used in example 11 were repeated except for using 1-acetyl-4- (6-aminopyridin-3-yl) piperazine instead of 1-methyl-4- (6-aminopyridin-3-yl) piperazine to give 4- (2-ethoxyphenylamino) -6- (5- (4-acetylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 36.3% yield. MS (ESI) m/z 476.24[ M+H ]] + 。
Example 16:4- (2-ethoxyphenylamino) -6- (5- (piperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- ((2-ethoxyphenyl) amino) nicotinamide (552 mg,2 mmol), tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (667 mg,2.4 mmol), sodium carbonate (424 mg,4 mmol), pd 2 (dba) 3 (92 mg,0.1 mmol), xantphos (116 mg,0.2 mmol), 20mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. Filtering with diatomite, performing silica gel column chromatography to obtain 220mg of pale yellow solid, dissolving the pale yellow solid in 10mL of dichloromethane, adding 1mL of trifluoroacetic acid, reacting overnight at room temperature, adding saturated sodium bicarbonate aqueous solution to adjust pH to 7, concentrating the solvent, adding 10mL of water, stirring for 1 hour, filtering, and washing the filter residue with 5mL of ethyl acetate to obtain 167mg of pale yellow solid, wherein the yield is 19.3%. 1 H NMR(400MHz,DMSO-d 6 )δ：10.93(s,1H),8.85(s,2H),8.49(s,1H),7.98(d,J＝3.0Hz,1H),7.68–7.58(m,1H),7.47(dd,J＝7.9,1.6Hz,1H),7.21(dd,J＝22.4,7.9Hz,2H),7.07(td,J＝7.6,1.4Hz,2H),4.11(q,J＝6.9Hz,2H),3.38–3.32(m,4H),3.28(s,4H),1.31(t,J＝6.9Hz,3H).MS(ESI)m/z:434.2283[M+H] + 。
Example 17:4- (2-methoxy-6-fluoroanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-fluoro-6-methoxy) phenylamino) nicotinamide
To 6-fluoro-2-methoxyThe alkylpyridine (846 mg,6 mmol) was dissolved in 5mL anhydrous tetrahydrofuran and protected with argon, and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 776mg of a white solid in 87.5% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.21(s,1H),8.57(s,1H),8.31(s,1H),7.75(s,1H),7.35(td,J＝8.5,6.6Hz,1H),7.12–6.87(m,2H),6.18(d,J＝3.0Hz,1H),3.84(s,3H).MS(ESI)m/z:296.0598[M+H] + 。
4- (2-fluoro-6-methoxy) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-fluoro-6-methoxy) phenylamino) nicotinamide (148 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (12 mg) in a yield of 5.3%. 1 H NMR(400MHz,Methanol-d 4 )δ：8.40(s,1H),7.79(d,J＝2.8Hz,1H),7.43–7.32(m,2H),7.32–7.21(m,1H),6.99–6.93(m,1H),6.91–6.83(m,1H),6.58(d,J＝3.3Hz,1H),3.87(s,3H),3.15(t,J＝5.0Hz,4H),2.63(t,J＝5.0Hz,4H),2.37(s,3H).MS(ESI)m/z:452.2231[M+H] + 。
Example 18:4- (2-ethoxy-3-fluoroanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
1-ethoxy-3-fluoro-2-nitrobenzene
3-fluoro-2-nitrophenol (2355 mg,15 mmol), potassium carbonate (4140 mg,30 mmol) and bromoethane (1962 mg,18 mmol) were dissolved in 20mL DMF and reacted at room temperature for 12 hours, and after the completion of the reaction, 40mL of water was added and the mixture was separatedThe organic phases were combined and washed 3 times with saturated brine and dried over anhydrous sodium sulfate. The mixture was evaporated to dryness under reduced pressure to give 1850mg of pale yellow solid, with a yield of 66.7%. 1 H NMR(400MHz,DMSO-d 6 )δ：7.61(td,J＝8.6,6.7Hz,1H),7.20(d,J＝8.7Hz,1H),7.12(t,J＝9.1Hz,1H),4.24(q,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H).
2-ethoxy-6-fluoroanilines
1-ethoxy-3-fluoro-2-nitrobenzene (1850 mg,10 mmol) was dissolved in 20mL of methanol, 300mg of 10% palladium on carbon was added thereto and reacted at room temperature under a hydrogen atmosphere for 6 hours, after the reaction was completed, evaporated to dryness under reduced pressure, and silica gel column chromatography (PE: EA 0-5%) was carried out to obtain 1503mg of colorless oil, with a yield of 97.0%. 1 H NMR(400MHz,DMSO-d 6 )δ：6.73–6.61(m,2H),6.59–6.38(m,1H),4.54(s,2H),4.02(q,J＝7.0Hz,2H),1.34(t,J＝7.0Hz,3H).MS(ESI)m/z:156.0814[M+H] + 。
6-chloro-4- (2-ethoxy-6-fluoroanilino) nicotinamide
2-ethoxy-6-fluoroaniline (930 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon atmosphere to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 820mg of an orange solid in 88.5% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.31(s,1H),8.57(s,1H),8.31(s,1H),7.75(s,1H),7.31(q,J＝8.1Hz,1H),7.10–6.86(m,2H),6.22(d,J＝2.9Hz,1H),4.12(q,J＝6.9Hz,2H),1.25(t,J＝6.9Hz,3H).MS(ESI)m/z:310.1006[M+H] + 。
4- (2-ethoxy-6-fluoroanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethoxy-6-fluoroanilino) nicotinamide (155 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL anhydrous dioxane were placed in a reaction flask, and replaced with argonThe reaction was carried out at 120℃for 2 hours by microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (29 mg) in 12.5% yield. 1 H NMR(400MHz,Methanol-d 4 )δ：8.39(s,1H),7.79(d,J＝2.9Hz,1H),7.39(dd,J＝9.1,3.0Hz,1H),7.33–7.18(m,2H),6.91(dt,J＝8.5,1.3Hz,1H),6.88–6.80(m,1H),6.55(d,J＝3.2Hz,1H),4.09(q,J＝7.0Hz,2H),3.19–3.10(m,4H),2.69–2.56(m,4H),2.36(s,3H),1.31(t,J＝7.0Hz,3H).MS(ESI)m/z:466.2338[M+H] + 。
Example 19:4- (2- (1-fluoroethoxy) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2- (1-fluoroethoxy) aniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2- (1-fluoroethoxy) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.4% yield. MS (ESI) m/z 466.23[ M+H ]] + 。
Example 20:4- (2-cyanophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) nicotinamide
6-chloro-4- (2-cyanophenylamino) nicotinamide
2-cyanoaniline (706 mg,6 mmol) was dissolved in 5mL anhydrous tetrahydrofuran and protected with argon, and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 417mg of a gray solid in a yield of 51.1%. 1 H NMR(400MHz,DMSO-d 6 )δ：11.17(s,1H),8.66(s,1H),8.40(s,1H),7.90(d,J＝7.8Hz,1H),7.86(s,1H),7.75(d,J＝8.0Hz,1H),7.66(d,J＝8.3Hz,1H),7.40(d,J＝7.9Hz,1H),6.88(s,1H).MS(ESI)m/z:273.0559[M+H] + 。
4- (2-cyanophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-cyanophenylamino) nicotinamide (136 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (24 mg) in 11.2% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.50(s,1H),7.85(d,J＝2.9Hz,1H),7.78–7.67(m,3H),7.52(s,1H),7.41(dd,J＝9.0,3.0Hz,1H),7.32(d,J＝9.0Hz,1H),7.30–7.22(m,1H),3.16(t,J＝5.1Hz,4H),2.62(t,J＝5.0Hz,4H),2.35(s,3H).MS(ESI)m/z:429.2152[M+H] + 。
Example 21:4- (2-ethynylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The procedure of example 1 was followed, using 2-ethynylaniline instead of aniline, to give 4- (2-ethynylanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.0% yield. MS (ESI) m/z 428.22[ M+H ]] + 。
Example 22:4- (2, 3-dihydrobenzo [ b ] [1,4] -dioxane-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2, 3-dihydrobenzo [1,4] dioxan-5-amino) nicotinamide
2, 3-Dihydrobenzo [1,4]]Dioxacyclohexane-5-amine (906 mg,6 mmol) was dissolved in 5mL dry tetrahydrofuran and argon shielded, and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃for 1 hour. Will be 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, added to the reaction solution, and allowed to react overnight at room temperature. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 377mg of a white solid in 41.1% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.47(s,1H),8.56(s,1H),8.28(s,1H),7.70(s,1H),6.94(dd,J＝7.9,1.6Hz,1H),6.87(t,J＝8.0Hz,1H),6.79(s,1H),6.76(dd,J＝8.1,1.6Hz,1H),4.36–4.20(m,4H).MS(ESI)m/z:306.0645[M+H] + 。
4- (2, 3-dihydrobenzo [1,4] dioxan-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2, 3-dihydrobenzo [1,4] in turn]Dioxacyclohexane-5-amino) nicotinamide (106 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (41 mg) in 17.8% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.41(s,1H),7.88(d,J＝2.9Hz,1H),7.47–7.38(m,2H),7.30(d,J＝8.9Hz,1H),7.06(dd,J＝8.0,1.5Hz,1H),6.86(t,J＝8.1Hz,1H),6.67(dd,J＝8.2,1.5Hz,1H),4.37–4.31(m,2H),4.30–4.23(m,2H),3.20–3.13(m,4H),2.71–2.59(m,4H),2.37(s,3H).MS(ESI)m/z:462.2254[M+H] + 。
Example 23:4- (2-methylbenzofuran-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-methylbenzofuran-7-amine in place of aniline, the experimental procedure was the same as in example 1 to give 4- (2-methylbenzofuran-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 12.5% yield. MS (ESI) m/z 460.24[ M+H ] ] + 。
Example 24:4- (2-methylbenzofuran-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-methylbenzofuran-7-amine in place of aniline, the experimental procedure was the same as in example 1 to give 4- (2-methylbenzofuran-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.2% yield. MS (ESI) m/z 458.23[ M+H ]] + 。
Example 25:4- (2-methylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methylanilino) -6-chloronicotinamide
2-methylaniline (640 mg,6 mmol) was dissolved in 5mL anhydrous tetrahydrofuran and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 494mg of a white solid in 62.9% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.52(s,1H),8.57(s,1H),8.30(s,1H),7.73(s,1H),7.37(d,J＝7.5Hz,1H),7.34–7.26(m,2H),7.25–7.18(m,1H),6.46(s,1H),2.18(s,3H).MS(ESI)m/z:262.0746[M+H] + 。
4- (2-methylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-methyl) phenylamino) nicotinamide (130 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL anhydrous dioxane was placed in a reaction flask, replaced with argon, and heated with microwavesThe reaction was carried out at 120℃for 2 hours. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (41 mg) in 19.6% yield. 1 H NMR(400MHz,Methanol-d 4 )δ：8.42(s,1H),7.81(d,J＝3.0Hz,1H),7.45–7.36(m,2H),7.35–7.23(m,3H),7.15(t,J＝7.5Hz,1H),6.95(s,1H),3.15(t,J＝5.0Hz,4H),2.63(t,J＝5.0Hz,4H),2.36(s,3H),2.29(s,3H).MS(ESI)m/z:418.2349[M+H] + 。
Example 26:4- (2-trifluoromethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-trifluoromethylaniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-trifluoromethylanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.1% yield. MS (ESI) m/z 472.21[ M+H ]] + 。
Example 27:4- (2-ethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethyl-anilino) nicotinamide
2-Ethylaniline (726 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran under argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 340mg of a white solid in 41.2% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.61(s,1H),8.58(s,1H),8.31(s,1H),7.73(s,1H),7.38(d,J＝7.3Hz,1H),7.33–7.30(m,2H),7.30–7.22(m,1H),6.48(s,1H),2.62–2.52(m,2H),1.11(t,J＝7.5Hz,3H).MS(ESI)m/z:276.0901[M+H] + 。
4- (2-ethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethylamino) nicotinamide (138 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (24 mg) in 11.1% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.40(s,1H),7.78(d,J＝2.9Hz,1H),7.39–7.23(m,5H),7.17(td,J＝7.4,1.4Hz,1H),6.92(s,1H),3.18–3.09(m,4H),2.68–2.59(m,6H),2.34(s,3H),1.18(t,J＝7.6Hz,3H).MS(ESI)m/z:432.2504[M+H] + 。
Example 28:4- (2- (1, 1-difluoroethyl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2- (1, 1-difluoroethyl) aniline instead of aniline, the same experimental procedure was followed as in example 1 to give 4- (2- (1, 1-difluoroethyl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.1% yield. MS (ESI) m/z 468.23[ M+H ]] + 。
Example 29:4- (2-propylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-propylphenylamino) nicotinamide
2-propylaniline (810 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran under argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃to react for 1 hour. Dissolving 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) in 5mL anhydrous tetrahydrofuran, adding into the reaction solution, cooling to room temperature, and reversing Should be overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 407mg of a beige solid in 46.9% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.64(s,1H),8.58(s,1H),8.31(s,1H),7.75(s,1H),7.42–7.29(m,3H),7.29–7.16(m,1H),6.53(s,1H),2.55–2.50(m,2H),1.57–1.47(m,2H),0.85(t,J＝7.3Hz,3H).MS(ESI)m/z:290.1094[M+H] + 。
4- (2-propylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-propylphenylamino) nicotinamide (149 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (43 mg) in 19.3% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.40(s,1H),7.79(d,J＝3.0Hz,1H),7.41–7.34(m,2H),7.33–7.22(m,3H),7.21–7.12(m,1H),6.93(s,1H),3.13(t,J＝5.0Hz,4H),2.65–2.57(m,6H),2.34(s,3H),1.68–1.51(m,2H),0.92(t,J＝7.3Hz,3H).MS(ESI)m/z:446.2645[M+H] + 。
Example 30:4- (2- (1, 1-difluoropropyl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2- (1, 1-difluoropropyl) aniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2- (1, 1-difluoropropyl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.6% yield. MS (ESI) m/z 482.25[ M+H ]] + 。
Example 31:4- (2-isobutylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-isobutylaniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-isobutylanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 12.8% yield. MS (ESI) m/z 460.28[ M+H ] ] + 。
Example 32:4- (2-isopropylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-isopropylalkylamino) nicotinamide
2-isopropylaniline (810 mg,6 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 307mg of an off-white solid in 35.4% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.60(s,1H),8.57(s,1H),8.30(s,1H),7.72(s,1H),7.50–7.39(m,1H),7.39–7.21(m,3H),6.41(s,1H),3.02(p,J＝6.9Hz,1H),1.16(d,J＝6.9Hz,6H).MS(ESI)m/z:290.1056[M+H] + 。
4- (2-isopropylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-isopropylaniline) nicotinamide (145 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the yellow-orange solid was obtained by silica gel column chromatography in a yield of 4.5%. 1 H NMR(400MHz,Methanol-d 4 )δ：8.40(s,1H),7.76(d,J＝2.9Hz,1H),7.41–7.37(m,1H),7.35–7.30(m,2H),7.29(s,1H),7.26–7.22(m,2H),6.84(s,1H),3.23–3.14(m,1H),3.12(t,J＝5.0Hz,4H),2.60(t,J＝5.0Hz,4H),2.34(s,3H),1.21(d,J＝6.9Hz,6H).MS(ESI)m/z:446.2646[M+H] + 。
Example 33:4- (4-isopropylpyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 4-isopropyl pyridine-3-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (4-isopropyl pyridine-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in a yield of 12.1%. MS (ESI) m/z 447.26[ M+H ]] + 。
Example 34:4- (2-isopropylpyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-isopropyl pyridine-3-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-isopropyl pyridine-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in a yield of 12.1%. MS (ESI) m/z 447.26[ M+H ]] + 。
Example 35:4- (4-isopropylpyrimidin-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 4-isopropyl pyrimidine-5-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (4-isopropyl pyrimidine-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.6% yield. MS (ESI) m/z 448.26[ M+H ]] + 。
Example 36:4- (3-isopropylpyridin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
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Using 3-isopropyl pyridine-4-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (3-isopropyl pyridine-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 13.1% yield. MS (ESI) m/z 447.26[ M+H ] ] + 。
Example 37:4- (2-cyclopropylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-cyclopropylaniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-cyclopropylamido) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.9% yield. MS (ESI) m/z 444.25[ M+H ]] + 。
Example 38:4- (2-vinylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-vinylaniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-vinylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 13.7% yield. MS (ESI) m/z 430.24[ M+H ]] + 。
Example 39:4- (2-fluorophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-fluoro-phenylamino) -6-chloronicotinamide
Dissolving 2-fluoroaniline (666 mg,6 mmol)3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added to 5mL of anhydrous tetrahydrofuran under argon at-70℃and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 367mg of a white solid in 46.0% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.64(s,1H),8.60(s,1H),8.34(s,1H),7.80(s,1H),7.62–7.48(m,1H),7.48–7.21(m,3H),6.67(s,1H).MS(ESI)m/z:266.0497[M+H] + 。
4- (2-fluorophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-fluoroanilino) nicotinamide (133 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (22 mg) in 10.4% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.41(s,1H),7.81(d,J＝2.9Hz,1H),7.54(td,J＝7.8,1.5Hz,1H),7.36(dd,J＝9.0,3.0Hz,1H),7.33–7.25(m,2H),7.24–7.11(m,3H),3.19–3.05(m,4H),2.59(t,J＝5.0Hz,4H),2.32(s,3H).MS(ESI)m/z:422.1769[M+H] + 。
Example 40:4- (2-Chloroamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-chlorophenylamino) nicotinamide
2-Chloroaniline (762 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran under argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, added to the reaction solution, and the mixture was cooled to room temperatureThe reaction was carried out overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 645mg of a white solid in 76.5% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.85(s,1H),8.62(s,1H),8.38(s,1H),7.79(s,1H),7.60(dd,J＝14.3,8.0Hz,2H),7.43(t,J＝7.6Hz,1H),7.27(t,J＝7.7Hz,1H),6.73(s,1H).MS(ESI)m/z:282.0198[M+H] + 。
4- (2-Chloroamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-chlorophenylamino) nicotinamide (142 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (25 mg) in 11.4% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.45(s,1H),7.85(dd,J＝3.1,0.7Hz,1H),7.64(dd,J＝8.0,1.5Hz,1H),7.50(dd,J＝8.0,1.5Hz,1H),7.42–7.27(m,4H),7.19–7.09(m,1H),3.21–3.08(m,4H),2.71–2.58(m,4H),2.35(s,3H).MS(ESI)m/z:438.1802[M+H] + 。
Example 41:4- (4-chloro-pyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The experimental procedure was as in example 1, substituting 4-chloro-pyridin-3-amine for aniline, to give 4- (4-chloro-pyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 14.1% yield. MS (ESI) m/z 439.17[ M+H ]] + 。
Example 42:4- (2-hydroxymethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-hydroxymethylphenylamino) nicotinamide
O-aminobenzyl alcohol (3820 mg,20 mmol) was dissolved in 50mL anhydrous tetrahydrofuran, and under argon, 40mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (4920 mg,40 mmol) was dissolved in 20mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water, 100mL of ethyl acetate were added and extracted 3 times, the organic phases were combined, washed with saturated brine 2 times, and dried over anhydrous sodium sulfate. After concentration, a solid precipitated and was collected by suction to give 2120mg of a white solid, the yield was 38.3%. 1 H NMR(400MHz,DMSO-d 6 )δ：10.47(s,1H),8.51(s,1H),8.21(s,1H),7.63(s,1H),7.49–7.44(m,1H),7.35–7.28(m,2H),7.28–7.19(m,1H),6.53(s,1H),5.18(s,1H),4.39(s,2H).MS(ESI)m/z:278.0688[M+H] + 。
4- (2-hydroxymethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-hydroxymethylphenylamino) nicotinamide (114 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (22 mg) in 10.1% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.50(s,1H),9.33(s,1H),8.49(s,1H),7.91(s,1H),7.74(d,J＝3.0Hz,1H),7.54–7.46(m,2H),7.42(dd,J＝8.1,1.3Hz,1H),7.37–7.29(m,3H),7.17(td,J＝7.4,1.3Hz,1H),5.18(s,1H),4.59–4.32(m,2H),3.03(dd,J＝6.3,3.7Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H).MS(ESI)m/z:434.2288[M+H] + 。
Example 43:4- (2-methoxymethyl-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
2-methoxymethylaniline
O-aminobenzyl alcohol (738 mg,6 mmol) was dissolved in 20mL of methanol, and 2mL of concentrated sulfuric acid was added to the solution in an ice-water bath, followed by thermal reflux reaction for 10 hours. After the reaction, saturated sodium bicarbonate solution was added to the ice bath until neutral, extracted 3 times with 50mL of ethyl acetate, respectively, the organic phases were combined and washed 3 times with saturated sodium bicarbonate solution, saturated brine in this order, and dried over anhydrous sodium sulfate. Evaporated to dryness under reduced pressure to give 730mg of pale yellow oil in 88.7% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：7.06–6.95(m,2H),6.64(dd,J＝7.8,1.2Hz,1H),6.52(td,J＝7.4,1.2Hz,1H),4.89(s,2H),4.31(s,2H),3.25(s,3H).MS(ESI)m/z:138.0940[M+H] + 。
6-chloro-4- (2-methoxymethyl-phenylamino) nicotinamide
2-Methoxymethylaniline (82 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran and protected with argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction mixture, and after the addition was completed, the mixture was allowed to stand at room temperature and reacted overnight. 50mL of water is added to precipitate a solid, the mixture is stirred for 2 hours, the filtration residue is leached by 10mL of ethyl acetate, 702mg of light yellow solid is obtained, and the yield is 85.5%. 1 H NMR(400MHz,DMSO-d 6 )δ10.65(s,1H),8.56(s,1H),8.26(s,1H),7.72(s,1H),7.52–7.36(m,3H),7.33–7.17(m,1H),6.74(s,1H),4.33(s,2H),3.31(s,3H).MS(ESI)m/z:292.08[M+H] + 。
4- (2-methoxymethyl-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-methoxymethyl-phenylamino) nicotinamide (146 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (35 mg) in 15.6% yield. 1 H NMR(400MHz,Methanol-d 4 )δ：8.42(s,1H),7.82(d,J＝2.9Hz,1H),7.54(dd,J＝7.9,1.3Hz,1H),7.48–7.37(m,3H),7.29(d,J＝9.1Hz,1H),7.25–7.15(m,2H),4.45(s,2H),3.43(s,2H),3.37(s,3H),3.16(t,J＝5.1Hz,4H),2.64(t,J＝5.0Hz,4H),2.37(s,3H).MS(ESI)m/z:448.2448[M+H] + 。
Example 44:4- (2-dimethylaminophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-dimethylaminophenylamino) nicotinamide
N, N-dimethyl-o-phenylenediamine (816 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon atmosphere to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 560mg of a brown solid in 64.4% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.50(s,1H),8.56(s,1H),8.27(s,1H),7.66(s,1H),7.37–7.29(m,1H),7.21–7.11(m,2H),7.10–7.00(m,1H),6.86(s,1H),2.61(s,6H).MS(ESI)m/z:291.2836[M+H] + 。
4- (2-dimethylaminophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-dimethylaminophenylamino) nicotinamide (145 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (21 mg) in 9.7% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.39(s,1H),7.87(d,J＝2.8Hz,1H),7.53–7.36(m,3H),7.27(d,J＝9.0Hz,1H),7.17–6.99(m,3H),3.16(t,J＝5.0Hz,4H),2.67(s,6H),2.63(t,J＝5.0Hz,4H),2.36(s,3H).MS(ESI)m/z:447.2618[M+H] + 。
Example 45:4- (2- (azetidin-1-yl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2- (azetidin-1-yl) aniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2- (azetidin-1-yl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 6.2% yield. MS (ESI) m/z 459.26[ M+H ]] + 。
Example 46:4- (2-acetamidophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-acetamido aniline instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-acetamido-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 9.7% yield. MS (ESI) m/z 461.24[ M+H ]] + 。
Example 47:4- (pyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (pyridin-2-amino) nicotinamide
2-aminopyridine (564 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran under argon, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 634mg of a white solid in 85.0% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.70(s,1H),8.77(s,1H),8.66(s,1H),8.42(s,1H),8.37(dd,J＝5.2,2.0Hz,1H),7.87(s,1H),7.80–7.64(m,1H),7.03(dd,J＝15.7,7.5Hz,2H).MS(ESI)m/z:249.0543[M+H] + 。
4- (pyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (pyridin-2-amino) nicotinamide (124 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were then added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (12 mg) in a yield of 5.9%. 1 H NMR(400MHz,Methanol-d 4 )δ：8.53(s,1H),8.45(s,1H),8.33–8.25(m,1H),7.93(d,J＝3.0Hz,1H),7.77–7.65(m,1H),7.52–7.40(m,2H),7.02(d,J＝8.3Hz,1H),6.94(dd,J＝7.3,5.0Hz,1H),3.17(t,J＝5.0Hz,4H),2.62(t,J＝5.1Hz,4H),2.34(s,3H).MS(ESI)m/z:405.2163[M+H] + 。
Example 48:4- (3-dimethylaminopyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 3-dimethylaminopyridin-2-amine in place of aniline, the experimental procedure was the same as in example 1 to give 4- (3-dimethylaminopyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 9.9% yield. MS (ESI) m/z 448.26[ M+H ] ] + 。
Example 49:4- (2-dimethylaminopyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-dimethylaminopyridin-3-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-dimethyl)Aminopyridine-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.5% yield. MS (ESI) m/z 448.26[ M+H ]] + 。
Example 50:4- (4-dimethylaminopyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 4-dimethylaminopyridin-3-amine in place of aniline, the experimental procedure was the same as in example 1 to give 4- (4-dimethylaminopyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.9% yield. MS (ESI) m/z 448.26[ M+H ]] + 。
Example 51:4- (4-Methylaminopyridine-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 4-methyl ethyl aminopyridine-3-amine instead of aniline, the experimental operation was the same as in example 1 to obtain 4- (4-methyl ethyl aminopyridine-3-amino) -6- (5- (4-methyl piperazine-1-yl) pyridine-2-amino) nicotinamide as a white solid with a yield of 8.2%. MS (ESI) m/z 462.27[ M+H ]] + 。
Example 52:4- (2-dimethylaminopyrazin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-dimethylaminopyrazin-3-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-dimethylaminopyrazin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 9.9% yield. MS (ESI) m/z 448.26[ M+H ]] + 。
Example 53:4- (3-dimethylaminopyridin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 3-dimethylaminopyridin-4-amine in place of aniline, the experimental procedure was the same as in example 1 to give 4- (3-dimethylaminopyridin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.3% yield. MS (ESI) m/z 448.26[ M+H ]] + 。
Example 54:4- (3-isopropylpyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 3-isopropyl pyridine-2-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (3-isopropyl pyridine-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.1% yield. MS (ESI) m/z 447.26[ M+H ]] + 。
Example 55:4- (2-isopropylpyrazin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-isopropyl pyrazine-3-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-isopropyl pyrazine-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 8.1% yield. MS (ESI) m/z 448.26[ M+H ] ] + 。
Example 56:4- (5-isopropylpyrimidin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The 5-isopropyl pyrimidine-4-amine is used for replacing aniline, and the experimental operation is the same as that of the real oneExample 1 gave 4- (5-isopropylpyrimidin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 9.8% yield. MS (ESI) m/z 448.26[ M+H ]] + 。
Example 57:4- (4-methoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (4-methoxypyridine-3-amino) nicotinamide
3-amino-4-methoxypyridine (744 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon atmosphere to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 310mg of a white solid in 37.2% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.42(s,1H),8.57(s,1H),8.46(s,1H),8.38(d,J＝5.7Hz,1H),8.30(s,1H),7.73(s,1H),7.21(d,J＝5.7Hz,1H),6.56(s,1H),3.89(s,3H).MS(ESI)m/z:279.0682[M+H] + 。
4- (4-methoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (4-methoxypyridin-3-amino) nicotinamide (139 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (38 mg) in 17.5% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.69(s,1H),8.45(s,1H),8.26(d,J＝5.7Hz,1H),7.99(d,J＝3.0Hz,1H),7.66(s,1H),7.41(dd,J＝9.0,3.1Hz,1H),7.26–7.17(m,2H),4.01(s,3H),3.20(t,J＝5.0Hz,4H),2.66(t,J＝5.0Hz,4H),2.38(s,3H).MS(ESI)m/z:435.2254[M+H] + 。
Example 58:4- (4-ethoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 4-ethoxypyridin-3-amine in place of aniline, the experimental procedure was the same as in example 1 to give 4- (4-ethoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 7.1% yield. MS (ESI) m/z 449.24[ M+H ]] + 。
Example 59:4- (2-ethoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-ethoxypyridin-3-amine in place of aniline, the experimental procedure was the same as in example 1 to give 4- (2-ethoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 8.1% yield. MS (ESI) m/z 449.24[ M+H ]] + 。
Example 60:4- (4-ethoxypyrimidin-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 4-ethoxypyrimidin-5-amine in place of aniline, the experimental procedure was the same as in example 1 to give 4- (4-ethoxypyrimidin-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.2% yield. MS (ESI) m/z 450.23[ M+H ] ] + 。
Example 61:4- (1-methylpyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (1-methyl-1H-pyrazol-4-amino) nicotinamide
1-methyl-1H-pyrazol-4-amine (552 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon atmosphere to react for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 405mg of an off-white solid in 53.8% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.10(s,1H),8.52(s,1H),8.24(s,1H),7.88(s,1H),7.68(s,1H),7.48(s,1H),6.64(s,1H),3.84(s,3H).MS(ESI)m/z:252.0666[M+H] + 。
4- (1-methylpyrazol-4-yl) amino-6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (1-methyl-1H-pyrazol-4-amino) nicotinamide (126 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. Filtration through celite and column chromatography on silica gel gave 29mg of yellow solid in 14.3% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.38(s,1H),7.94–7.88(m,1H),7.69(d,J＝0.8Hz,1H),7.55(d,J＝0.8Hz,1H),7.41(dd,J＝9.0,3.0Hz,1H),7.30(dd,J＝9.0,0.7Hz,1H),7.18(s,1H),3.93(s,3H),3.25–3.10(m,4H),2.74–2.59(m,4H),2.37(s,3H).MS(ESI)m/z:408.2249[M+H] + 。
Example 62:4- (3-dimethylamino-1-methylpyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
3-dimethylamino-1-methylpyrazol-4-amine is used instead of aniline,the experimental procedure was as in example 1 to give 4- (3-dimethylamino-1-methylpyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.6% yield. MS (ESI) m/z 451.27[ M+H ]] + 。
Example 63:4- (1-methyl-3-trifluoromethylpyrazole-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 1-methyl-3-trifluoromethylpyrazole-4-amine in place of aniline, the same procedure was followed in example 1 to give 4- (1-methyl-3-trifluoromethylpyrazole-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 7.8% yield. MS (ESI) m/z 476.21[ M+H ]] + 。
Example 64:4- (1-methyl-5-ethoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 1-methyl-5-ethoxypyrazol-4-amine in place of aniline, the experimental procedure was identical to example 1, affording 4- (1-methyl-5-ethoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.2% yield. MS (ESI) m/z 452.25[ M+H ] ] + 。
Example 65:4- (1-methyl-5-propoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 1-methyl-5-propoxypyrazol-4-amine in place of aniline, the experimental procedure was identical to example 1, affording 4- (1-methyl-5-propoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 8.9% yield. MS (ESI) m/z 466.27[ M+H ]] + 。
Example 66:4- (3-dimethylaminoisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The experimental procedure was as in example 1, substituting 3-dimethylaminoisoxazol-4-amine for aniline, to give 4- (3-dimethylaminoisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.1% yield. MS (ESI) m/z 454.21[ M+H ]] + 。
Example 67:4- (2-isopropylthiophen-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 2-isopropyl thiophene-3-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (2-isopropyl thiophene-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.7% yield. MS (ESI) m/z 452.22[ M+H ]] + 。
Example 68:4- (5-isopropylisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The experimental procedure was as in example 1, substituting 5-isopropylisoxazol-4-amine for aniline, to give 4- (5-isopropylisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 9.2% yield. MS (ESI) m/z 437.24[ M+H ]] + 。
Example 69:4- (5-acetamidoisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 5-acetamidoisothiazol-4-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (5-acetamidoisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 14.1% yield. MS (ESI) m/z 468.19[ M+H ]] + 。
Example 70:4- (1-ethylpyrazol-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (1-ethylpyrazole-5-amino) nicotinamide
5-amino-1-ethylpyrazole (666 mg,6 mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and 3.3mL of sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon atmosphere and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water was added to precipitate a solid, stirred for 2 hours, and the residue was filtered off with 10mL of ethyl acetate to give 360mg of a yellow solid in 45.3% yield. 1 H NMR(400MHz,DMSO-d 6 )δ：10.67(s,1H),8.64(s,1H),8.38(s,1H),7.84(s,1H),7.51(d,J＝1.9Hz,1H),6.56(s,1H),6.28(d,J＝2.0Hz,1H),3.98(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H).MS(ESI)m/z:266.0825[M+H] + 。
4- (1-ethylpyrazol-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (1-ethylpyrazole-5-amino) nicotinamide (134 mg,0.5 mmol), 1-methyl-4- (6-aminopyridin-3-yl) piperazine (115 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were then added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (23 mg) in 10.9% yield. MS (ESI) m/z 422.2404[ M+H ]] + 。
Example 71:4- (5-ethylisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
The experimental procedure was as in example 1, substituting 5-ethylisoxazol-4-amine for aniline, to give 4- (5-ethylisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 11.1% yield. MS (ESI) m/z 423.22[ M+H ]] + 。
Example 72:4- (3-isopropylisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 3-isopropyl isothiazol-4-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (3-isopropyl isothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 9.2% yield. MS (ESI) m/z 453.22[ M+H ] ] + 。
Example 73:4- (5-isopropylthiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 5-isopropylthiazol-4-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (5-isopropylthiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 8.5% yield. MS (ESI) m/z 453.22[ M+H ]] + 。
Example 74:4- (4-isopropylthiazol-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
Using 4-isopropylthiazol-5-amine instead of aniline, the experimental procedure was the same as in example 1 to give 4- (4-isopropylthiazol-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide as a white solid in 10.2% yield. MS (ESI) m/z 453.22[ M+H ]] + 。
Example 75:4- (2-hydroxymethylphenylamino) -6- (5-carbamoylpyridin-2-ylamino) nicotinamide
6-chloro-4- (2-hydroxymethylphenylamino) nicotinamide
O-aminobenzyl alcohol (3820 mg,20 mmol) was dissolved in 50mL anhydrous tetrahydrofuran, and under argon, 40mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (4920 mg,40 mmol) was dissolved in 20mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water, 100mL of ethyl acetate were added and extracted 3 times, the organic phases were combined, washed with saturated brine 2 times, and dried over anhydrous sodium sulfate. After concentration, a solid precipitated and was collected by suction to give 2120mg of a white solid, the yield was 38.3%. 1 H NMR(400MHz,DMSO-d 6 )δ：10.47(s,1H),8.51(s,1H),8.21(s,1H),7.63(s,1H),7.49–7.44(m,1H),7.35–7.28(m,2H),7.28–7.19(m,1H),6.53(s,1H),5.18(s,1H),4.39(s,2H).MS(ESI)m/z:278.0688[M+H] + 。
4- (2-hydroxymethylphenylamino) -6- (5-carbamoylpyridin-2-ylamino) nicotinamide
6-chloro-4- (2-hydroxymethylphenylamino) nicotinamide (114 mg,0.5 mmol), 6-amino-nicotinamide (83 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (9 mg) in 4.8% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.59–8.47(m,2H),7.94(dd,J＝8.9,2.5Hz,1H),7.77(s,1H),7.58–7.51(m,1H),7.49–7.44(m,1H),7.44–7.37(m,1H),7.33–7.24(m,1H),6.60(d,J＝8.9Hz,1H),4.64(s,2H).MS(ESI)m/z:379.1516[M+H] + 。
Example 76:4- (2-ethoxyphenylamino) -6- (5-methoxyformylpyridin-2-amino) nicotinamide
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The procedure of example 11 was followed, using methyl 6-aminonicotinate instead of 5- (4-methylpiperazin-1-yl) pyridin-2-amine, to give 4- (2-ethoxyphenylamino) -6- (5-methoxyformylpyridin-2-amine) nicotinamide as a white solid in 15.2% yield. 1 H NMR(400MHz,DMSO-d6)δ：10.76(s,1H),9.67(s,1H),8.52(s,1H),8.06(s,1H),7.90-7.88(m,2H),7.75(s,1H),7.67-7.42(m,1H),7.35(s,1H),7.25(s,1H),7.18-6.80(m,3H),4.35(q,J＝6.9Hz,2H),4.09(s,3H),1.34(t,J＝6.9Hz,3H).
MS(ESI)m/z:408.1658[M+H] + 。
Example 77:4- (2-ethoxyphenylamino) -6- (5-hydroxyethylaminoformyl pyridin-2-amino) nicotinamide
The procedure of example 11 was followed using 5-hydroxyethylaminoformylpyridin-2-amine instead of 5- (4-methylpiperazin-1-yl) pyridin-2-amine to give 4- (2-ethoxyphenylamino) -6- (5-hydroxyethylaminoformylpyridin-2-amine) nicotinamide as a white solid in 9.1% yield. 1 H NMR(400MHz,DMSO-d6)δ：10.77(s,1H),10.02(s,1H),8.63(d,J＝12.5Hz,1H),8.56(s,1H),8.41(t,J＝5.5Hz,1H),8.07(dd,J＝8.8,2.3Hz,1H),8.01(s,1H),7.88(s,1H),7.63(d,J＝8.8Hz,1H),7.52(d,J＝18.7Hz,1H),7.34(s,1H),7.12-6.94(m,3H),4.74(t,J＝5.5Hz,1H),4.08(q,J＝6.9Hz,2H),3.54-3.43(m,2H),1.34(t,J＝6.9Hz,3H).MS(ESI)m/z:437.18[M+H] + 。
Example 78:4- (2-ethoxyphenylamino) -6- (5-hydroxymethylpyridin-2-amino) nicotinamide
The procedure of example 11 was followed using 5-hydroxypyridine-2-amine instead of 5- (4-methylpiperazin-1-yl) pyridin-2-amine to give 4- (2-ethoxyphenylamino) -6- (5-hydroxypyridine-2-amine) nicotinamide as a white solid in 11.1% yield. 1 H NMR(400MHz,DMSO-d6)δ:10.76(s,1H),9.67(s,1H),8.52(s,1H),8.06(s,1H),7.90-7.88(m,2H),7.67-7.42(m,3H),7.35(s,1H),7.18-6.80(m,3H),5.11(t,J＝5.6Hz,1H),4.41(d,J＝5.6Hz,2H),4.08(q,J＝6.9Hz,2H),1.34(t,J＝6.9Hz,3H).MS(ESI)m/z:380.1716[M+H] + 。
Example 79:4- (2-ethoxyphenylamino) -6- (5-hydroxydifluoromethylpyridin-2-amino) -nicotinamide
The procedure of example 11 was followed using 5-hydroxydifluoromethylpyridin-2-amine instead of 5- (4-methylpiperazin-1-yl) pyridin-2-amine to give 4- (2-ethoxyphenylamino) -6- (5-hydroxydifluoromethylpyridin-2-amino) -nicotinamide as a white solid in 10.5% yield. MS (ESI) m/z 416.16[ M+H ]] + 。
Example 80:4- (4-ethoxypyridin-3-amino) -6- (5-aminomethylpyridin-2-amino) -nicotinamide
The procedure of example 11 was repeated except for using 5-tert-butoxyformylaminomethyl-pyridin-2-amine instead of 5- (4-methylpiperazin-1-yl) pyridin-2-amine to give 4- (2-ethoxyphenylamino) -6- (5-aminomethylpyridin-2-amino) -nicotinamide as a white solid in 6.5% yield. MS (ESI) m/z 379.19[ M+H ]] + 。
Example 81:6- (5-carbamoyl-pyridin-2-amino) -4- (2- (hydroxymethyl) phenylamino) nicotinamide
6-chloro-4- (2-hydroxymethylphenylamino) nicotinamide
O-aminobenzyl alcohol (3820 mg,20 mmol) was dissolved in 50mL anhydrous tetrahydrofuran, and under argon, 40mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (4920 mg,40 mmol) was dissolved in 20mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water, 100mL of ethyl acetate were added and extracted 3 times, the organic phases were combined, washed with saturated brine 2 times, and dried over anhydrous sodium sulfate. After concentration, a solid precipitated and was collected by suction to give 2120mg of a white solid, the yield was 38.3%. 1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),8.51(s,1H),8.21(s,1H),7.63(s,1H),7.49–7.44(m,1H),7.35–7.28(m,2H),7.28–7.19(m,1H),6.53(s,1H),5.18(s,1H),4.39(s,2H).MS(ESI)m/z:278.0688[M+H] + 。
6- (5-carbamoyl-pyridin-2-amino) -4- (2- (hydroxymethyl) phenylamino) nicotinamide
6-chloro-4- ((2-hydroxymethyl) phenyl) amino) nicotinamide (114 mg,0.5 mmol), 6-amino nicotinamide (83 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL anhydrous dioxane, argon substitution, and microwave heating at 120deg.C for 2 hours. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (9 mg) in 4.8% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.59–8.47(m,2H),7.94(dd,J＝8.9,2.5Hz,1H),7.77(s,1H),7.58–7.51(m,1H),7.49–7.44(m,1H),7.44–7.37(m,1H),7.33–7.24(m,1H),6.60(d,J＝8.9Hz,1H),4.64(s,2H).MS(ESI)m/z:379.1516[M+H] + 。
Example 82:4- (2-ethoxyphenylamino) -6- (5- (4-methoxyformylpiperidin-1-yl) pyridin-2-amino) nicotinamide
1- (6-aminopyridin-3-yl) piperidine-4-carboxylic acid methyl ester
Methyl 1- (6-nitropyridin-3-yl) piperidine-4-carboxylate (952 mg,3.6 mmol) was dissolved in 20mL of methanol, 300mg of 10% palladium on carbon was added thereto, and the mixture was reacted at room temperature under a hydrogen atmosphere for 10 hours, followed by filtration through celite, chromatography on a silica gel column to give 680mg of gray solid with a yield of 80.4%. 1 H NMR(400MHz,DMSO-d 6 )δ7.60(d,J＝2.9Hz,1H),7.15(dd,J＝8.9,2.9Hz,1H),6.39(d,J＝8.9Hz,1H),5.41(s,2H),3.62(s,3H),3.31–3.24(m,2H),2.65–2.54(m,2H),2.48–2.36(m,1H),1.95–1.85(m,2H),1.75–1.59(m,2H).MS(ESI)m/z:236.1397[M+H] + 。
4- (2-ethoxyphenylamino) -6- (5- (4-methoxyformylpiperidin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethoxyphenylamino) nicotinamide (146 mg,0.5 mmol), methyl 1- (6-aminopyridin-3-yl) piperidine-4-carboxylate (141 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (24 mg) in 9.8% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.36(s,1H),7.85(d,J＝3.0Hz,1H),7.50–7.45(m,1H),7.41–7.35(m,2H),7.23(d,J＝9.1Hz,1H),7.13(d,J＝1.6Hz,1H),7.06(d,J＝1.5Hz,2H),4.06(dd,J＝7.2,5.7Hz,7H),3.67(s,3H),2.75(t,J＝11.9Hz,2H),1.99(s,2H),1.38(t,J＝7.0Hz,3H).MS(ESI)m/z:491.2394[M+H] + 。
Example 83:4- (2-ethoxyphenylamino) -6- (5- (4-hydroxymethylpiperidin-1-yl) pyridin-2-amino) nicotinamide
1- (6-nitropyridin-3-yl) piperidin-4-methanol
5-chloro-2-nitropyridine (552 mg,4 mmol), 4-hydroxymethylpiperidine (552 mg,4.8 mmol) and triethylamine (178 mg,8 mmol) were dissolved in 20mL of LDMSO in this order, and reacted at 120℃for 12 hours, after the completion of the reaction, 50mL of water was added, and 50mL of water was usedEthyl acetate extraction was performed 3 times, the organic phases were combined, washed with saturated brine 2 times, and dried over anhydrous sodium sulfate. Silica gel column chromatography gave 930mg of yellow solid with a yield of 98.1%. 1 H NMR(400MHz,DMSO-d 6 )δ8.24(d,J＝3.1Hz,1H),8.12(d,J＝9.3Hz,1H),7.45(dd,J＝9.3,3.1Hz,1H),4.51(t,J＝5.3Hz,1H),3.31–3.23(m,2H),3.07–2.93(m,2H),1.86–1.74(m,2H),1.74–1.63(m,1H),1.31–1.13(m,2H),1.06(t,J＝7.0Hz,1H).
1- (6-aminopyridin-3-yl) piperidin-4-ylmethanol
1- (6-nitropyridin-3-yl) piperidine-4-methanol (930 mg,3.9 mmol) was dissolved in 20mL of methanol, then 300mg of 10% palladium on carbon was added and reacted at room temperature for 10 hours under hydrogen atmosphere, after the reaction was completed, celite was filtered, silica gel column chromatography (DCM: meOH 6-8%) to give 608mg of gray solid with a yield of 75.3%. 1 H NMR(400MHz,DMSO-d 6 )δ7.59(d,J＝2.9Hz,1H),7.17(dd,J＝8.9,3.0Hz,1H),6.40(d,J＝8.9Hz,1H),5.46(s,2H),4.45(t,J＝5.4Hz,1H),3.35–3.27(m,4H),2.50–2.40(m,2H),1.81–1.65(m,2H),1.48–1.34(m,1H),1.29–1.19(m,2H)..MS(ESI)m/z:208.1447[M+H] + 。
4- (2-ethoxyphenylamino) -6- (5- (4-hydroxymethylpiperidin-1-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethoxyphenylamino) nicotinamide (146 mg,0.5 mmol), 1- (6-aminopyridin-3-yl) piperidin-4-ylmethanol (124 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (30 mg) in 13.0% yield. 1 H NMR(400MHz,Methanol-d 4 )δ8.38(s,1H),7.87(d,J＝3.0Hz,1H),7.49(dd,J＝7.9,1.6Hz,1H),7.47–7.37(m,2H),7.25(d,J＝9.0Hz,1H),7.11–7.01(m,2H),7.01–6.95(m,1H),4.09(q,J＝7.0Hz,2H),3.58(d,J＝11.9Hz,2H),3.45(d,J＝6.4Hz,2H),2.77–2.61(m,2H),1.86(d,J＝13.0Hz,2H),1.69–1.52(m,1H),1.46–1.37(m,5H).MS(ESI)m/z:463.2448[M+H] + 。
Example 84:4- (2-ethoxyphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethoxyanilino) nicotinamide
2-ethoxyaniline (82 mg,6 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon, and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water is added to precipitate a solid, the mixture is stirred for 2 hours, the filtration residue is leached by 10mL of ethyl acetate, and 720mg of light yellow solid is obtained, and the yield is 82.5%. 1 H NMR(400MHz,DMSO-d 6 )δ10.64(s,1H),8.55(s,1H),8.26(s,1H),7.70(s,1H),7.39(dd,J＝7.9,1.6Hz,1H),7.18(ddd,J＝8.7,7.2,1.6Hz,1H),7.12(dd,J＝8.3,1.6Hz,1H),7.00(td,J＝7.5,1.6Hz,1H),6.81(s,1H),4.08(q,J＝7.0Hz,2H),1.29(t,J＝7.0Hz,3H).MS(ESI)m/z:292.0870[M+H] + 。
2- (6-Aminopyridin-3-yl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
Sequentially 5-chloro-2-nitropyridine (552 mg,3.68 mmol), 2, 7-diazaspiro [3.5] ]1000mg of nonane-7-carboxylic acid tert-butyl ester, 4.42 mmol) and triethylamine (743 mg,7.36 mmol) were dissolved in 20mL of DMSO, the reaction was carried out for 12 hours at 120℃and 50mL of water was added after the reaction, extraction was carried out 3 times with 50mL of ethyl acetate, the organic phases were combined, washed with saturated brine for 2 times and dried over anhydrous sodium sulfate. The yellow solid 909mg is obtained by silica gel column chromatography, dissolved in 20mL of methanol, added with 300mg of 10% palladium carbon and reacted for 10 hours at room temperature under the hydrogen atmosphere, after the reaction is finished, diatomite is filtered, and the brown solid 456mg is obtained by silica gel column chromatography, and the yield is 39.2%. 1 H NMR(400MHz,DMSO-d 6 )δ7.21(d,J＝2.8Hz,1H),6.69(dd,J＝8.6,3.0Hz,1H),6.37(d,J＝8.7Hz,1H),5.16(s,2H),3.45(s,4H),3.29(t,J＝5.7Hz,4H),1.70–1.62(m,4H),1.39(s,9H).MS(ESI)m/z:319.2141[M+H] + 。
4- (2-ethoxyphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
6-chloro-4- (2-ethoxyphenylamino) nicotinamide (146 mg,0.5 mmol), 2- (6-aminopyridin-3-yl) -2, 7-diazaspiro [3.5 ] compound]Nonane-7-carboxylic acid tert-butyl ester (191 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. Filtering with diatomite, dissolving 30mg of pale yellow solid in 10mL of dichloromethane, adding 1mL of trifluoroacetic acid, reacting overnight at room temperature, adding saturated sodium bicarbonate aqueous solution to adjust pH to 7, concentrating the solvent, adding 10mL of water, stirring for 1 hour, filtering, and washing filter residues with 0.5mL of ethyl acetate to obtain 15mg of pale yellow solid with a yield of 6.3%. 1 H NMR(400MHz,Methanol-d 4 )δ：8.41(s,1H),7.62(d,J＝2.8Hz,1H),7.41(dd,J＝7.9,1.6Hz,1H),7.30(ddd,J＝8.4,7.5,1.6Hz,1H),7.15(dd,J＝8.4,1.3Hz,1H),7.13–7.02(m,2H),6.88(d,J＝8.8Hz,1H),6.40(s,1H),4.13(q,J＝7.0Hz,2H),3.76(s,4H),3.22(t,J＝5.8Hz,4H),2.17–2.04(m,4H),1.38(t,J＝7.0Hz,3H).MS(ESI)m/z:474.2609[M+H] + 。
Example 85:4- (4-ethoxypyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The procedure of example 82 was followed, using 4-ethoxypyridin-3-amine instead of 2-ethoxyaniline, to give 4- (4-ethoxypyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 8.5% yield. MS (ESI) m/z 475.26[ M+H ]] + 。
Example 86:4- (2-ethoxypyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
Using 2-ethoxypyridin-3-amine in place of 2-ethoxyaniline, the experimental procedure was the same as in example 82 to give 4- (2-ethoxypyridin-3-amino) -6- (5- (2, 7-diazaspiro [3, 5)]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 9.5% yield. MS (ESI) m/z 475.26[ M+H ]] + 。
Example 87:4- (2-isopropylphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The procedure of example 82 was followed, using 2-isopropylaniline instead of 2-ethoxyaniline, to give 4- (2-isopropylaniline) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 10.5% yield. MS (ESI) m/z 472.28[ M+H ] ] + 。
Example 88:4- (2-dimethylaminophenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The experimental procedure was carried out in the same manner as in example 82 except for using 2-dimethylaminoaniline instead of 2-ethoxyaniline to obtain 4- (2-dimethylaminophenylamino) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 8.5% yield. MS (ESI) m/z 473.28[ M+H ]] + 。
Example 89:4- (2-Methylaminophenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The experimental procedure was carried out in the same manner as in example 82 except for using 2-methylacetanilide instead of 2-ethoxyanilin, to give 4- (2-methylacetanilide) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 7.1% yield. MS (ESI) m/z 487.29[ M+H ]] + 。
Example 90:4- (4-dimethylaminopyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The procedure of example 82 was followed, using 4-dimethylaminopyridin-3-amine instead of 2-ethoxyaniline, to give 4- (4-dimethylaminopyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 8.8% yield. MS (ESI) m/z 474.27[ M+H ] ] + 。
Example 91:4- (4-isopropylpyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The procedure of example 82 was followed, using 4-isopropylpyridin-3-amine instead of 2-ethoxyaniline, to give 4- (4-isopropylpyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 9.7% yield. MS (ESI) m/z 473.28[ M+H ]] + 。
Example 92:4- (2-dimethylaminopyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
Using 2-dimethylaminopyridine-3-amine in place of 2-ethoxyaniline, the procedure of example 82 was followed to give 4- (2-dimethylaminopyridine-3-amino) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 6.7% yield. MS (ESI) m/z 474.27[ M+H ]] + 。
Example 93:4- (2-isopropylpyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The procedure of example 82 was followed, using 2-isopropylpyridin-3-amine instead of 2-ethoxyaniline, to give 4- (2-isopropylpyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 8.6% yield. MS (ESI) m/z 473.28[ M+H ] ] + 。
Example 94:4- (2-dimethylaminopyrazin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The experimental procedure was carried out in the same manner as in example 82 except for using 2-dimethylaminopyrazin-3-amine instead of 2-ethoxyaniline to give 4- (2-dimethylaminopyrazin-3-amino) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 6.6% yield. MS (ESI) m/z 475.27[ M+H ]] + 。
Example 95:4- (2-isopropylpyrazin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
The experimental procedure was carried out in the same manner as in example 82 except for using 2-isopropylpyrazin-3-amine instead of 2-ethoxyaniline, to give 4- (2-isopropylpyrazin-3-amino) -6- (5- (2, 7-diazaspiro [3,5 ])]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 8.6% yield. MS (ESI) m/z 474.27[ M+H ]] + 。
Example 96:4- (2-ethoxyphenylamino) -6- (5- (2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
With 2, 6-diazaspiro [3,3]]Heptane-6-carboxylic acid tert-butyl ester instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (2, 6-diazaspiro [3,3 ]) 5]Heptane-2-yl) pyridin-2-amino) nicotinamide as a white solid in 7.2% yield. MS (ESI) m/z 446.23[ M+H ] ] + 。
Example 97:4- (2-ethoxyphenylamino) -6- (5- (6-methyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
With 6-methyl-2, 6-diazaspiro [3,3]]Heptane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (6-methyl-2, 6-diazaspiro [3,3 ])]Heptane-2-yl) pyridin-2-amino) nicotinamide as a white solid in 14.1% yield. MS (ESI) m/z 460.24[ M+H ]] + 。
Example 98:4- (2-ethoxyphenylamino) -6- (5- (6-isopropyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
With 6-isopropyl-2, 6-diazaspiro [3,3]]Heptane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure of example 82 was followed to give 4- (2-ethoxyphenylamino) -6- (5- (6-isopropyl-2, 6-diazaspiro [3,3 ]) was performed on tert-butyl nonane-7-carboxylate]Heptane-2-yl) pyridin-2-amino) nicotinamide as a white solid in 12.5% yield. MS (ESI) m/z 488.27[ M+H ]] + 。
Example 99:4- (2-ethoxyphenylamino) -6- (5- (6-acetyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
With 6-acetyl-2, 6-diazaspiro [3,3]]Heptane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (6-acetyl-2, 6-diazaspiro [3,3 ]) 6- (6-acetyl-2, 6-diazaspiro [3,3 ]) ]Heptane-2-yl) pyridin-2-amino) nicotinamide as a white solid in 10.1% yield. MS (ESI) m/z 488.24[ M+H ]] + 。
Example 100:4- (2-ethoxyphenylamino) -6- (5- (7-methyl-2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
With 7-methyl-2, 7-diazaspiro [3,5]]Nonane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (7-methyl-2, 7-diazaspiro [3,5 ]) 5]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 12.4% yield. MS (ESI) m/z 488.27[ M+H ]] + 。
Example 101:4- (2-ethoxyphenylamino) -6- (5- (7-isopropyl-2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
With 7-isopropyl-2, 7-diazaspiro [3,5]]Nonane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (7-isopropyl-2, 7-diazaspiro [3,5 ]) 5]Nonan-2-yl) pyridin-2-amino) nicotinamide as a white solid in 10.6% yield. MS (ESI) m/z 516.30[ M+H ]] + 。
Example 102:4- (2-ethoxyphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
With 2, 7-diazaspiro [3,5] ]Nonane-2-carboxylic acid tert-butyl ester instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (2, 7-diazaspiro [3,5 ]) 5]Nonan-7-yl) pyridin-2-amino) nicotinamide as a white solid in 7.6% yield. MS (ESI) m/z 474.26[ M+H ]] + 。
Example 103:4- (2-ethoxyphenylamino) -6- (5- (2-methyl-2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
With 2-methyl-2, 7-diazaspiro [3,5]]Nonane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (2-methyl-2, 7-diazaspiro [3,5 ]) 5]Nonan-7-yl) pyridin-2-amino) nicotinamide as a white solid in 12.6% yield. MS (ESI) m/z 488.27[ M+H ]] + 。
Example 104:4- (2-ethoxyphenylamino) -6- (5- (2-isopropyl-2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
With 2-isopropyl-2, 7-diazaspiro [3,5]]Nonane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (2-isopropyl-2, 7-diazaspiro [3,5 ]) 5]Nonan-7-yl) pyridin-2-amino) nicotinamide as a white solid in 11.4% yield. MS (ESI) m/z 516.30[ M+H ] ] + 。
Example 105:4- (2-ethoxyphenylamino) -6- (5- (3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
With 3, 9-diazaspiro [5,5]]Undecane-9-carboxylic acid tert-butyl ester instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (3, 9-diazaspiro [5,5 ]) 5]Undecan-3-yl) pyridin-2-amino) nicotinamide as a white solid in 6.4% yield. MS (ESI) m/z 502.29[ M+H ]] + 。
Example 106:4- (2-ethoxyphenylamino) -6- (5- (9-methyl-3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
With 9-methyl-3, 9-diazaspiro [5,5]]Undecane in place of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (9-methyl-3, 9-diazaspiro [5,5 ]) 5]Undecan-3-yl) pyridin-2-amino) nicotinamide as a white solid in 9.5% yield. MS (ESI) m/z 516.30[ M+H ]] + 。
Example 107:4- (2-ethoxyphenylamino) -6- (5- (9-isopropyl-3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
With 9-isopropyl-3, 9-diazaspiro [5,5]]Undecane in place of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (9-isopropyl-3, 9-diazaspiro [5,5 ]) 5 ]Undecan-3-yl) pyridin-2-amino) nicotinamide as a white solid in 7.1% yield. MS (ESI) m/z 544.34[ M+H ]] + 。
Example 108:4- (2-ethoxyphenylamino) -6- (5- (2-oxo-7-azaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
With 2-oxo-7-azaspiro [3,5]]Nonane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to give 4- (2-ethoxyphenylamino) -6- (5- (2-oxo-7-azaspiro [3,5 ]) as a result of tert-butyl nonane-7-carboxylate]Nonan-7-yl) pyridin-2-amino) nicotinamide as a white solid in 13.1% yield. MS (ESI) m/z 487.26[ M+H ]] + 。
Example 109:4- (2-ethoxyphenylamino) -6- (5- (3-oxo-2, 8-diazaspiro [4,5] nonan-8-yl) pyridin-2-amino) nicotinamide
With 3-oxo-2, 8-diazaspiro [4,5]]Nonane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure of example 82 was followed to give 4- (2-ethoxyphenylamino) -6- (5- (3-oxo-2, 8-diazaspiro [ 4.5 ]) as a result of tert-butyl nonane-7-carboxylate]Nonan-8-yl) pyridin-2-amino) nicotinamide as a white solid in 10.1% yield. MS (ESI) m/z 502.25[ M+H ]] + 。
Example 110:4- (2-ethoxyphenylamino) -6- (5- (7-oxo-2, 6-diazaspiro [3,4] oct-2-yl) pyridin-2-amino) nicotinamide
With 7-oxo-2, 6-diazaspiro [3,4] ]Octane instead of 2, 7-diazaspiro [3.5 ]]The experimental procedure was carried out in the same manner as in example 82 to obtain 4- (2-ethoxyphenylamino) -6- (5- (7-oxo-2, 6-diazaspiro [3,4 ]) 6- (7-oxo-2, 6-diazaspiro [3,4 ])]Octane-2-yl) pyridin-2-amino) nicotinamide as a white solid in 8.1% yield. MS (ESI) m/z 474.22[ M+H ]] + 。
Example 111:4- (2-ethoxyphenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
6-chloro-4- (2-ethoxyanilino) nicotinamide
2-ethoxyaniline (82 mg,6 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and 3.3mL sodium bis (trimethylsilyl) amide (2M tetrahydrofuran solution) was added at-70℃under argon, and reacted for 1 hour. 4, 6-dichloropyridine-3-amide (573 mg,3 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, and the mixture was added to the reaction solution, warmed to room temperature, and reacted overnight. 50mL of water is added to precipitate a solid, the mixture is stirred for 2 hours, the filtration residue is leached by 10mL of ethyl acetate, and 720mg of light yellow solid is obtained, and the yield is 82.5%. 1 H NMR(400MHz,DMSO-d 6 )δ10.64(s,1H),8.55(s,1H),8.26(s,1H),7.70(s,1H),7.39(dd,J＝7.9,1.6Hz,1H),7.18(ddd,J＝8.7,7.2,1.6Hz,1H),7.12(dd,J＝8.3,1.6Hz,1H),7.00(td,J＝7.5,1.6Hz,1H),6.81(s,1H),4.08(q,J＝7.0Hz,2H),1.29(t,J＝7.0Hz,3H).MS(ESI)m/z:292.0870[M+H] + 。
6-chloro-4- (2-ethoxyphenylamino) nicotinamide (146 mg,0.5 mmol), 6- (4-methylpiperazin-1-yl) pyridazin-3-amine (116 mg,0.6 mmol), sodium carbonate (106 mg,1 mmol), pd were successively added 2 (dba) 3 (23 mg,0.025 mmol), xantphos (29 mg,0.05 mmol), 4mL of anhydrous dioxane were placed in a reaction flask, replaced with argon, and the reaction was carried out at 120℃for 2 hours with microwave heating. The mixture was filtered through celite, and the pale yellow solid was obtained by silica gel column chromatography (40 mg) in 18% yield. 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.65(s,1H),8.49(s,1H),7.93(s,1H),7.82(d,J＝9.8Hz,1H),7.51-7.45(m,2H),7.31(d,J＝9.8Hz,1H),7.27(s,1H),7.11-6.90(m,3H),4.08(q,J＝6.9Hz,2H),3.48(t,J＝4.6Hz,4H),2.41(t,J＝4.6Hz,4H),2.22(s,3H),1.34(t,J＝6.9Hz,3H).MS(ESI)m/z:449.23978[M+H] + 。
Example 112:4- (2-isopropylphenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
With 2-isopropyl groupThe procedure of example 109 was followed, except for using aniline instead of 2-ethoxyaniline, to give 4- (2-isopropylaniline) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide as a white solid in 17.5% yield. MS (ESI) m/z 447.26[ M+H ]] + 。
Example 113:4- (2-dimethylaminophenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
The procedure of example 109 was followed, using 2-dimethylaminoaniline instead of 2-ethoxyaniline, to give 4- (2-dimethylaminophenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide as a white solid in 15.5% yield. MS (ESI) m/z 448.26[ M+H ]] + 。
Example 114:4- (2-isopropylphenylamino) -6- (6- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridazin-3-amino) nicotinamide
2-ethoxyaniline was replaced with 2-isopropylaniline and 6- (2, 7-diazaspiro [3,5]]The procedure of example 109 was followed except for substituting 5- (4-methylpiperazin-1-yl) pyridin-2-amine with nonan-2-yl) pyridazin-3-amine to give 4- (2-isopropylphenylamino) -6- (6- (2, 7-diazaspiro [3, 5)]Nonan-2-yl) pyridazin-3-amino) nicotinamide as a white solid in 12.8% yield. MS (ESI) m/z 473.28[ M+H ] ] + 。
Example 115:4- (2-ethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyrimidin-2-amino) nicotinamide
The experimental procedure was as in example 11, substituting 5- (4-methylpiperazin-1-yl) pyridin-2-amine with 5- (4-methylpiperazin-1-yl) pyrimidin-2-amine, to give 4- (2-ethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyrimidine-2-amino) nicotinamide white solid in 3.8% yield. MS (ESI) m/z 449.24[ M+H ]] + 。
Pharmacological Activity
1. In vitro activity evaluation: ADP-Glo is adopted for HPK1 small molecule inhibitor activity screening TM A kinase assay method.
The experimental steps are as follows:
1. table 1 preparation of 1x kinase reaction buffer:
name of the name Concentration of stock solution Volume of Final concentration
Tris 1M(25X) 240μL 40mM
MgCl 2 1M(50X) 120μL 20mM
BSA 7.5％(75X) 80μL 0.10％
DTT 1M(500X) 3μL 0.5mM
ddH2O 5557μL
2. Compound screening:
1) Compounds were diluted 4-fold in a dilution plate with DMSO at an initial concentration of 10000nM.
2) The compound was 50-fold diluted in 1X kinase reaction buffer and shaken on a shaker for 20 minutes.
3) Preparation of 2X kinase with 1X enzyme reaction buffer.
4) Mu.l kinase (formulated in step 3) was added to each well of the reaction plate.
5) Mu.l of the diluted compound in buffer was added to each well, and the plate was sealed with a sealing plate membrane and centrifuged at 1000g for 30 seconds and left at room temperature for 10 minutes.
6) A4 XATP mixture was prepared with 1 Xenzyme reaction buffer, and 1. Mu.l of the 4 XATP mixture was added to the reaction plate.
7) 1000g of the plate is sealed by a sealing plate membrane and centrifuged for 60 seconds, and the reaction is carried out at room temperature for 60 minutes.
8) Transfer 4. Mu.L ADP-Glo to 384 reaction plates at 1000rpm/min, centrifuge 1min, incubate at 25℃for 40min.
9) Transfer 8. Mu.L of Detection solution to 384 reaction plates at 1000rpm/min, centrifuge 1min, incubate at 25℃for 40min.
10 RLU (Relative luminescence unit) signals were read using a Biotek multifunctional reader. The signal intensity was used to characterize the extent of kinase activity.
3. Data analysis:
calculating the ratio per well
The inhibition rate was calculated as follows:
×100
average of read values from 10. Mu.M Sunitinib wells for all positive control wells
Mean value of readings from DMSO wells of all negative control wells
IC50 was calculated and inhibition curves for compounds were plotted:
4. the screening results are shown in Table 2:
TABLE 2 evaluation of the inhibitory Activity of the title Compounds of the examples on HPK1 at the enzyme level wherein A represents 10 or less -9 The method comprises the steps of carrying out a first treatment on the surface of the B represents 10 -8 And 10 -7 Between them.
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By ADP-Glo TM Kinase assay screening example title compounds for inhibition of HPK1 showed individual compounds IC 50 <10 -10 mol/L。
Determination of tumor cell survival by MTT method
Digesting cells in logarithmic growth phase with pancreatin to obtain the product with concentration of 0.8-2×10 4 The cells/ml of cell fluid were seeded in 96-well plates at 1000 cells/well, and 100. Mu.l each well was added. Fresh medium containing different concentrations of drug and corresponding solvent controls was added the next day, 100 μl per well (final DMSO concentration <0.5 percent of each medicine is provided with 5 to 7 dose groups, each group is provided with at least three parallel holes, after the culture is continued for 120 hours at 37 ℃, the supernatant is discarded, 100 mu l of freshly prepared serum-free culture medium containing 0.5mg/ml MTT is added into each hole, the culture is continued for 4 hours, 200 mu l of DMSO is added into each hole to dissolve MTT formazan precipitate, the mixture is uniformly mixed by a micro-oscillator in an oscillating way, an MK3 type enzyme-labeling instrument is used for measuring an optical density value (OD) under the conditions of reference wavelength of 450nm and detection wavelength of 570nm, and a solvent is used for measuringThe tumor cells treated by the control are used as a control group, the inhibition rate of the drug to the tumor cells is calculated by the following formula, and IC is calculated according to the intermediate equation 50 ：
TABLE 3 MTT screening results for the title compounds of some examples
Table 4 MTT screening results for the title compounds of part of the examples
2. Example in vivo efficacy of Compounds
The pharmacodynamics research method is as follows:
subcutaneous tumor transplantation methods were as follows: digesting cultured specific tumor cells, centrifuging to collect cells, washing with sterile physiological saline twice, counting, and adjusting cell concentration to 5×10 with physiological saline 6 Per ml, 0.2ml of the cell suspension was inoculated into the right armpit of C57BL/6 or Bablc mice. Animals were randomly grouped the next day after inoculation, 6-7 animals per group were dosed after weighing, the compounds to be tested were dosed 1 time per day, the tumor volume size of the mice was monitored, after the tumor volume reached a certain size, the weight of the mice was weighed, the mice were sacrificed by cervical removal after orbital blood collection, and tumor tissue, thymus tissue and spleen tissue were removed and weighed separately. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor action intensity according to the tumor inhibition rate.
The B16F10 lung metastasis model method is as follows: digesting and centrifuging the cultured B16F10 tumor cells, washing with sterile physiological saline twice, counting, and adjusting the cell concentration to 2.5X10 with physiological saline 6 Per ml, 0.2ml of cells were injected into C57BL/6 mice via the tail vein, and tumor cells would accumulate in the lungs of the mice. Animal following the next day after inoculationThe animals were grouped, 6-7 animals per group were dosed after weighing, the test compounds were dosed 1 time per day, the mice were weighed after 3 weeks, the animals were sacrificed, the mice lung tissue was removed and weighed, and the lung tumor numbers were counted after fixing the bag. And finally, calculating the inhibition rate of the compound on the tumor, and evaluating the anti-tumor action intensity by using the inhibition rate of the tumor.
The Lewis lung cancer hydrothorax model method is as follows: homogenizing mouse subcutaneous Lewis transplanted tumor, washing with sterile physiological saline twice, counting, and regulating cell concentration with physiological saline to 2.5X10 5 Per ml, 0.2ml of cells were injected into the chest of the C57BL/6 mice. Animals were randomly grouped the next day after inoculation, 6-7 animals per group were dosed after weighing, the test compound was dosed 1 time per day, animals were sacrificed when the weight of the mice in the control group suddenly decreased, fluid accumulation in the chest was drawn by syringe, and fluid accumulation volume was recorded.
In the research of the action mechanism of each model, the test method of the total cell proportion of each type of T cells adopts a flow cytometry method, and the specific steps are as follows: firstly, treating a sample, for blood tissues, when treating a mouse, taking orbital blood of the mouse, firstly removing red blood cells by using a red blood cell lysate, and then rinsing by using a PBS solution to collect cells; for tumor and spleen organs of mice, tissues were ground with a homogenizer, diluted with PBS buffer, and filtered with 300 mesh screen. After counting the number of cells in each sample, 1X 10 cells were taken 6 After addition to the EP tube, staining with flow-through antibodies was performed, and after incubation on ice for 1h, rinsing with PBS solution was performed 2 times. Analysis of the cell population was performed with a VERSE flow instrument from BD company. Wherein the total number of cells loaded on tumor tissue is 1×10 5 The total number of cells loaded in blood and spleen tissues was 1X 10 4 And each. The proportion of each type of T cells to the total number of injected cells was analyzed after the flow instrument was closed.
(1) Melanoma high-transfer strain B16F10 subcutaneous transplantation tumor model
For the melanoma high metastasis strain B16F10, the compound of the example can obviously inhibit the growth of subcutaneous tumors both in terms of tumor volume and weight.
From their mechanism of action analysis, the example compounds increase the proportion of lymphocytes in the spleen by increasing tumor infiltration.
(2) Melanoma high metastasis strain B16F10 lung metastasis model
For the melanoma high metastasis strain B16F10 lung metastasis model, the compound of the example can obviously inhibit the number of lung metastases.
From their mechanism of action analysis, the compounds of the examples increase the number of individual lymphocytes in the blood of mice.
(3) Mouse breast cancer EMT6 subcutaneous transplantation tumor model
For the mouse breast cancer EMT6 subcutaneous transplantation tumor model, the compound of the embodiment has a certain anti-tumor effect. In addition, the compounds of the examples provide improved tumor inhibition of cyclophosphamide after administration in combination with cyclophosphamide.
(4) Mouse Lewis lung cancer hydrothorax model
For a mouse Lewis lung cancer hydrothorax model, the compound of the embodiment has a certain anti-tumor effect. The compounds of the examples reduce the incidence of hydrothorax.
(5) Mouse colon cancer MC38 subcutaneous transplantation tumor model
For a mouse colon cancer MC38 subcutaneous transplantation tumor model, the compound of the embodiment has obvious anti-tumor effect. After the combined cyclophosphamide CTX is administrated, the compound has good synergistic effect.

Claims (26)

1. The diarylheterocyclic amine compound shown in the general formula I or the pharmaceutically acceptable salt thereof,
In the middle of
R 1 Selected from:
wherein R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
wherein n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Or two R 31 Or two R 32 Or two R 33 Can be linked to form a heterocycle, forming a C6-C9 benzo heterocycle or a C4-C8 heterocyclo heterocycle, the heterocycle being an aromatic or alicyclic heterocycle selected from nitrogen, oxygen, sulfur heteroatoms;
X 1 、X 2 、X 3 can be selected from: CH. N, CR 3 Wherein R is 3 Halogen, methyl; y may be selected from: o, S, NH, CO, N (C1-C6 alkyl);
R 2 selected from:-NHR 5 、-N(R 5 ) 2 、-CH 2 OR 5 、-CF 2 OR 5 、-CH 2 NHR 5 、-CF 2 NHR 5 、-CH 2 NR 5 、-CF 2 NR 5 、-CH 2 N(R 5 ) 2 、-CF 2 N(R 5 ) 2 、-CON(R 5 ) 2 、-CONHR 5 the method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 5 Can be selected from hydrogen, hydroxy, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituents are each independently selected from fluorine Chlorine, hydroxyl, < >>C1-5 alkyl, amino, the said substituent group includes mono-substituted, di-substituted, tri-substituted independently each other; wherein D may be selected from CH 2 、CO、O、S、SO、SO 2 、NO、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 When R is 4 Selected from the group consisting of a substituted or unsubstituted C3-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxy, -/->C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
2. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IA):
in the middle of
R 30 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Can be connected to form a heterocycle to form a C6-C9 benzo heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
3. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IB):
in the middle of
R 30 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azacycloalkyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamine A group, a substituted di (C1-5 alkyl) amine group, wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Can be connected to form a heterocycle to form a C6-C9 benzo heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
4. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IC):
In the middle of
R 30 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Can be connected to form a heterocycle to form a C6-C9 benzo heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like, C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
5. The diarylamines compound or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (ID):
in the middle of
R 30 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 30 Can be connected to form a heterocycle to form a C6-C9 benzo heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
6. The diarylamines compound or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IE):
in the middle of
R 31 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 31 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
7. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IF):
in the middle of
R 31 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 31 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
8. The diarylamines compound or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IG):
in the middle of
R 31 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 31 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of substituted or unsubstituted C4-C6 alkyl chain diradicals, substituted or unsubstitutedA C1-C6 heteroduplex containing N, O, S heteroatoms; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
9. The diarylamines compound or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IH):
in the middle of
R 31 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 31 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, and,Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
10. The diarylamines compound or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (II):
in the middle of
R 33 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 33 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
11. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IJ):
in the middle of
R 33 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 33 Can be linked to form a heterocycle to form a C6-C9 pyrido heterocycle, the heterocycle being selected from nitrogen, oxygen and sulfurHeteroaromatic or alicyclic hetero-atoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
12. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IK):
in the middle of
R 32 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently；
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 32 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
13. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IL):
in the middle of
R 32 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azetidinyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2, 3, 4, wherein two adjacent R' s 32 Can be connected to form a heterocycle to form a C6-C9 pyrido heterocycle, wherein the heterocycle is an aromatic heterocycle or an alicyclic heterocycle selected from nitrogen, oxygen and sulfur heteroatoms;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
14. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IM):
in the middle of
R 34 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, C3-6 cycloalkyl, C2-5 azacycloalkyl, substituted C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamine A group, a substituted di (C1-5 alkyl) amine group, wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted and tetrasubstituted independently; n is selected from 0, 1, 2;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
15. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IN):
in the middle of
X 1 Can be selected from: CH. N, CR 3, Wherein R is 3 Halogen, methyl; y may be selected from: o, S, NH, CO, N (C1-C6 alkyl);
R 36 can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propylAlkenyl, isopropenyl, ethynyl, C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from the group consisting of: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
16. The diarylamines or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IN):
In the middle of
X 1 Can be selected from: CH. N, CR 3, Wherein R is 3 Halogen, methyl; y may be selected from: o, S, NH, CO, N (C1-C6 alkane)A base);
R 35 can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like,C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
17. The diarylamines compound or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is represented by formula (IN):
in the middle of
X 1 Can be selected from: CH. N, CR 3 Wherein R is 3 Halogen, methyl; y may be selected from: o, S, NH, CO, N (C1-C6 alkyl);
R 37 can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, C1-5 alkyl, substituted C1-5 alkoxy, substituted C1-5 alkylamino, substituted di (C1-5 alkylamino), wherein the substituents are any selected from: H. f, cl, NH 2 、OH、OCH 3 The substituent groups comprise monosubstituted, disubstituted, trisubstituted, tetrasubstituted and pentasubstituted independently;
n is selected from 0, 1, 2;
d may be selected from CH 2 、O、S、CO、NO、SO、SO 2 、NR 4 、CHR 4 、CR 4 Except D is CR 4 In addition, the rest of D wherein R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, formyl, acetyl, hydroxyacetyl, aminoacetyl, methanesulfonyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl; when D is CR 4 In which R is 4 Selected from the group consisting of a substituted or unsubstituted C4-C6 alkanediyl group, a substituted or unsubstituted C1-C6 heterodiyl group comprising a N, O, S heteroatom; wherein the substituents are each independently selected from fluorine, chlorine, hydroxyl, and the like, C1-5 alkyl, amino, the said substituent includes mono-substituted, di-substituted, tri-substituted independently of each other.
18. The diarylamines or pharmaceutically acceptable salts thereof, as claimed in any one of claims 1 to 17,
the R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 Can be selected from H, F, cl, br, CN, NH 2 、OH、SO 2 CH 3 Vinyl, propenyl, isopropenyl, ethynyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, azetidinyl, piperidinyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, methoxyethyl, ethoxy, propoxy, isopropoxy, isobutoxy, fluoro-substituted methyl, fluoro-substituted ethyl, fluoro-substituted propyl, fluoro-substituted isopropyl, fluoro-substituted butyl, fluoro-substituted isobutyl, chloro-substituted methyl, chloro-substituted ethyl, chloro-substituted propyl, chloro-substituted isopropyl, chloro-substituted butyl, chloro-substituted isobutyl, fluoro-substituted methoxy, fluoro-substituted ethoxy, fluoro-substituted propoxy, fluoro-substituted isopropoxy, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, diisopropylamino, methylamino, methylamine, dimethylamine, ethyleneoxydi-propyl, ethylenedioxy di-propylamine, di-isopropylamino di-ethylenedi-and di-isopropylamino;
Except D is selected from CR 4 In addition, the rest of D wherein R 4 Any one selected from the group consisting of hydrogen, methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminomethyl, aminoethyl, aminopropyl, methoxy, ethoxy, methoxyethyl, methoxyethoxy, methylamino, dimethylamino, ethylamino, methoxyethylamino, methylethoxy, dimethylaminoethoxy, methoxyethylamino, carbamoyl, hydroxyethyl carbamoyl, carbamoyl methyl, methoxyethylcarbamoylmethyl, carbamoyl ethyl, methoxyethylcarbamoethyl, hydroxyethyl carbamoyl methyl, carbamoyl ethyl, dimethylcarbamoyl ethyl, hydroxyethyl amino, dihydroxyethylamino, hydroxyacetamino, acetamido, methoxyacetamido, fluoro, chloro, bromo, hydroxy, amino, cyano, methanesulfonyl.
D is CR 4 When R is 2 Is of spiro structure selected from:
19. the diarylamines compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
4- (phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2, 5-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2, 4-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2, 3-Dimethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxy-6-fluoroanilino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-propoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropoxy-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-cyclopropylmethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (1-fluoroethoxy) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2, 3-dihydrobenzo [ b ] [1,4] -dioxane-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (benzofuranan-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methylbenzofuran-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methylbenzofuran-7-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-trifluoromethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (1, 1-difluoroethyl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-propylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (1, 1-difluoropropyl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isobutylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-tert-butylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-cyclopropylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-vinylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethynylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-hydroxymethylphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-methoxymethyl-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-ethylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-isopropylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-cyclopropylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-acetylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (piperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-ethylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-carbamoyl piperidin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-oxopiperidin-1-yl) pyridin-2-amino) nicotinamide
4- (2-fluorophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-Chloroamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-fluoro-6-methoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethylamino-phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-Methylaminophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
/>
4- (2- (aziridin-1-yl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (azetidin-1-yl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2- (pyrrolidin-1-yl) phenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-cyanophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-isopropylpyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-dimethylaminopyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-Methylaminopyridine-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-isopropylpyrimidin-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
/>
4- (5-isopropylpyrimidin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminopyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylpyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-isopropylpyridin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-dimethylaminopyridin-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-dimethylaminopyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-isopropylpyridin-2-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxypyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylpyrazin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminopyrazin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-ethoxypyrimidin-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-chloro-pyridin-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-dimethylaminoisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-dimethylamino-1-methylpyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-isopropylisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylthiophen-3-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-ethylisoxazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-isopropylisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (3-ethylisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-acetamidoisothiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (1-methyl-5-ethoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (1-isopropyl-5-ethoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (1-methyl-5-propoxypyrazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (5-isopropylthiazol-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (1-methyl-3-trifluoromethylpyrazole-4-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (4-isopropylthiazol-5-amino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxypyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminophenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
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4- (2-Methylaminophenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (4-dimethylaminopyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (4-isopropylpyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminopyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylpyridin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-dimethylaminopyrazin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-isopropylpyrazin-3-amino) -6- (5- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (6-methyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (6-isopropyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (6-acetyl-2, 6-diazaspiro [3,3] heptane-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (7-methyl-2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (7-isopropyl-2, 7-diazaspiro [3,5] nonan-2-yl) pyridin-2-amino) nicotinamide
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4- (2-ethoxyphenylamino) -6- (5- (2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2-methyl-2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2-isopropyl-2, 7-diazaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (9-methyl-3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (9-isopropyl-3, 9-diazaspiro [5,5] undec-3-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (2-oxo-7-azaspiro [3,5] nonan-7-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (3-oxo-2, 8-diazaspiro [4,5] nonan-8-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (7-oxo-2, 6-diazaspiro [3,4] oct-2-yl) pyridin-2-amino) nicotinamide
4- (2-acetamidophenylamino) -6- (5- (4-methylpiperazin-1-yl) pyridin-2-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
4- (2-isopropylphenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
4- (2-dimethylaminophenylamino) -6- (6- (4-methylpiperazin-1-yl) pyridazin-3-amino) nicotinamide
4- (2-isopropylphenylamino) -6- (6- (2, 7-diazaspiro [3,5] nonan-2-yl) pyridazin-3-amino) nicotinamide
4- (2-ethoxyphenylamino) -6- (5- (4-methylpiperazin-1-yl) pyrimidin-2-amino) nicotinamide
4- (2-hydroxymethyl-phenylamino) -6- (5-carbamoyl-pyridin-2-amino) -nicotinamide
4- (2-ethoxyphenylamino) -6- (5-carbamoylpyridin-2-amino) -nicotinamide
4- (2-ethyl-phenylamino) -6- (5-carbamoyl-pyridin-2-amino) -nicotinamide
4- (2-propylphenylamino) -6- (5-carbamoyl-pyridin-2-amino) -nicotinamide
4- (2, 3-dimethoxy) phenylamino) -6- (5-carbamoylpyridin-2-amino) nicotinamide
4- (2, 4-dimethoxy) phenylamino) -6- (5-carbamoylpyridin-2-amino) nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5-carbamoyl pyridin-2-amino) -nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5-hydroxymethylpyridine-2-amino) -nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5-aminomethylpyridin-2-amino) -nicotinamide
4- (4-ethoxypyridin-3-amino) -6- (5-hydroxydifluoromethylpyridin-2-amino) -nicotinamide
4- (2-ethoxyphenylamino) -6- (5-hydroxymethylpyridin-2-amino) -nicotinamide
4- (2-ethoxyphenylamino) -6- (5-hydroxydifluoromethylpyridin-2-amino) -nicotinamide
20. The diarylamines or pharmaceutically acceptable salts thereof according to any one of claims 1 to 19, wherein the pharmaceutically acceptable salts include salts formed in combination with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions, or organic bases capable of providing physiologically acceptable cations, and ammonium salts.
21. The diarylamines or pharmaceutically acceptable salts thereof according to claim 20, wherein the mineral acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, matrimony vine acid, maleic acid tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions and potassium ions; the alkaline earth metal ions are selected from calcium ions and magnesium ions; the organic base capable of providing a physiologically acceptable cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine.
22. A process for preparing the diarylamines of any of claims 1-19:
the synthetic route is
To prepare the compounds of formula I, the synthetic route for preparing the compounds of formula I follows the structure of formula I:
(a) Halogenated nicotinamide compound 1 is taken as a raw material and is reacted with R containing nucleophilic groups under alkaline conditions 1 Carrying out nucleophilic substitution reaction on the H compound 2 to obtain a compound 3;
(b) Reacting the compound 3 with an amino-substituted azaaromatic ring compound 4 under the condition of a palladium catalyst to generate a target compound I;
said R is 1 、R 2 、X 1 、X 2 、X 3 Is as defined in any one of claims 1 to 18.
23. A pharmaceutical composition comprising as an active ingredient the diarylamines compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
24. Use of a diarylamines compound or its pharmaceutically acceptable salt as claimed in any one of claims 1 to 19 in the manufacture of a medicament for the prophylaxis and/or treatment of diseases which are associated with the HPK1 signalling pathway.
25. Use according to claim 24, wherein the disease associated with the HPK1 signalling pathway is selected from cancer, infectious disease or autoimmune disease.
26. The use according to claim 25, wherein said cancer is selected from skin cancer, lung cancer, urinary system tumor, hematological tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, head and neck cancer; the infectious disease is selected from bacterial infection and virus infection; the autoimmune disease is selected from organ specific autoimmune diseases and systemic autoimmune diseases, wherein the organ specific autoimmune diseases comprise chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia accompanied by chronic atrophic gastritis, lung hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebral spinal sclerosis, acute idiopathic polyneuritis, and the systemic autoimmune diseases comprise rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue diseases and autoimmune hemolytic anemia.
CN202210321485.9A 2022-03-30 2022-03-30 Diaryl heterocyclic amine compound, preparation method, pharmaceutical composition and application thereof Pending CN116924976A (en)

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