CN107922405B - Compound with ERK kinase inhibitory activity, preparation method and application thereof - Google Patents

Compound with ERK kinase inhibitory activity, preparation method and application thereof Download PDF

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CN107922405B
CN107922405B CN201680004577.7A CN201680004577A CN107922405B CN 107922405 B CN107922405 B CN 107922405B CN 201680004577 A CN201680004577 A CN 201680004577A CN 107922405 B CN107922405 B CN 107922405B
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CN107922405A (en
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曹建华
耿美玉
黄敏
江磊
李磊
唐帅
冯加权
杨晓彤
郑红艳
吴英雄
任芳芳
丁健
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Shanghai Haihe Pharmaceutical Co Ltd
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Shanghai Haihe Pharmaceutical Co Ltd
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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Abstract

The invention provides a compound with ERK kinase inhibitory activity, a preparation method and application thereof, and particularly provides a compound shown in formula I, a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof, and application thereof in preparation of medicines for preventing and treating diseases related to ERK kinase.

Description

Compound with ERK kinase inhibitory activity, preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound or the salt, which is used as a regulator of an ERK pathway or an inhibitor of ERK kinase, particularly ERK1 and ERK2 kinase.
Background
Extracellular signal-regulated kinases (ERKs) are a class of serine/threonine protein kinases found in the 90's of the 20 th century, and are one of the important subfamilies of the mitogen-activated protein kinase MAPKs family. Activated ERK can transmit extracellular signals to the nucleus, promote phosphorylation of cytoplasmic target proteins or regulate the activity of other protein kinases, thereby regulating gene expression. Its signaling is central to the signaling network involved in regulating cell growth, development and differentiation. Thus, ERK is involved in various biological effects of cell proliferation, differentiation, migration, invasion and apoptosis.
The Ras/Raf/MEK/ERK pathway is a main signal pathway related to the function of ERK, and node proteins on the pathway are hot spots for developing cancer-targeted drugs in recent years because the pathway regulates the proliferation, differentiation and apoptosis of cells. Specific B-Raf inhibitors Vemurafenib and dabrafenib are marketed in 2011 and 2013 respectively for the treatment of melanoma, wherein dabrafenib is used for treating B-RafV600E mutant non-small cell lung cancer and achieves breakthrough drug qualification of FDA. The MEK1/2 inhibitor trametinib was also marketed in 2013 for the treatment of melanoma. However, inhibition of these upstream pathway nodes has its limitations, tumors can rapidly develop drug resistance to B-Raf and MEK inhibitors, and the mechanism of drug resistance generation includes point mutation, change of protein polymeric form, change of protein peptide chain length, etc., which is a great obstacle for the next generation of drug resistance Raf and MEK drugs. ERK is used as a downstream key node of the pathway, no drug-resistant mutation is found at present, and the ERK targeting drug can greatly improve the treatment of patients with drug resistance to upstream target inhibitors, so that the ERK targeting drug is a promising anti-cancer drug research and development field.
In view of the above, there is an urgent need in the art to develop new ERK inhibitor drugs.
Disclosure of Invention
The invention aims to provide a compound which has a novel structure and can effectively inhibit ERK kinase, and a preparation method and application thereof.
In a first aspect of the invention, there is provided a compound of formula I, stereoisomers, racemates, or pharmaceutically acceptable salts thereof:
Figure GPA0000243696240000031
in the formula, X1、X2、X3、X4、X5And X6Each independently selected from: substituted or unsubstituted CR5Or N, wherein said "substituted" refers to having one or more (e.g., 1, 2, 3, or 4) substituents selected from group a: -CN, -NH2、-CONH2or-CON- (C)1-C3Alkyl groups);
R1selected from the group consisting of: H. substituted or unsubstituted arylacetyl;
R2selected from the group consisting of: substituted or unsubstituted C1-C10An alkyl group, a substituted or unsubstituted 5-8 membered aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, and a substituted or unsubstituted 3-8 membered heterocyclic group; or R1And R2Taken together with the adjacent N atom to form a substituted or unsubstituted 5-8 membered heterocyclic group;
R3selected from the group consisting of: H. substituted or unsubstituted C1-C8Alkyl, -OH, cyano, halogen, C1-C8An alkylenehydroxy group, a substituted or unsubstituted 3-to 8-membered cycloalkyl group, a substituted or unsubstituted 3-to 8-membered heterocyclic group, a substituted or unsubstituted 3-to 8-membered aryl group, and a substituted or unsubstituted 3-to 8-membered heteroaryl group;
or, R3And X4And adjacent C and N atoms together form a substituted or unsubstituted 4-8 membered ring, wherein said ring contains at least 1N heteroatom and contains a total of 1-3 heteroatoms selected from O, S and N, and said ring is saturated or unsaturated;
R4selected from H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkoxy, -CO (CR)6R7)mR8、-SO2(CR6R7)mR8、-CONR9(CR6R7)mR8、-COO(CR6R7)mR8Amino group, C1-C8A carboxyl group; wherein m is 0, 1, 2 or 3;
wherein R is5Selected from the group consisting of: H. d, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkoxy, -OH, cyano, -CON (C)1-C4Alkyl radical)2、-CONH2Halogen, -CF3Amino, substituted or unsubstituted C1-C8Alkylamino radical, substituted or unsubstituted C1-C8Alkylcarbonyl, substituted or unsubstituted C1-C8Alkoxycarbonyl, substituted or unsubstituted C1-C8Carboxy, substituted or unsubstituted C1-C8An ester group, a substituted or unsubstituted 3-to 8-membered cycloalkyl group, a substituted or unsubstituted 3-to 8-membered heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
each R6And R7Each independently selected from the group consisting of: H. d, substituted or unsubstituted C1-C8Alkyl radical, C1-C8Alkylene hydroxy, substituted or unsubstituted C1-C8Alkoxy and halogen, or R6And R7Joined to form a substituted or unsubstituted 3 to 6 membered ring;
each R8Selected from the group consisting of: H. substituted or unsubstituted C1-C8An alkyl group, a substituted or unsubstituted 5-8 membered aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, and a substituted or unsubstituted 3-8 membered heterocyclic group;
each R9Selected from the group consisting of: H. substituted or unsubstituted C1-C8An alkyl group;
wherein, R is1、R2、R3、R4、R5、R6、R7、R8、R9Wherein said "substituted" means having one or more selected from group B(e.g., 1, 2, 3, 4, or 5) substituents: D. halogen, -OH, -CN, -CD3、-COOH、-NH2、-NO2、C1-C4Alkyl radical, C1-C4Haloalkyl, -C1-C4alkyl-O-R11、C1-C8Alkoxy radical, C1-C8Alkylamino radical, (C)1-C6Alkyl) COO-, C1-C6Alkoxycarbonyl, substituted or unsubstituted 5-8 membered heteroarylcarbonyl, N (R)11R12) CO-, substituted or unsubstituted C3-C6Heterocyclylcarbonyl, substituted or unsubstituted C1-C4Alkylsulfonyl radical, C1-C4Hydroxyalkyl radical, C1-C4Alkylamino, aminosulfonyl, piperazinosulfonyl, substituted or unsubstituted 3-to 8-membered cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, benzyloxyacyl, benzyloxycarbonyl; wherein R is11、R12Each independently selected from: c1-C3Alkyl and H, wherein "substituted" refers to having one or more (e.g., 1, 2, 3) substituents selected from group C: c1-C6Alkoxycarbonyl, C1-C4Alkyl radical, C1-C4Alkoxy, -OH, -NH2、Boc。
In another preferred embodiment, R is3And X4And the linked "═ C-N-" or "— C-N-" together form a substituted or unsubstituted 4-8 membered ring.
In another preferred embodiment, R is3And X4And the linked "═ C-N-" or "— C-N-" together form a 4-8 membered ring including fused rings, spiro rings, or bridged rings.
In another preferred embodiment, the aryl group is phenyl.
In another preferred embodiment, the heteroaryl is selected from the group consisting of: pyridyl, pyrazolyl, thiazolyl, imidazolyl, isoxazolyl, or oxazolyl.
In another preferred embodiment, X is1、X2、X3、X4、X5、X6Each independently selected from CR5Or N; and, X1、X2、X5At least one of which is N.
In another preferred embodiment, X is1、X2、X5、X6At least one or two of them are N, and the rest are C; and X3、X4Is C.
In another preferred embodiment, X is1、X2、X3、X4、X5、X6Are all substituted or unsubstituted CR5。
In another preferred embodiment, X is5To substituted CR5And the substituents are selected from the group consisting of: -CN, -NH2or-CONH2。
In another preferred embodiment, R2Is a substituted or unsubstituted 4-6 membered saturated or unsaturated heterocyclic group, wherein said substitution means having one or more (e.g., 1-3) substituents selected from the group consisting of: halogen, C1-C3Alkyl, -OH, amino, cyano, CF3-、CF3CH2-、CD3-、C1-C8Alkoxy radical, C1-C8Alkylamino radical, C1-C4Alkoxycarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Hydroxyalkyl, benzyloxycarbonyl, (C)1-C3Alkyl radical)2NCO-, unsubstituted piperidinyl, or substituted by one or more (e.g. 1-3) C1-C4Alkoxycarbonyl-substituted piperidinyl groups.
In another preferred embodiment, R2Is a substituted or unsubstituted 5-membered heterocyclic group.
In another preferred embodiment, R2Selected from a 5-membered heterocyclic group containing 1 to 3N atoms, a six-membered heterocyclic group containing 1 to 2N atoms, or a 4-6-membered heterocyclic group containing 1 oxygen atom.
In another preferred embodiment, R2Is a 5-6 membered heteroaryl group containing 1-3 substituents selected from the group consisting of: halogen, C1-C3Alkyl, -OH, amino, cyano, CF3-、CF3CH2-、CD3-、C1-C8Alkoxy radical、C1-C8Alkylamino radical, C1-C4Alkoxycarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Hydroxyalkyl, benzyloxycarbonyl, (C)1-C3Alkyl radical)2NCO-, unsubstituted piperidinyl, or substituted by one or more (e.g. 1-3) C1-C4Alkoxycarbonyl-substituted piperidinyl groups.
In another preferred embodiment, R2Is a substituted or unsubstituted saturated or unsaturated 4-6 membered cycloalkyl group, said substituent means a substituent having one or more (e.g., 1 to 3) substituents selected from the group consisting of: halogen, -OH, -NH2、-CN、-COOH、C1-C4Alkyl radical, C1-C4Alkoxy, substituted or unsubstituted aminocarbonyl, C1-C4Alkoxycarbonyl, tetrahydropyrrolocarbonyl, C1-C4Alkylsulfonyl radical, C1-C4Alkylamino, substituted or unsubstituted piperazinylcarbonyl, substituted or unsubstituted tetrahydropyrrolylcarbonyl, substituted or unsubstituted piperazinesulfonyl, wherein said substitution refers to having one or more (e.g., 1-3) substituents selected from the group consisting of: c1-C3Alkyl radical, C1-C4Alkoxycarbonyl, C1-C4An alkoxy group.
In another preferred embodiment, R2Is a substituted or unsubstituted phenyl group.
In another preferred embodiment, R4is-CO (CR)6R7)mR8And R is8Selected from: H. substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 3-8 membered cycloalkyl, and substituted or unsubstituted 3-8 membered heterocyclyl, wherein said substitution refers to having one or more (e.g., 1-5) substituents selected from the group consisting of: halogen, C1-C3Alkyl, -OH, amino, cyano, -CF3、C1-C8Alkoxy radical, C1-C8Alkylamino radical, or C3-C8A cycloalkyl group.
In another preferred embodiment, R8Selected from the group consisting of: H. substituted or substituted phenyl, substitutedOr unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted cyclohexyl.
In another preferred embodiment, for R3And X4And a linked "═ C-N-" or "— C-N-" together form a substituted or unsubstituted 4-to 8-membered ring, preferably a 5-to 8-membered ring, more preferably a 5-, 6-, 7-or 8-membered ring containing 1 or 2N, or a 5-, 6-, 7-and 8-membered ring containing N and O.
In another preferred embodiment, R4is-CO (CR)6R7)mR8Wherein R is6And R7Each independently selected from H, D, or substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkylene hydroxy, substituted or unsubstituted C1-C8Alkoxy and halogen, and m is 0, 1 or 2, wherein R8Selected from the group consisting of H, substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyrimidyl.
In another preferred embodiment, the compound of formula I is represented by formula Ia:
Figure GPA0000243696240000061
wherein, X1、X2、X3、X4、X5、X6Each independently selected from substituted or unsubstituted CR5Or N, wherein said "substituted" refers to having one or more (e.g., 1, 2, 3, or 4) substituents selected from group a: -CN, -NH2、-CONH2or-CON- (C)1-C3Alkyl groups);
R3selected from the group consisting of: H. substituted or unsubstituted C1-C8Alkyl, -OH, cyano, halogen, C1-C8Alkylene hydroxy, substituted or unsubstituted 3-to 8-membered cycloalkyl,A substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted 3-8 membered aryl group, and a substituted or unsubstituted 3-8 membered heteroaryl group;
R2、R4、R5the definitions of (a) are the same as the previous definitions.
In another preferred embodiment, the compound of formula Ia is represented by the formula:
Figure GPA0000243696240000062
wherein R is3Selected from the group consisting of: H. substituted or unsubstituted C1-C8Alkyl, -OH, cyano, halogen, C1-C8An alkylenehydroxy group, a substituted or unsubstituted 3-to 8-membered cycloalkyl group, a substituted or unsubstituted 3-to 8-membered heterocyclic group, a substituted or unsubstituted 3-to 8-membered aryl group, and a substituted or unsubstituted 3-to 8-membered heteroaryl group;
R2、R4、R5the definitions of (a) are the same as the previous definitions.
In another preferred embodiment, R2Selected from the group consisting of:
Figure GPA0000243696240000063
wherein each Ra is independently selected from: H. halogen, C1-C4Alkoxycarbonyl group, C1-C3Alkyl, -OH, cyano, amino, -COOH, CF3-、CF3CH2-、CD3-、C1-C8Alkylamino radical, C1-C4Alkoxycarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Hydroxyalkyl, benzyloxycarbonyl, substituted or unsubstituted piperidinyl, C1-C4Alkoxy, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted piperazinylcarbonyl, substituted or unsubstituted tetrahydropyrrolylcarbonyl, substituted or unsubstituted piperazinesulfonyl, substituted or unsubstituted C1-C4An alkylcarboxyl group; wherein the substituent is a substituent having oneOr a plurality (e.g., 1 to 3) of substituents selected from the group consisting of: c1-C3Alkyl radical, C1-C4Alkoxycarbonyl, C1-C4Alkoxy, wherein n is 0, 1, 2 or 3;
R3selected from H, substituted or unsubstituted C1-C8Alkyl, -OH, cyano, halogen, C1-C8An alkylenehydroxy group, a substituted or unsubstituted 3-to 8-membered cycloalkyl group, a substituted or unsubstituted 3-to 8-membered heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group;
or, R3And X4And linked "═ C-N-" or "— C-N-" together form a substituted or unsubstituted 4-8 membered ring, wherein said ring contains at least 1N heteroatom and contains a total of 1 to 3 members selected from the group consisting of: o, S and N, and the ring is a saturated or unsaturated ring;
R4selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkoxy, -CO (CR)6R7)mR8、-SO2(CR6R7)mR8、-CONR9(CR6R7)mR8、-COO(CR6R7)mR8Amino group, C1-C8A carboxyl group; wherein m is 0, 1, 2 or 3;
each R6、R7Each independently selected from the group consisting of: H. substituted or unsubstituted C1-C8Alkyl radical, C1-C8Alkylene hydroxy, substituted or unsubstituted C1-C8Alkoxy, and halogen, or R6And R7Joined to form a substituted or unsubstituted 3-to 6-membered ring;
each R8Selected from the group consisting of: H. substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-to 8-membered cycloalkyl, and substituted or unsubstituted 3-to 8-membered heterocyclyl;
each R9Selected from the group consisting of: H. -OH, substituted or notSubstituted C1-C8 alkyl, C1-C8 alkylenehydroxy, and substituted or unsubstituted C1-C8 alkoxy;
X1、X2、X3、X4、X5and X6Each independently selected from CR5Or N;
R5selected from H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkoxy, -OH, cyano, halogen, amino, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkylcarbonyl, substituted or unsubstituted C1-C8 alkoxycarbonyl, substituted or unsubstituted C1-C8 carboxyl, substituted or unsubstituted C1-C8 ester, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
In another preferred embodiment, R5Selected from H or cyano.
In another preferred embodiment, the compound of formula I is represented by formula Ib below:
Figure GPA0000243696240000071
wherein, X1、X2、X3、X5、X6Each independently selected from substituted or unsubstituted CR5Or N, wherein said "substituted" refers to having one or more (e.g., 1, 2, 3, or 4) substituents selected from group a: -CN, -NH2、-CONH2or-CON- (C)1-C3Alkyl groups);
p is 0, 1, 2, 3 or 4;
q is 1, 2, 3, 4 or 5;
and p + q is less than or equal to 5;
y and Z are each independently selected from-CRcRd、O、S、-NRc(ii) a Wherein each R isc、RdEach independently selected from: H. substituted or unsubstituted C1-C8Alkyl, -OH, amino, halogen, cyano, substituted or unsubstituted C1-C8Alkylene hydroxy, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted amino C1-C8Alkyl-, substituted or unsubstituted C1-C8Alkylamino radical, or-CRcRdis-C (═ O) -;
R2、R4、R5the definitions of (a) are the same as the previous definitions.
In another preferred embodiment, the compound of formula I is:
Figure GPA0000243696240000081
wherein p is 0, 1, 2, 3 or 4;
q is 1, 2, 3, 4 or 5;
and p + q is less than or equal to 5;
y and Z are each independently selected from-CRcRd、O、S、-NRc(ii) a Wherein each Rc、RdEach independently selected from: H. substituted or unsubstituted C1-C8Alkyl, -OH, amino, halogen, cyano, substituted or unsubstituted C1-C8Alkylene hydroxy, substituted or unsubstituted C1-C8Alkoxy, substituted or unsubstituted amino C1-C8Alkyl, substituted or unsubstituted C1-C8Alkylamino radical, or-CRcRdis-C (═ O);
R2、R4、R5the definitions of (a) are the same as the previous definitions.
In another preferred embodiment, in said compound of formula Ib, R2Selected from the group consisting of:
Figure GPA0000243696240000082
wherein each Ra is independently selected from: H. halogen, C1-C4Alkoxycarbonyl group, C1-C3Alkyl, -OH, cyano, amino, -COOH, CF3-、CF3CH2-、CD3-、C1-C8Alkylamino radical, C1-C4Alkoxycarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Hydroxyalkyl, benzyloxycarbonyl, substituted or unsubstituted piperidinyl, C1-C4Alkoxy, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted piperazinylcarbonyl, substituted or unsubstituted tetrahydropyrrolylcarbonyl, substituted or unsubstituted piperazinesulfonyl, substituted or unsubstituted C1-C4An alkylcarboxyl group; wherein the substituent is a substituent having one or more (e.g., 1 to 3) substituents selected from the group consisting of: c1-C3Alkyl radical, C1-C4Alkoxycarbonyl, C1-C4Alkoxy, n is 0, 1, 2 or 3;
wherein each Ra is independently selected from: c1-C4An alkyl group;
rb is selected from halogen, -OH, cyano, amino, substituted or unsubstituted C1-C3Alkyl radical, C1-C3Haloalkyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8A heterocycloalkyl group;
n is 0, 1, 2 or 3;
p is 0, 1, 2, 3 or 4;
q is 1, 2, 3, 4 or 5;
and p + q is less than or equal to 5;
y and Z are each independently selected from-CRcRd、O、S、-NRc(ii) a Wherein R isc、RdEach independently selected from: H. substituted or unsubstituted C1-C8Alkyl, -OH, amino, halogen, cyano, C1-C8Alkylene hydroxy, substituted or unsubstituted C1-C8Alkoxy, amino C1-C8Alkyl, substituted or unsubstituted C1-C8Alkylamino radical, or-CRcRdis-C (═ O);
R4selected from substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkoxy, -CO (CR)6R7)mR8、-SO2(CR6R7)mR8、-CONR9(CR6R7)mR8、-COO(CR6R7)mR8Amino, carboxyl; wherein m is 0, 1, 2 or 3;
each R6、R7Each independently selected from the group consisting of: H. substituted or unsubstituted C1-C8Alkyl radical, C1-C8Alkylene hydroxy, substituted or unsubstituted C1-C8Alkoxy, and halogen, or R6And R7Joined to form a substituted or unsubstituted 3-to 5-membered ring;
each R8Selected from the group consisting of: H. substituted or unsubstituted C1-C8An alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted 3-to 8-membered cycloalkyl group, and a substituted or unsubstituted 3-to 8-membered heterocyclic group;
each R9Selected from the group consisting of: H. -OH, substituted or unsubstituted C1-C8Alkyl radical, C1-C8Alkylene hydroxy, and substituted or unsubstituted C1-C8An alkoxy group.
In another preferred embodiment, in the compound I, R is1＝H，R2Methyl-substituted five-membered heterocycles, R4＝-CO(CR6R7)mR8Wherein R is6＝R7H, alkyl, alkylhydroxy, and m is 1 or 2, R8Substituted or unsubstituted phenyl, pyridyl, or H.
In another preferred embodiment, the compound of formula I is compound A1-A252.
In another preferred embodiment, said compound I is selected from the group consisting of:
Figure GPA0000243696240000091
Figure GPA0000243696240000101
Figure GPA0000243696240000111
Figure GPA0000243696240000121
Figure GPA0000243696240000131
Figure GPA0000243696240000141
Figure GPA0000243696240000151
Figure GPA0000243696240000161
in a second aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound according to the first aspect of the invention, stereoisomers, racemates thereof or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
In a third aspect of the present invention, there is provided a compound according to the first aspect of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect of the present invention for use in the preparation of a medicament for the prevention and treatment of diseases associated with ERK kinase and targeted inhibitors of ERK kinase.
In a fourth aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of:
a) reacting (1e) with (1f) in an inert solvent under metal catalysis or acid/base catalysis to obtain a compound shown in the formula I;
Figure GPA0000243696240000171
wherein, X1、X2、X3、X4、X5、X6、R1、R2、R3The groups are as defined in the first aspect of the invention;
LG2is a leaving group selected from the group consisting of: halogen, sulfonate, methylthio, methyl sulfone.
In another preferred example, the method further comprises: steps (a-1) and (a-2), thereby producing a compound of formula (1 e):
Figure GPA0000243696240000172
(a-1) in an inert solvent, the (1a) and (1b) are subjected to condensation reaction or reductive amination reaction to obtain a compound (1 c);
(a-2) carrying out a coupling reaction of the (1c) and the compound (1d) in an inert solvent under the action of a metal catalyst to obtain a compound (1 e);
in the formula, LG1Is a leaving group selected from the group consisting of: halogen, sulfonate, boric acid, borate, organotin, organozinc;
LG2is a leaving group selected from the group consisting of: halogen, sulfonate, methylthio, methyl sulfone;
LG3is a leaving group selected from the group consisting of: halogen, sulfonate, boric acid, borate;
FG is selected from the group consisting of: carboxylic acids, aldehydes, halogens;
X1、X2、X3、X4、X5、X6、R1、R2、R3the definition of each group is as described in the first aspect of the invention.
In another preferred embodiment, in the (a-1), the reaction is carried out in an inert solvent selected from the group consisting of: water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
In another preferred embodiment, in the (a-1), the condensation reaction is carried out in the presence of a condensing agent selected from the group consisting of: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, O-benzotriazol-tetramethyluronium hexafluorophosphate, or a combination thereof.
In another preferred embodiment, in the (a-1), the reductive amination reaction is carried out in the presence of a catalyst and a reducing agent, and the catalyst is selected from the group consisting of: titanium tetraisopropoxide, trifluoroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or combinations thereof; the reducing agent is selected from the group consisting of: sodium borohydride, sodium cyanoborohydride, sodium borohydride acetate, sodium trifluoroacetyloxyborohydride, polymer-supported sodium borohydride reducing agent, sodium trimethoxyborohydride, sodium triethylborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, or a combination thereof.
In another preferred embodiment, in the (a-2), the metal catalyst is selected from the group consisting of: tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) Tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) Palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (tri-o-phenylphosphino) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof.
In another preferred embodiment, in the (a), the reaction is carried out in the presence of a catalyst ligand selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-o-benzylphosphine, or combinations thereof.
In another preferred embodiment, in the (a), the reaction is carried out in the presence of a base, and the base includes an inorganic base and an organic base.
In another preferred embodiment, in the (a), the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof.
In another preferred embodiment, in the (a), the organic base is selected from the group consisting of: pyridine, triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.
In another preferred embodiment, in the (a), the reaction is carried out in the presence of an acid selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, or combinations thereof.
In another preferred embodiment, the temperature of step a) is-78 ℃ to 250 ℃.
In another preferred example, the step a) is performed under normal temperature conditions.
In another preferred embodiment, said step a) is carried out under dry ice bath or ice bath conditions.
In another preferred embodiment, said step a) is carried out under heating selected from the group consisting of: electrical heating, microwave heating, or a combination thereof.
In a fifth aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of:
b) carrying out coupling reaction on the (1c) and the (1g) compound in an inert solvent under the catalysis of metal to prepare a compound shown in the formula I;
Figure GPA0000243696240000181
wherein, X1、X2、X3、X4、X5、X6、R1、R2、R3The groups are as defined in the first aspect of the invention;
LG1is a leaving group selected from the group consisting of: halogen, sulfonate, boric acid, borate, organotin, organozinc;
LG3is a leaving group selected from the group consisting of: halogen, sulfonate, boric acid, borate.
In another preferred example, the method further comprises: step (b-1) and/or (b-2):
(b-1) (1a) and (1b) are coupled by condensation, reductive amination or the like in an inert solvent to obtain (1 c);
Figure GPA0000243696240000191
(b-2) (1d) and (1f) in an inert solvent in the presence of a base to give (1 g);
Figure GPA0000243696240000192
in the formula, LG1Is a leaving group selected from the group consisting of: halogen, sulfonate, boric acid, borate, organotin, organozinc;
LG2is a leaving group selected from the group consisting of: halogen, sulfonate, methylthio, methyl sulfone;
LG3is a leaving group selected from the group consisting of: halogen, sulfonate, boric acid, borate; FG is selected from the group consisting of: carboxylic acids, aldehydes, halogens;
X1、X2、X3、X4、X5、X6、R1、R2、R3the definition of each group is as described in the first aspect of the invention.
In another preferred embodiment, the (b-1) is carried out in an inert solvent selected from the group consisting of: water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
In another preferred embodiment, in the (b-1), the condensation reaction is carried out in the presence of a condensing agent selected from the group consisting of: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, O-benzotriazol-tetramethyluronium hexafluorophosphate, the like, or combinations thereof.
In another preferred embodiment, in the (b-1), the reductive amination reaction is carried out in the presence of a catalyst and a reducing agent, the catalyst being selected from the group consisting of tetraisopropoxytitanium, trifluoroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or a combination thereof; the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium acetate borohydride, sodium trifluoroacetyloxyborohydride, polymer-supported sodium borohydride reducing agent, sodium trimethoxyborohydride, sodium triethylborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum tetrahydroborate, or combinations thereof.
In another preferred embodiment, in the (b), (1c) and (1g) are coupled in the presence of a metal catalyst selected from the group consisting of: tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) Tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) Palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (tri-o-phenylphosphino) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof.
In another preferred embodiment, in the (b), (1c) and (1g) are coupled in the presence of a metal catalyst ligand selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-o-benzylphosphine, or combinations thereof.
In another preferred embodiment, in the (b-2), (1d) and (1f) are coupled in the presence of a base, wherein the base comprises an inorganic base and an organic base.
In another preferred embodiment, in the (b-2), (1d) and (1f) are coupled in the presence of an inorganic base selected from the group consisting of: sodium hydroxide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, butyl lithium, lithium diisopropylamide, potassium hydroxide, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof.
In another preferred embodiment, the coupling of (1d) and (1f) in (b-2) is carried out in the presence of an organic base selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.
In another preferred embodiment, in the (b-2), (1d) and (1f) are coupled in the presence of an acid selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, or combinations thereof.
In another preferred embodiment, the temperature of step b) is-78 ℃ to 250 ℃.
In another preferred example, the step b) is performed under normal temperature conditions.
In another preferred embodiment, said step b) is carried out under dry ice bath or ice bath conditions.
In another preferred embodiment, said step b) is carried out under heating selected from the group consisting of: electrical heating, microwave heating, or a combination thereof.
In a sixth aspect of the invention, there is provided a method of non-therapeutically inhibiting ERK kinase activity comprising the steps of: contacting a compound according to the first aspect of the invention, a stereoisomer, racemate or pharmaceutically acceptable salt thereof, with ERK kinase, thereby inhibiting ERK kinase.
In another preferred embodiment, the contacting is contacting purified ERK kinase or cells expressing ERK kinase.
In a seventh aspect of the invention, there is provided a method of preventing and/or treating a disease associated with ERK kinase activity in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to the first aspect of the invention, a stereoisomer, racemate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect of the invention.
In another preferred embodiment, the ERK kinase comprises ERK1, ERK2, or a combination.
In another preferred embodiment, the diseases related to ERK kinase activity refer to diseases related to high expression or high activity of ERK kinase.
In another preferred embodiment, the disease associated with ERK kinase activity is selected from the group consisting of: a tumor.
In another preferred embodiment, the disease associated with ERK kinase activity is selected from the group consisting of: skin cancer, carcinoma of large intestine, ovarian cancer, pancreatic cancer, lung cancer, renal cancer, hepatocarcinoma, melanoma, colorectal cancer, acute myelogenous leukemia, myelodysplastic syndrome, breast cancer, and glioma.
In an eighth aspect of the invention, there is provided a compound of the first aspect of the invention or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention and/or treatment of a disease associated with ERK kinase activity.
In another preferred embodiment, the diseases related to ERK kinase activity refer to diseases related to high expression or high activity of ERK kinase.
In another preferred embodiment, the disease associated with ERK kinase activity is selected from the group consisting of: a tumor.
In another preferred embodiment, the disease associated with ERK kinase activity is selected from the group consisting of: skin cancer, carcinoma of large intestine, ovarian cancer, pancreatic cancer, lung cancer, renal cancer, hepatocarcinoma, melanoma, colorectal cancer, acute myelogenous leukemia, myelodysplastic syndrome, breast cancer, and glioma.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention unexpectedly finds that a compound shown as a formula I or a pharmaceutically acceptable salt thereof can be used as an ERK kinase inhibitor and has high inhibitory activity for the first time through extensive and intensive research. The present invention has been completed based on this finding.
Description of the terms
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
Unless defined otherwise, the following terms used in the specification and claims have the meanings that are commonly understood by those skilled in the art. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the terms "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of, or" consisting of.
Definitions for the terms of the standardization sector can be found in the literature references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols.A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH2O-is equivalent to-OCH2-。
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
"hydroxy" means an-OH group.
"hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxyl group (-OH).
"carbonyl" refers to a-C (═ O) -group.
"nitro" means-NO2。
"cyano" means-CN.
"amino" means-NH2。
"substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino.
"carboxyl" means-COOH.
In this application, the term "alkyl" as a group or as part of another group (e.g., as used in halo-substituted alkyl and the like groups) refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and attached to the remainder of the molecule by a single bond, including, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like. For the purposes of the present invention, the term "alkyl" refers to alkyl groups containing from 1 to 6 carbon atoms.
In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "alkynyl" as a group or part of another group refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, optionally containing at least one double bond, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being connected to the rest of the molecule by single bonds, such as but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic mono-or polycyclic alkyl group consisting of only carbon and hydrogen atoms, which may include fused, bridged or spiro ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may be optionally oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1, 2, 3, 4-tetrahydro-naphthyl, 5, 6, 7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6, 7, 8, 9-tetrahydro-5H-benzocycloheptenyl, 5, 6, 7, 8, 9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, Bicyclo [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene-1H-indenyl, octahydro-2, 5-methylene-pentalenyl and the like.
In this application, the term "heterocyclyl" as a group or part of another group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused ring systems, bridged ring systems or spiro ring systems; wherein the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In this application, the term "aryl" as a group or as part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or higher polycyclic ring system and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In this application, the term "heteroaryl" as a group or part of another group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5-to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5-to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4, 5, 6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [1, 2, 4] triazolo [4, 3-b ] pyridazine, [1, 2, 4] triazolo [4, 3-a ] pyrazine, [1, 2, 4] triazolo [4, 3-c ] pyrimidine, [1, 2, 4] triazolo [4, 3-a ] pyridine, imidazo [1, 2-b ] pyridazine, imidazo [1, 2-a ] pyrazine and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.
In this application, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups. The "optionally" substituents described in the claims and the description section of the present invention are selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.
The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.
"stereoisomers" refers to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.
When the compounds of the present invention contain olefinic double bonds, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
The compounds of the present invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting as starting materials or intermediates racemates, diastereomers or enantiomers. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., crystallization and chiral chromatography.
Conventional techniques for the preparation/separation of individual isomers include Chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, Chiral high performance liquid chromatography, as described, for example, in Gerald Gubitz and Martin G.Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; stalup, Chiral Separations, annu. rev. anal. chem.3: 341-63, 2010; fumiss et al (eds.), VOGEL' S ENCYCOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; heller, acc, chem, res, 1990, 23, 128.
In the present application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
"polymorph" refers to different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form and the present invention is intended to include the various crystalline forms and mixtures thereof.
Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrate, hemihydrate, sesquihydrates, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases it is also possible to retain only adventitious water or a mixture of water plus a portion of adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" denotes a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to a subject in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific prodrug preparation methods can be found in Saulnier, m.g., et al, bioorg.med.chem.lett.1994, 4, 1985-1990; greenwald, r.b., et al, j.med.chem.2000, 43, 475.
In the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
As used herein, "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.
The "tumor" and "diseases related to abnormal cell proliferation" include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
The terms "preventing," "prevention," and "prevention" as used herein include reducing the likelihood of occurrence or worsening of a disease or disorder in a patient.
As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii) inhibiting the disease or disorder, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the state of the disease or condition; or
(iv) Alleviating the symptoms caused by the disease or disorder.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Administration techniques useful for The compounds and methods described herein are well known to those skilled in The art, for example, in Goodman and Gilman, The pharmaceutical Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "drug combination", "administering other treatment", "administering other therapeutic agent" and the like as used herein refer to a drug treatment obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one co-agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, concomitant administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic formulation to a patient as separate entities. These also apply to cocktail therapy, for example the administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include-C (O) -R "(where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting Groups is described in detail in Greene, T.W. and P.G.M.Wuts, Protective Groups in organic Synthesis, (1999), 4th Ed., Wiley. The protecting group may also be a polymeric resin.
Preparation of Compounds of formula I
The following reaction schemes illustrate methods for preparing compounds of formula I, stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof:
Figure GPA0000243696240000271
wherein the content of the first and second substances,
X1、X2、X3、X4、X5、X6、R1、R2、R3、R4are as described above in the section for the embodiments of the compounds of formula I. It is understood that in the following reaction schemes, combinations of substituents and/or variables in the general formulae are permissible only if such combinations result in stable compounds. It will also be appreciated that other general formulae, such as general formula (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ib-1), (Ib-2), (Ib-3), (Ib-4), and other compounds of formula I specifically disclosed herein, may be prepared by methods disclosed herein (by applying appropriately substituted starting materials and modifying the synthesis parameters as required using methods well known to those skilled in the art) or known methods by those skilled in the art of organic chemistry.
The skilled person will appreciate that in some cases the starting materials and intermediates in the preparation of the compounds of the invention may contain functional groups which need to be protected during the synthesis. The exact nature of any protecting group used will depend on the identity of the functional group being protected, as will be apparent to those skilled in the art. Guidance in the selection of suitable protecting Groups and synthetic strategies for their attachment and removal can be found, for example, in Green & Wuts, Green's protective Groups in Organic Synthesis, ("protecting Groups in Organic Synthesis") 3d Edition, Jon Wiley & Sons, Inc., New York (1999) and the references cited therein.
Thus, a protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of that functional group. Generally, the protecting group can be selectively removed as desired during the synthesis.
Reaction scheme 1:
Figure GPA0000243696240000281
in each formula, X1、X2、X3、X4、X5、X6、R1、R2、R3、R4、LG1And LG2Are as described above in the section for the embodiments of the compounds of formula I.
Reaction scheme 2:
Figure GPA0000243696240000282
X1、X2、X3、X4、X5、X6、R1、R2、R3、R4、LG1、LG2and LG3Are as described above in the section for the embodiments of the compounds of formula I.
The main advantages of the invention are:
1. provides a compound shown as a formula I.
2. Provides an ERK kinase inhibitor with novel structure, a preparation method and application thereof, wherein the inhibitor has higher inhibitory activity to ERK kinase.
3. Pharmaceutical compositions for treating diseases associated with ERK kinase activity are provided.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
Example 1: synthesis of 1- (5-bromoindolin-1-yl) -2-phenyl ethanone
Figure GPA0000243696240000283
In a dry 50mL three-necked flask, compound 1(1.10g, 5.55mmol), phenylacetyl chloride (858mg, 5.55mmol), and triethylamine (1.68g, 16.66mmol) were sequentially added, and dissolved in dichloromethane (20 mL). After completion of the reaction by LCMS, concentrated directly under reduced pressure and purified by silica gel column (ethyl acetate: petroleum ether: 1: 10) to give product 2(1.2g, white solid) in yield: 68 percent.
LCMS：m/z 318.1(M+H)；RT＝1.40min(2min).
Synthesis of 2-phenyl-1- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indolin-1-yl) ethanone
Figure GPA0000243696240000291
To a dry 50mL three-necked flask were added compound 2(1.4g, 4.42mmol), pinacol diboron (2.25g, 8.84mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (322mg, 0.44mmol), potassium acetate (866mg, 8.84mmol), 1, 4-dioxane (20mL) in that order. Heating to 100 ℃ under the protection of nitrogen and reacting for 3 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column (ethyl acetate: petroleum ether ═ 1: 20) to give product 3(1.3g, yellow solid) in yield: 94 percent.
LCMS：m/z 364.4(M+H)；RT＝1.53min(2min).
Synthesis of 1- (5- (2-chloropyrimidin-4-yl) indolin-1-yl) -2-phenylethanone
Figure GPA0000243696240000292
In a dry 50mL three-necked flask, compound 3(700mg, 1.92mmol), 2, 4-dichloropyrimidine (286mg, 1.92mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (139mg, 0.19mmol), potassium carbonate (400mg, 2.89mmol), 1, 4-dioxane (8mL) and water (2mL) were added in that order. Heating to 100 ℃ under the protection of nitrogen, and reacting for 3 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure using a thick preparative plate (ethyl acetate: petroleum ether ═ 1: 5) to give product 5(250mg, yellow solid) in yield: 37 percent.
LCMS：m/z 350.1(M+H)；RT＝1.48min(2min).
Synthesis of 1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indolin-1-yl) -2-phenylethanone
Figure GPA0000243696240000293
Compound 4(200mg, 0.57mmol), 1-methyl-5-aminopyrazole (55mg, 0.57mmol), tris (dibenzylideneacetone) dipalladium (55mg, 0.06mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (35mg, 0.06mmol), cesium carbonate (279mg, 0.86mmol)1, 4-dioxane (10mL) were added in this order to a dry 50mL three-necked flask. Heating to 100 ℃ under the protection of nitrogen, and reacting for 4 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product HE153(16mg, yellow solid) by reverse phase preparative column, yield: 7 percent.
LCMS：m/z 411.4(M+H)；RT＝1.27min(2min).
1H-NMR(MeOD 400MHz)：8.38-8.39(m，1H)，8.19-8.21(m，1H)，7.96-7.98(m，2H)，7.56(s，1H)，7.26-7.38(m，7H)，4.19-4.23(m，2H)，3.89(s，2H)，3.79(s，3H)，3.20-3.23(m，2H).
Example 2: synthesis of 1- (5-bromo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) -2-phenylethanone
Figure GPA0000243696240000301
Compound 5(398mg, 2.0mmol), phenylacetic acid (272mg, 2.0mmol), HATU (1.1g, 3.0mmol) and DMF (10mL) were added successively to a dry 50mL one-neck flask, and N, N-diisopropylethylamine (517mg, 4.0mmol) was added dropwise and reacted at room temperature overnight. After completion of the reaction, 15ml of water was added, extracted with ethyl acetate (20 ml. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (15 ml. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6: 1) to give compound 6(539mg, yield: 85%) as a yellow solid.
LCMS：m/z 318.8(M+H)+；RT＝1.652min(254nm)。
Synthesis of 1- (2-phenylacetyl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-5-ylboronic acid
Figure GPA0000243696240000302
In a dry 50mL three-necked flask, compound 7(317mg, 1.0mmol), 1, 4-dioxane (8mL), bis pinaboronate (381mg, 1.5mmol), potassium acetate (194mg, 2.0mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg, 0.1mmol) were added. The reaction was stirred for 6 hours at 90 ℃ under nitrogen with purging with nitrogen under vacuum for 3 times, and the reaction was completed by TLC, the reaction solution was cooled to room temperature, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol 5: 1) to obtain compound 8(169mg, yield: 60%) as a yellow solid.
LCMS：m/z 282.9(M+H)+。
Synthesis of 1- (5- (2-chloropyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) -2-phenylethanone
Figure GPA0000243696240000303
In a dry 50mL three-necked flask, compound 9(169mg, 0.6mmol), 2, 4-dichloropyrimidine (134mg, 0.9mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (44mg, 0.06mmol), cesium carbonate (391mg, 1.2mmol), 1, 4-dioxane (8mL) and water (0.5mL) were added. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 2: 1) to give compound 10(105mg, yield: 50%) as a yellow solid.
LCMS：m/z 350.9(M+H)+。
Synthesis of 1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) -2-phenylethane-1-one
Figure GPA0000243696240000311
In a dry 50mL three-necked flask, compound 10(70mg, 0.2mmol), 1-methyl-5-aminopyrazole (29mg, 0.3mmol), tris (dibenzylideneacetone) dipalladium (18mg, 0.02mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (10mg, 0.02mmol), cesium carbonate (130mg, 0.4mmol) and 1, 4-dioxane (6mL) were added in this order. The mixture was heated to 105 ℃ under nitrogen and reacted overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (15mL), washed with saturated brine (10 mL. times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 1: 2) to give compound A2(5mg, yield: 6%) as a yellow solid.
1HNMR(400MHz，CDCl3-d)δ8.81(s，1H)，8.46(d，1H，J＝5.2Hz)，8.09(s，1H)，7.51(d，1H，J＝2.0Hz)，7.39(d，2H，J＝7.2Hz)，7.32-7.17(m，4H)，6.89(s，1H)，6.35(d，1H，J＝2.0Hz)，4.61(s，2H)，4.18(t，2H，J＝8.8Hz)，3.82(s，3H)，3.12(t，2H，J＝8.4Hz)。
LCMS：m/z 412.1(M+H)+；RT＝1.179min(254nm)。
Example 3: synthesis of N- (5-bromopyridin-2-yl) -2-phenylacetamide
Figure GPA0000243696240000312
Compound 11(2.00g, 14.71mmol), 2-amino-5-bromopyridine (2.54g, 14.71mmol) and HATU (5.59g, 14.71mmol) were sequentially added to a dry 50mL single-necked flask in DMF (20mL), and N, N-diisopropylethylamine (1.91g, 14.71mmol) was added dropwise and the mixture was reacted at room temperature for 4 hours. After LCMS detection, water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated, which was then passed through a silica gel column (developing solvent ethyl acetate: petroleum ether: 1: 10) to give compound 2(2.8g, white solid) in yield: 67%.
LCMS：m/z291.1(M+H)；RT＝1.33min(2.0min).
Synthesis of (6- (2-phenylacetylamino) pyridin-3-yl) boronic acid
Figure GPA0000243696240000313
In a dry 50mL three-necked flask were added compound 12(1.4g, 4.81mmol), pinacol diboron (2.44g, 9.62mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (351mg, 0.48mmol), potassium acetate (942mg, 9.62mmol), 1, 4-dioxane (20mL) in that order. Heating to 100 ℃ under the protection of nitrogen and reacting for 3 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column (ethyl acetate: petroleum ether ═ 1: 3) to give product 13(1.0g, yellow solid), yield: 81 percent.
LCMS：m/z257.1(M+H)；RT＝0.39min(2min).
Synthesis of N- (5- (2-chloropyrimidin-4-yl) pyridin-2-yl) -2-phenylacetamide
Figure GPA0000243696240000321
In a dry 50mL three-necked flask were added compound 13(1.0g, 3.91mmol), 2, 4-dichloropyrimidine (582mg, 3.91mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (293mg, 0.40mmol), potassium carbonate (810mg, 5.87mmol), 1, 4-dioxane (20mL) and water (5mL) in that order. Heating to 100 ℃ under the protection of nitrogen, and reacting for 3 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a plate (ethyl acetate: petroleum ether ═ 1: 3) after use to obtain the product 14(500mg, yellow solid), yield: 40 percent.
LCMS：m/z325.2(M+H)；RT＝1.28min(2min).
Synthesis of N- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) -2-phenylacetamide
Figure GPA0000243696240000322
Compound 14(50mg, 0.15mmol), 1-methyl-5-aminopyrazole (15mg, 0.15mmol), tris (dibenzylideneacetone) dipalladium (18mg, 0.02mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (12mg, 0.02mmol), cesium carbonate (49mg, 0.15mmol)1, 4-dioxane (10mL) were added sequentially in a dry 50mL three-necked flask. Heating to 100 ℃ under the protection of nitrogen, and reacting for 2 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product a3(16mg, yellow solid) in reverse phase: 28 percent.
LCMS：m/z386.2(M+H)；RT＝1.26min(2min).
1H-NMR(MeOD 400MHz)：9.01-9.02(m，1H)，8.46-8.47(m，2H)，8.15-8.16(m，1H)，7.52-7.53(m，1H)，7.33-7.40(m，6H)，6.42-6.43(m，1H)，3.78-3.79(m，5H).
Example 4: synthesis of 2-phenyl-N- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetamide
Figure GPA0000243696240000323
Compound 15(500mg, 2.28mmol), phenylacetic acid (310mg, 2.28mmol) and HATU (1.30g, 3.42mmol) were sequentially added to a dry 50mL single-necked flask, and then dissolved in DMF (10mL) and triethylamine (461mg, 4.56mmol) was added dropwise, followed by reaction at room temperature for 3 hours. After LCMS detection, water was added to the reaction mixture, which was extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated, which was then passed through a silica gel column (developing solvent ethyl acetate: petroleum ether: 1: 20) to give compound 16(520mg, white solid) in yield: 68 percent.
LCMS：m/z338.2(M+H)；RT＝1.09min(2.0min).
Synthesis of N- (5- (2-chloropyrimidin-4-yl) pyridin-2-yl) -2-phenylethyl
Figure GPA0000243696240000331
In a dry 50mL three-necked flask were added compound 16(520mg, 1.54mmol), 2, 4-dichloropyrimidine (275mg, 1.85mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (110mg, 0.15mmol), potassium carbonate (319mg, 2.31mmol), 1, 4-dioxane (8mL) and water (2mL) in that order. Heating to 100 ℃ under the protection of nitrogen, and reacting for 3 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a used plate (ethyl acetate: petroleum ether ═ 1: 5) to obtain the product 17(480mg, yellow solid) in yield: 96 percent.
LCMS：m/z324.3(M+H)；RT＝1.10min(2min).
Synthesis of N- (4- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) phenyl) -2-phenylacetamide
Figure GPA0000243696240000332
Compound 17(200mg, 0.62mmol), 1-methyl-5-aminopyrazole (60mg, 0.62mmol), tris (dibenzylideneacetone) dipalladium (155mg, 0.06mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (35mg, 0.06mmol), cesium carbonate (302mg, 0.93mmol)1, 4-dioxane (10mL) were added in this order to a dry 50mL three-necked flask. Heating to 100 ℃ under the protection of nitrogen, and reacting for 2 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product a4(50mg, yellow solid) in reverse phase preparation column, yield: 21 percent.
LCMS：m/z385.4(M+H)；RT＝1.13min(2min).
1H-NMR(CDCl3，400MHz)：8.22-8.24(m，1H)，8.00(d，j＝8.4，2H)，7.62(d，j＝8.4，2H)，7.50-7.54(m，2H)，7.34-7.44(m，6H)，6.47(s，1H)，3.79-3.88(m，5H).
Example 5: synthesis of 4-bromo-2-fluoroaniline
Figure GPA0000243696240000333
In a100 mL round-bottom flask was added 4-bromo-2-fluoro-1-nitrobenzene (2.2g, 10mmol), iron powder (2.8g, 50mmol) and tetrahydrofuran (20mL), and hydrochloric acid (30mL, 2N) was added dropwise with stirring at room temperature, and stirred at room temperature for 2h, and anhydrous sodium carbonate (2g) and anhydrous sodium sulfate were added, followed by filtration, washing with ethyl acetate, and concentration under reduced pressure to give compound 19 as a yellow solid (1.65g, yield: 87%).
LCMS：m/z 191.1(M+H)+；RT＝1.405min。
N- (4-bromo-2-fluorophenyl) -2-phenylacetamide
Figure GPA0000243696240000334
In a dry 50mL one-neck flask were added compound 19(950mg, 5mmol), phenylacetic acid (680mg, 5mmol), HATU (3.42g, 9mmol), DMF (15mL) and N, N-diisopropylethylamine (1.29g, 10mmol) in that order. After stirring at room temperature for 6 hours, the mixture was diluted with ethyl acetate (20mL), washed with saturated brine (10 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 8: 1) to give compound 20(1.07g, yield: 70%) as a yellow solid.
LCMS：m/z 309.8(M+H)+；RT＝1.457min。
Synthesis of N- (2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2-phenylacetamide
Figure GPA0000243696240000341
In a dry 50mL three-necked flask was added compound 20(1.01g, 3.3mmol), 1, 4-dioxane (10mL), bis pinaboronate (4.2g, 16.7mmol), potassium acetate (648mg, 6.6mmol) and [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (220mg, 0.3 mmol). The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1) to give compound 21(703mg, yield: 60%) as a yellow solid.
LCMS：m/z 355.8(M+H)+；RT＝1.699min。
Synthesis of N- (4- (2-chloropyrimidin-4-yl) -2-fluorophenyl) -2-phenylacetamide
Figure GPA0000243696240000342
In a dry 10mL round bottom flask was added, in order at room temperature, 21(355mg, 1.0mmol), 2, 4-dichloropyrimidine (222mg, 1.5mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg, 0.1mmol), cesium carbonate (652mg, 2.0mmol), 1, 4-dioxane (6mL) and water (1 mL). The reaction was stirred for 6h at 90 ℃ under nitrogen and purged with nitrogen under vacuum for 3 times, the reaction was complete by TLC, the reaction was cooled to room temperature and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 3: 1) to give compound 22(174mg, yield: 51%) as a yellow solid.
LCMS：m/z 341.9(M+H)+；RT＝1.677min。
Synthesis of N- (2-fluoro-4- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) phenyl) -2-phenylacetamide
Figure GPA0000243696240000343
In a dry 25mL three-necked flask, compound 22(68mg, 0.2mmol), 1-methyl-5-aminopyrazole (29mg, 0.3mmol), tris (dibenzylideneacetone) dipalladium (18mg, 0.02mmol), 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (12mg, 0.02mmol), cesium carbonate (130mg, 0.4mmol) and 1, 4-dioxane (3mL) were added in this order. And (3) heating to 100 ℃ by microwave under the protection of nitrogen, and reacting for 2 hours. After completion of the reaction, it was diluted with ethyl acetate (20mL), washed with saturated brine (10 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by acidic prep-HPLC to give Compound A5(6mg, yield: 7%) as a yellow solid.
1HNMR(400MHz，CDCl3-d)δ8.49(t，1H，J＝8.4Hz)，8.41(d，1H，J＝5.2Hz)，7.78(s，1H)，7.76(d，1H，J＝4.8Hz)，7.50-7.35(m，7H)，7.16(d，1H，J＝5.6Hz)，6.35(d，1H，J＝1.6Hz)，3.81(s，5H)。
LCMS：m/z 402.9(M+H)+；RT＝1.385min。
The following compounds 6-44 can be prepared by the present invention using the above similar method:
example 6: synthesis of tert-butyl-5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) indoline-1-carboxylic acid tert-butyl ester
Figure GPA0000243696240000351
1HNMR(400MHz，CDCl3-d)δ8.38(d，1H，J＝5.2Hz)，7.85(s，2H)，7.49(d，1H，J＝1.6Hz)，7.15(d，1H，J＝5.2Hz)，6.87(s，1H)，6.35(d，1H，J＝1.2Hz)，4.03(t，2H，J＝8.8Hz)，3.80(s，3H)，3.15(t，2H，J＝8.8Hz)，1.58(s，9H)。
LCMS：m/z 393.3(M+H)+；RT＝1.461min(254nm)。
Example 7: synthesis of 1- (5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) indolin-1-yl) -3-phenylpropan-1-one
Figure GPA0000243696240000352
1HNMR(400MHz，CDCl3-d)δ8.40(d，1H，J＝5.2Hz)，8.32(d，1H，J＝8.4Hz)，7.88-7.86(m，2H)，7.49(d，1H，J＝1.6Hz)，7.32-7.16(m，6H)，6.95(s，1H)，6.35(d，1H，J＝1.6Hz)，4.03(t，2H，J＝8.4Hz)，3.80(s，3H)，3.21(t，2H，J＝8.4Hz)，3.08(t，2H，J＝7.6Hz)，2.76(t，2H，J＝7.6Hz)。
LCMS：m/z 425.0(M+H)+；RT＝1.339min(254nm)。
Example 8: synthesis of 4- (indolin-5-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine
Figure GPA0000243696240000353
1HNMR(400MHz，DMSO-d6)δ8.38(d，1H，J＝5.6Hz)，7.93-7.91(m，3H)，7.47(d，1H，J＝1.6Hz)，7.40(d，1H，J＝5.6Hz)，6.82(d，1H，J＝8.0Hz)，6.36(d，1H，J＝1.6Hz)，5.74(d，1H，J＝2.8Hz)，3.73(s，3H)，3.64(t，2H，J＝8.4Hz)，3.09(t，2H，J＝8.4Hz)。
LCMS：m/z 293.2(M+H)+；RT＝0.958min(254nm)。
Example 9: synthesis of 2- (2-chlorophenyl) -1- (5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) indolin-1-yl) ethanone
Figure GPA0000243696240000354
1HNMR(400MHz，CDCl3-d)δ8.41(d，1H，J＝5.2Hz)，8.31(d，1H，J＝8.8Hz)，7.91(s，1H)，7.86(d，1H，J＝8.4Hz)，7.49(d，1H，J＝1.6Hz)，7.43(d，1H，J＝2.0Hz)，7.42-7.24(m，3H)，7.17(d，1H，J＝5.2Hz)，6.80(s，1H)，6.35(d，1H，J＝2.0Hz)，4.23(t，2H，J＝8.8Hz)，3.95(s，2H)，3.81(s，3H)，3.30(t，2H，J＝8.4Hz)。
LCMS：m/z 445.4(M+H)+；RT＝1.36min(254nm)。
Example 10: synthesis of 2- (3-chlorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indolin-1-yl) ethanone
Figure GPA0000243696240000361
1H-NMR(CDCl3，400MHz)：8..30-8.35(m，2H)，7.88-7.91(m，2H)，7.51-7.52(d，J＝1.2Hz，1H)，7.29-7.32(m，3H)，7.20-7.25(m，2H)，6.41(d，J＝1.2Hz，1H)，4.15-4.19(m，2H)，3.85(s，3H)，3.82(s，2H)，3.25-3.29(m，2H).
LCMS：m/z444.9(M+H)；RT＝1.475min(2.50min).
Example 11: synthesis of 2- (4-chlorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indolin-1-yl) ethanone
Figure GPA0000243696240000362
LCMS：m/z445.4(M+H)；RT＝1.39min(2.0min).
1H-NMR(CDCl3，400MHz)：8.28-8.34(m，2H)，7.88-7.91(m，2H)，7.52(s，1H)，7.33-7.35(m，2H)，7.24-7.26(m，4H)，6.42(s，1H)，4.17(t，j＝8.0，2H)，3.85(s，3H)，3.81(s，2H)，3.26(t，j＝8.0，2H).
Example 12: synthesis of 3-hydroxy-1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indolin-1-yl) -2-phenylpropan-1-one
Figure GPA0000243696240000363
LCMS：m/z441.3(M+H)；RT＝1.15min(2.0min).
1H-NMR(CDCl3，400MHz)：7.95-7.97(m，1H)，7.83-7.85(m，1H)，7.69(s，1H)，7.52(s，1H)，7.31-7.39(m，5H)，7.09-7.10(m，1H)，6.43-6.54(m，2H)，4.00-4.11(m，2H)，3.85(s，3H)，3.47-3.67(m，2H)，3.43-3.61(m，1H)，3.02-3.07(m，2H).
Example 13: synthesis of 1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indolin-1-yl) -2-phenylpropan-1-one
Figure GPA0000243696240000364
1H-NMR(CDCl3，400MHz)：8..43-8.45(d，J＝7.6Hz，1H)，7.19-8.20(d，J＝7.6Hz，1H)，7.91-7.93(d，J＝8.4Hz，1H)，7.81(s，1H)，7.54-7.55(d，J＝2.0Hz，1H)，7.27-7.37(m，6H)，6.45-6.46(d，J＝2.0Hz，1H)，4.17-4.22(m，1H)，3.86-3.91(m，5H)，3.04-3.12(m，2H)，1.54-1.55(d，J＝6.8Hz，3H).
LCMS：m/z425.3(M+H)；RT＝1.462min(2.50min).
Example 14: 2- (2-chlorophenyl) -N- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) acetamide
Figure GPA0000243696240000371
1H-NMR(CDCl3，400MHz)：8.92(d，J＝2.0Hz，1H)，7.99-8.01(d，J＝9.2Hz，1H)，8.49-8.52(m，1H)，8.44-8.46(d，J＝6.0Hz，1H)，7.61-7.62(d，J＝3.6Hz，1H)，7.7.43-7.46(dd，J1＝3.6Hz，J2＝7.2Hz，1H)，7.37-7.39(dd，J1＝3.6Hz，J2＝7.2Hz，1H)，7.28-7.32(m，3H)，6.50-6.51(d，J＝2.4Hz，1H)，4.01(s，2H)，3.92(s，3H).
LCMS：m/z419.9(M+H)；RT＝1.375min(2.50min).
Example 15: synthesis of 3N- (5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) pyridin-2-yl) acetamide
Figure GPA0000243696240000372
1HNMR(400MHz，CDCl3-d)δ10.77(s，1H)，9.49(s，1H)，9.04(s，1H)，8.52(d，1H，J＝4.8Hz)，8.44(d，1H，J＝8.4Hz)，8.21(d，1H，J＝8.8Hz)，7.47(d，1H，J＝4.8Hz)，7.36(s，1H)，6.28(s，1H)，3.70(s，3H)，2.13(s，3H)。
LCMS：m/z 310.0(M+H)+；RT＝0.771min。
Example 17: synthesis of N- (1-methyl-1H-pyrazol-5-yl) -4- (6- (phenethylamino) pyridin-3-yl) pyrimidin-2-amine
Figure GPA0000243696240000373
1H-NMR(CDCl3，400MHz)：8.74(s，1H)，8.35(d，j＝5.6，1H)，8.06-8.08(m，1H)，7.47-7.48(m，1H)，7.30-7.34(m，2H)，7.22-7.24(m，2H)，6.95-7.09(m，2H)，6.34-6.43(m，2H)，4.93(s，1H)，3.80(s，3H)，3.62-3.66(m，2H)，2.93-2.97(m，2H).
LCMS：m/z372.2(M+H)；RT＝1.08min(2.0min).
Example 18: synthesis of 4N- (2-chloro-4- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) phenyl) -2-phenylacetamide
Figure GPA0000243696240000374
1HNMR(400MHz，CDCl3-d)δ8.44(d，1H，J＝8.8Hz)，8.32(d，1H，J＝5.2Hz)，7.92(d，1H，J＝2.0Hz)，7.78(dd，1H，J＝2.0Hz，8.8Hz)，7.72(s，1H)，7.39-7.27(m，6H)，7.03(d，1H，J＝6.0Hz)，6.86(s，1H)，6.24(d，1H，J＝2.4Hz)，3.73(s，2H)，3.70(s，3H)。
LCMS：m/z 418.9(M+H)+；RT＝1.504min。
Example 19: synthesis of N- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) -1-phenylmethanesulfonamide
Figure GPA0000243696240000381
1H-NMR(CDCl3 400MHz)：8.47-8.57(m，2H)，8.18-8.21(m，1H)，7.52-7.53(m，1H)，7.30-7.33(m，1H)，7.25-7.26(m，1H)，7.00-7.23(m，5H)，6.36(s，1H)，4.46(s，2H)，3.83(m，3H).
LCMS: m/z421.9(M + H); RT ═ 1.14min (2.5 min.) example 20: synthesis of 2- (2, 6-dichlorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indolin-1-yl) ethanone
Figure GPA0000243696240000382
1H-NMR(CDCl3，400MHz)：8.41(d，j＝5.2，1H)，8.26(d，j＝8.8，1H)，7.94(s，1H)，7.84(d，j＝8.4，1H)，7.49-7.50(m，1H)，7.36-7.38(m，2H)，7.16-7.22(m，2H)，6.81(m，1H)，6.35-6.36(m，1H)，4.34(t，j＝8.4，2H)，4.16(s，2H)，3.81(s，3H)，3.37(t，j＝8.4，2H)，2.80(s，1H).
LCMS：m/z479.3(M+H)；RT＝1.43min(2.0min).
Example 21: synthesis of 2- (2-chlorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone
Figure GPA0000243696240000383
1H-NMR(CDCl3 400MHz)：8.90(s，1H)，8.44-8.45(m，1H)，8.29(s，1H)，7.26-7.49(m，7H)，6.39(s，1H)，4.65-4.66(m，2H)，4.18-4.19(m，2H)，3.77(s，3H)，3.21-3.23(m，2H).
LCMS：m/z446.2(M+H)；RT＝1.30min(2min).
Example 22: synthesis of 2- (2, 6-dichlorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone
Figure GPA0000243696240000384
1H-NMR(CDCl3 400MHz)：8.81(s，1H)，8.45(s，1H)，8.13(s，1H)，7.51(s，1H)，7.33-7.35(m，2H)，7.17-7.19(m，2H)，6.96(s，1H)，6.35(s，1H)，4.88(s，2H)，4.23(t，j＝8.4，2H)，3.82(s，3H)，3.18(t，j＝8.4，2H).
LCMS：m/z480.2(M+H)；RT＝1.41min(2min).
Example 23: synthesis of N-methyl N- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) -2-phenylacetamide
Figure GPA0000243696240000391
1H-NMR(CDCl3 400MHz)：9.08(s，1H)，8.50-8.51(m，1H)，8.27-8.29(m，1H)，7.49-7.50(m，2H)，7.26-7.27(m，1H)，7.05-7.27(m，6H)，6.36(s，1H)，3.82-3.86(m，5H)，3.46(s，2H).
LCMS：m/z400.3(M+H)；RT＝0.99min(2min).
Example 24: synthesis of 3-methyl-N- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) butanamide
Figure GPA0000243696240000392
LCMS：m/z352.3(M+H)；RT＝0.91min(2min).
1H-NMR(CDCl3 400MHz)：8.85(s，1H)，8.57(s，1H)，8.38(d，j＝5.2，1H)，8.23-8.30(m，2H)，7.59(s，1H)，7.43(s，1H)，7.08(d，j＝5.2，1H)，6.26(s，1H)，3.73(s，3H)，2.21-2.22(m，2H)，2.15-2.16(m，1H)，0.93-0.94(d，j＝6.4，6H).
Example 25: synthesis of 2- (3-chlorophenyl) -N- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) acetamide
Figure GPA0000243696240000393
LCMS：m/z419.91(M+H)；RT＝1.429min(2.5min).
1H-NMR(CDCl3 400MHz)：δ8.83(s，1H)，8.39(d，J＝5.6Hz，1H)，8.25(s，1H)，8.01(s，1H)，7.42(d，J＝2.0Hz，1H)，7.27(m，3H)，7.18(m，1H)，7.09(d，J＝5.2，1H)，6.83(s，1H)，6.27(d，J＝2.0Hz，1H)，3.74(s，3H)，3.69(s，2H).
Example 26: synthesis of 1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) -3-phenylurea
Figure GPA0000243696240000394
1H-NMR(MeOD，400MHz)：9.03(s，1H)，8.48-8.52(m，2H)，7.53-7.58(m，4H)，7.31-7.43(m，4H)，7.08-7.09(m，1H)，6.48(s，1H)，3.81(s，3H).
LCMS：m/z387.3(M+H)；RT＝1.09min(2min).
Example 27: synthesis of N- (2-cyano-4- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) phenyl) -2-phenylacetamide
Figure GPA0000243696240000401
1H-NMR(DMSO，400MHz)：9.55(s，1H)，8.86(s，1H)，8.54(d，j＝4.2，1H)，8.46-8.48(m，1H)，7.73(d，j＝8.8，1H)，7.56(d，j＝4.2，1H)，7.25-7.41(m，6H)，6.29(s，1H)，3.97(s，2H)，3.71(s，3H).
LCMS：m/z410.3(M+H)；RT＝0.97min(2min).
Example 28: synthesis of 2- (2-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethan-1-one
Figure GPA0000243696240000402
1H-NMR(CDCl3 400MHz)：8.86(s，1H)，8.31(d，J＝6.4，1H)，8.10(S，1H)，7.61(s，1H)，7.36(d，J＝6.4，2H)，7.06-7.12(m，2H)，6.50(s，2H)，4.56(s，2H)，4.22-4.26(m，2H).3.93(s，3H)3.17-3.21(m，2H)。
LCMS：m/z430.0(M+H)；RT＝1.339min(2min)
Example 29: synthesis of 2- (3-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethan-1-one
Figure GPA0000243696240000403
1H-NMR(CDCl3 400MHz)：8.86(s，1H)，8.31(d，J＝6.4，1H)，8.09(s，1H)，7.58(s，1H)，7.33(d，J＝6.0Hz，2H)，7.08-7.15(m，2H)，6.46(s，1H)，4.59(s，2H)，4.19-4.23(m，2H).3.90(s，3H)3.14-3.18(m，2H)，
LCMS：m/z430.0(M+H)；RT＝1.352min(2min)
Example 30: synthesis of 2-cyclohexyl-N- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) acetamide (A30)
Figure GPA0000243696240000404
1H-NMR(MeOD，400MHz)：9.03(s，1H)，8.57-8.60(m，1H)，8.51(d，j＝5.2，1H)，8.07(d，j＝8.8，1H)，7.57(s，1H)，7.44(d，j＝5.2，1H)，6.47(s，1H)，3.80(s，3H)，2.37(d，j＝7.2，2H)，1.80-1.81(m，1H)，1.68-1.77(m，5H)，1.31-1.34(m，3H)，1.05-1.08(m，2H).
LCMS：m/z392.0(M+H)；RT＝1.40min(2.5min).
Example 31: synthesis of 2- (2-chloro-4-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A31)
Figure GPA0000243696240000411
1H-NMR(MeOD，400MHz)：8.90(s，1H)，8.34-8.50(m，2H)，7.03-7.62(m，6H)，4.55-4.88(m，2H)，4.14-4.21(m，2H)，3.82(s，3H)，3.15(s，2H).
LCMS：m/z464.2(M+H)；RT＝1.34min(2min).
Example 32: synthesis of 2- (2, 3-dichlorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A32)
Figure GPA0000243696240000412
1H-NMR(CDCl3，400MHz)：8.78(s，1H)，8.45(d，j＝4.2，1H)，8.12(s，1H)，7.51(s，1H)，7.38-7.40(m，1H)，7.16-7.20(m，3H)，6.92(s，1H)，6.34(s，1H)，4.69(s，2H)，4.22(t，j＝8.4，2H)，3.81(s，3H)，3.17(t，j＝8.4，2H).
LCMS：m/z480.2(M+H)；RT＝1.42min(2min).
Example 33: synthesis of 2- (2-chloro-6-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A33)
Figure GPA0000243696240000413
1H-NMR(CDCl3，400MHz)：8.72(s，1H)，8.38(d，j＝4.2，1H)，8.04(s，1H)，7.44(s，1H)，7.09-7.19(m，4H)，6.93-6.94(m，1H)，6.28(s，1H)，4.63(s，2H)，4.13(t，j＝8.4，2H)，3.74(s，3H)，3.09(t，j＝8.4，2H).
LCMS：m/z464.2(M+H)；RT＝1.34min(2min).
Example 34: synthesis of 2- (2-chloro-3-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A34)
Figure GPA0000243696240000414
1H-NMR(DMSO-d4，400MHz)：9.49(s，1H)，8.91(s，1H)，8.52(d，j＝4.2，1H)，8.32(s，1H)，7.48(d，j＝4.2，1H)，7.25-7.38(m，4H)，6.29(s，1H)，4.65(s，2H)，4.08(t，j＝8.4，2H)，3.70(s，3H)，3.18(t，j＝8.4，2H).
LCMS：m/z464.2(M+H)；RT＝1.33min(2min).
Example 35: synthesis of 2- (2-chloropyridin-3-yl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A35)
Figure GPA0000243696240000421
1H-NMR(DMSO-d4，400MHz)：9.50(s，1H)，8.91(s，1H)，8.52(d，j＝4.2，1H)，8.32(s，1H)，7.86(d，j＝7.2，1H)，7.48(d，j＝4.2，1H)，7.37-7.43(m，2H)，6.29(s，1H)，4.62(s，2H)，4.09(t，j＝8.4，2H)，3.70(s，3H)，3.18(t，j＝8.4，2H).
LCMS：m/z447.2(M+H)；RT＝1.02min(2min).
Example 36: synthesis of 2- (3-chloro-4-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A36)
Figure GPA0000243696240000422
1H-NMR(DMSO-d4，400MHz)：9.50(s，1H)，8.92(s，1H)，8.52(d，j＝4.2，1H)，8.31(s，1H)，7.31-7.53(m，5H)，6.30(s，1H)，4.50(s，2H)，4.06(t，j＝8.4，2H)，3.70(s，3H)，3.15(t，j＝8.4，2H).
LCMS：m/z464.2(M+H)；RT＝1.46min(2min).
Example 37: synthesis of 2- (3-chloro-2-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A37)
Figure GPA0000243696240000423
LCMS：m/z464.2(M+H)；RT＝1.37min(2min).
1H-NMR(DMSO-d4，400MHz)：9.50(s，1H)，8.91(s，1H)，8.52(d，j＝4.2，1H)，8.32(s，1H)，7.47-7.49(m，2H)，7.34-7.38(m，2H)，7.18-7.20(m，1H)，6.30(s，1H)，4.57(s，2H)，4.08(t，j＝8.4，2H)，3.70(s，3H)，3.17(t，j＝8.4，2H).
Example 38: synthesis of 2- (4-chloro-3-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A38)
Figure GPA0000243696240000424
LCMS：m/z464.2(M+H)；RT＝1.39min(2min).
1H-NMR(DMSO-d4，400MHz)：9.49(s，1H)，8.91(s，1H)，8.52(d，j＝4.2，1H)，8.31(s，1H)，7.47-7.53(m，2H)，7.34-7.38(m，2H)，7.16-7.18(m，2H)，6.30(s，1H)，4.52(s，2H)，4.06(t，j＝8.4，2H)，3.70(s，3H)，3.15(t，j＝8.4，2H).
Example 39: synthesis of 2- (2-chlorophenyl) -1- (5- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A39)
Figure GPA0000243696240000431
LCMS：m/z450.2(M+H)；RT＝1.31min(2min).
1H-NMR(DMSO-d4，400MHz)：8.91(s，1H)，8.33-8.36(m，2H)，7.38-7.46(m，3H)，7.29-7.31(m，2H)，7.20-7.22(m，1H)，4.60(s，2H)，4.06-4.10(m，2H)，3.87-3.89(m，2H)，3.40-3.44(m，2H)，3.15-3.19(m，2H)，1.85-1.88(m，2H)，1.52-1.56(m，2H).
Example 40: synthesis of 2- (2-chlorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A40)
Figure GPA0000243696240000432
LCMS：m/z445.2(M+H)；RT＝1.09min(2min).
1H-NMR(MeOD，400MHz)：8.60(s，1H)，8.06-8.07(m，2H)，7.64(s，1H)，7.24-7.49(m，7H)，6.49(s，1H)，4.62-4.63(m，2H)，4.20(s，2H)，3.84(s，3H)，3.2-3.26(m，2H).
Example 41: synthesis of 2- (2-chloro-5-fluorophenyl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A41)
Figure GPA0000243696240000433
LCMS：m/z464.2(M+H)；RT＝1.34min(2min).
1H-NMR(DMSO-d4，400MHz)：9.50(s，1H)，8.91(s，1H)，8.52(d，j＝4.2，1H)，8.32(s，1H)，7.47-7.51(m，2H)，7.31-7.38(m，2H)，7.16-7.18(m，1H)，6.30(s，1H)，4.61(s，2H)，4.08(t，j＝8.4，2H)，3.70(s，3H)，3.17(t，j＝8.4，2H).
Example 42: synthesis of 2- (3-chloropyridin-4-yl) -1- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A42)
Figure GPA0000243696240000434
LCMS：m/z447.2(M+H)；RT＝0.88min(2min).
1H-NMR(DMSO-d4，400MHz)：9.50(s，1H)，8.89(s，1H)，8.63(s，1H)，8.47-8.53(m，2H)，8.33(s，1H)，7.47-7.49(m，2H)，7.37-7.38(m，1H)，6.29(s，1H)，4.66(s，2H)，4.05-4.11(m，2H)，3.70(s，3H)，3.18(t，j＝8.4，2H).
Example 43: synthesis of (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) (phenyl) methanone (A43)
Figure GPA0000243696240000441
LCMS：m/z398.2(M+H)；RT＝0.94min(2min).
1H-NMR(DMSO-d4，400MHz)：9.49(s，1H)，8.46-8.53(m，1H)，8.29(s，1H)，7.50-7.55(m，3H)，7.39-7.44(m，4H)，6.28(s，1H)，4.61(s，2H)，4.18(t，j＝8.4，2H)，3.69(s，3H)，3.20(t，j＝8.4，2H).
Example 44: synthesis of 2- (2-chlorophenyl) -1- (5- (6- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A44)
Figure GPA0000243696240000442
LCMS：m/z446.2(M+H)；RT＝1.25min(2min).
1H-NMR(MeOD，400MHz)：8.66(s，1H)，8.74(s，1H)，8.11(s，1H)，7.56-7.57(m.1H)，7.38-7.39(m，1H)，7.20-7.24(m，2H)，6.74(s，1H)，6.24-6.25(m，1H)，5.31-5.32(m，1H)，4.64(s，2H)，4.21(t，j＝8.4，2H)，3.80(s，3H)，3.16(t，j＝8.4，2H).
Example 45: synthesis of 1- (5- (5-chloro-2- (isopropylamino) pyridin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) -2- (2-chlorophenyl) ethanone (A45)
Figure GPA0000243696240000443
LCMS：m/z441.1(M+H)；RT＝1.62min(2min).
1H-NMR(MeOD，400MHz)：8.29(s，1H)，8.04(s，1H)，7.83(s，1H)，7.25-7.41(m，4H)，6.94(s，1H)，4.66(s，2H)，4.19(t，j＝8.4，2H)，3.91-3.95(m，1H)，3.23(t，j＝8.4，3H)，1.29-1.33(m，2H).
Example 46: synthesis of 3- ((2-bromopyridin-3-yl) oxy) propan-1-amine (27)
Figure GPA0000243696240000444
Compound 26(7.0g, 40.30mmol), 3-amino-1-propanol (3.63g, 48.28mmol) and triphenylphosphine (12.66g, 48.28mmol) were dissolved in 1, 4-dioxane (250mL) in a dry 500mL three-necked flask under nitrogen atmosphere, diethyl azodicarboxylate (8.41g, 48.28mmol) was added dropwise at room temperature, and the mixture was heated under reflux overnight. After completion of the reaction, it was directly concentrated under reduced pressure and applied to an acidic silica gel column (dichloromethane: methanol 100: 7) to give the product 27(3.5g, yellow oil) in yield: 38 percent of
LCMS：m/z233.0(M+H)；RT＝0.32min(2min).
1H-NMR(CDCl3400MHz)：7.95-7.97(m，1H)，7.14-7.22(m，2H)，4.14(t，j＝6.0，2H)，2.97(t，j＝6.4，2H)，1.98-2.03(m，2H).
Synthesis of 2, 3, 4, 5-tetrahydropyrido [3, 2-B ] [1, 4] oxazepine (28)
Figure GPA0000243696240000451
In a dry 100mL three-necked flask, compound 27(2.0g, 8.63mmol), 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (498mg, 0.90mmol), palladium acetate (193mg, 0.86mmol) and cesium carbonate (2.81g, 8.63mmol) were sequentially added and dissolved in 1.4-dioxane (60mL) under nitrogen. After the reaction was completed, brine was added, and then dichloromethane was added to extract, and the reaction was concentrated under reduced pressure to obtain a crude product, which was then subjected to an acidic silica gel column (petroleum ether: ethyl acetate 2: 1) to obtain 28(750mg, colorless oil) in yield: 58 percent.
1H-NMR(CDCl3 400MHz)：7.80(d，j＝4.4，1H)，7.15(d，j＝4.4，1H)，6.65-6.68(m，1H)，4.67(s，1H)，4.16(t，j＝6.0，2H)，3.35-3.39(m，2H)，2.01-2.07(m，2H).
Synthesis of 8-bromo-2, 3, 4, 5-tetrahydropyrido [3, 2-B ] [1, 4] oxazepine (29)
Figure GPA0000243696240000452
In a dry 50mL three-necked flask, compound 28(750mg, 5.00mmol), bromine (958mg, 6.00mmol), and potassium carbonate (1035mg, 7.50mmol) were dissolved in dichloromethane (30mL) in that order. The reaction was carried out at room temperature for 0.5 hour. After the reaction was completed, the mixture was poured into an appropriate amount of sodium hydrogen sulfite solution, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product 29(900mg, yellow solid) in yield: 79 percent
LCMS：m/z231.0(M+H)；RT＝1.17min(2min).
1- (8-bromo-3, 4-dihydropyrido [3, 2-B ]][1，4]Synthesis of Oxazepin-5 (2H) -yl) -2- (2-chlorophenyl) ethanone (30)
Figure GPA0000243696240000453
In a dry 50mL three-necked flask, compound 29(600mg, 2.62mmol), o-chlorophenylacetic acid (535mg, 3.14mmol), HATU (1.19g, 3.14mmol), and triethylamine (397mg, 3.93mmol) were sequentially added and dissolved in N, N-dimethylformamide (10 mL). The reaction was carried out overnight at 50 ℃ and after completion of the reaction by LCMS, the reaction mixture was poured directly into 30mL of water, extracted with ethyl acetate (30 mL. times.2) and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 30(310mg, yellow solid) with an acidic silica gel column, yield: 31 percent of
LCMS：m/z 383.0(M+H)；RT＝1.51min(2min).
1- (2- (3-chloropyridin-4-yl) acetyl) -2, 3-dihydro-1H-pyrrolo [2, 3-b]Synthesis of pyridin-5-yl) boronic acid (31)
Figure GPA0000243696240000461
In a dry 50mL three-necked flask were added compound 30(150mg, 0.39mmol), pinacol diboron (150mg, 0.59mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (29mg, 0.04mmol), potassium acetate (58mg, 0.59mmol), 1, 4-dioxane (4mL) in this order. And heating to 100 ℃ by microwave under the protection of nitrogen to react for 1.5 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain a crude product 31 as a red solid.
LCMS：m/z429.3(M+H)；RT＝1.69min(2.0min).
Synthesis of 2- (2-chlorophenyl) -1- (8- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -3, 4-dihydropyrido [3, 2-B) (1, 4) oxazepin-5 (2H) -yl) ethanone (A46)
Figure GPA0000243696240000462
In a dry 50mL three-necked flask were added compound 31(103mg, 0.24mmol), 4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (50mg, 0.24mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (22mg, 0.03mmol), potassium carbonate (50mg, 0.36mmol), 1, 4-dioxane (4mL) and water (1mL) in that order. Heating to 100 ℃ under the protection of nitrogen, and reacting for 2 hours. After completion of the reaction, the reaction mixture was poured into 20mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product a46(81mg, yellow solid) by reverse phase preparative column, yield: 71 percent of
LCMS：m/z476.2(M+H)；RT＝1.18min(2min).
1H-NMR(DMSO-d4，400MHz)：9.59(s，1H)，8.89(s，1H)，8.57-8.59(m，1H)，8.10(s，1H)，8.57-8.58(m，1H)，7.22-7.40(m，5H)，6.30(s，1H)，4.23(s，2H)，3.87-3.89(m，4H)，3.70(s，3H)，1.99-2.00(m，2H).
The following 47-50 compounds were prepared using a similar procedure as in example 5:
example 47: synthesis of 2- (2-chlorophenyl) -N- (2-cyano-4- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) phenyl) acetamide (A47)
Figure GPA0000243696240000463
LCMS：m/z444.2(M+H)；RT＝1.23min(2min).
1H-NMR(DMSO，400MHz)：10.61(s，1H)，9.54(s，1H)，8.53-8.56(m，2H)，8.39-8.41(m，1H)，7.63-7.66(m，1H)，7.31-7.54(m，6H)，6.29(s，1H)，3.96(s，2H)，3.69(s，3H).
Example 48: synthesis of 2- (2-chloropyridin-3-yl) -N- (2-cyano-4- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) phenyl) acetamide (A48)
Figure GPA0000243696240000471
LCMS：m/z445.2(M+H)；RT＝1.14min(2min).
1H-NMR(CDCl3，400MHz)：8.52-8.59(m，3H)，8.23-8.31(m，2H)，7.96(s，1H)，7.81-7.83(m，1H)，7.53(s，1H)，7.34-7.37(m，1H)，7.17-7.19(m，1H)，6.83(s，1H)，6.36(s，1H)，3.99(s，2H)，3.83(s，3H).
Example 49: synthesis of 2- (2-chloropyridin-3-yl) -1- (5- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone (A49)
Figure GPA0000243696240000472
LCMS：m/z451.2(M+H)；RT＝1.23min(2min).
1H-NMR(DMSO-d4，400MHz)：8.94(s，1H)，8.35-8.38(m，3H)，7.85-7.87(m，1H)，7.61-7.65(m，1H)，7.27-7.41(m，2H)，4.63(s，2H)，4.20(s，3H)，3.90-3.95(m，2H)，3.42-3.43(m，2H)，3.18-3.19(m，2H)，1.87-1.88(m，2H)，1.55-1.57(m，2H).
Example 50: synthesis of 2- ((2-chlorophenethyl) amino) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) benzonitrile (A50)
Figure GPA0000243696240000473
LCMS：m/z430.4(M+H)；RT＝1.47min(2min).
1H-NMR(CDCl3，400MHz)：8.31(d，j＝4.2，1H)，8.00-8.04(m，2H)，7.43(s，1H)，7.34(d，j＝6.0，1H)，7.15-7.17(m，2H)，6.99-7.00(s，1H)，6.74-6.76(m，1H)，6.67(s，1H)，6.27(s，1H)，4.97(s，1H)，3.74(s，3H)，3.49-3.54(m，2H)，3.03-3.06(m，2H).
Example 51: synthesis of 5-bromo-1- (2-chlorophenethyl) -2, 3-dihydro-1H-pyrrolo [2, 3-b) pyridine (33)
Figure GPA0000243696240000474
Compound 32(250mg, 0.72mmol) was added sequentially in dry 50mL three-necked flask, dissolved in borane tetrahydrofuran (4 mL). Heat to reflux overnight. After the reaction was completed, concentration was performed under reduced pressure to obtain a crude product 33.
LCMS：m/z339.0(M+H)；RT＝1.46min(2.0min).
Synthesis of 1- (2-chlorophenylethyl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) boronic acid (34)
Figure GPA0000243696240000481
In a dry 50mL three-necked flask were added compound 33(160mg, 0.47mmol), pinacol diboron (180mg, 0.71mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (37mg, 0.05mmol), potassium acetate (70mg, 0.71mmol), 1, 4-dioxane (4mL) in that order. And heating to 100 ℃ by microwave under the protection of nitrogen to react for 1.5 hours. After the reaction was complete, concentration was carried out under reduced pressure to obtain crude product 34 as a red solid.
LCMS：m/z302.7(M+H)；RT＝0.71min(2.5min).
Synthesis of 4- (1- (2-chlorophenylethyl) -2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-5-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (A51)
Figure GPA0000243696240000482
In a dry 50mL three-necked flask were added compound 34(72mg, 0.24mmol), 4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (50mg, 0.24mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (22mg, 0.03mmol), potassium carbonate (50mg, 0.36mmol), 1, 4-dioxane (4mL) and water (1mL) in that order. Heating to 100 ℃ under the protection of nitrogen, and reacting for 2 hours. After completion of the reaction, the reaction mixture was poured into 20mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product a51(18mg, yellow solid) by reverse preparative column, yield: 17 percent of
LCMS：m/z432.4(M+H)；RT＝1.03min(2min).
1H-NMR(MeOD，400MHz)：8.45(d，j＝4.2，1H)，8.25(s，1H)，8.15(s，1H)，7.39-7.48(m，3H)，7.25-7.30(m，3H)，6.34(s，1H)，3.80-3.91(m，4H)，3.75(s，3H)，3.18-3.25(m，2H).
Example 52: synthesis of 5-chloro-4-iodo-N- (tetrahydro-2H-pyran-4-yl) pyridin-2-amine (36)
Figure GPA0000243696240000483
In a dry 25mL round-bottomed flask, compound 35(300mg, 1.17mmol), tetrahydro-2H-pyran-4-amine hydrochloride (241mg, 1.755mmol), DIPEA (454mg, 3.51mmol), and DMSO (2mL) were added in this order at room temperature, and nitrogen was replaced 3 times. The mixture was heated to 90 ℃ with stirring and reacted for 16 hours. After completion of the TLC plate detection, 10mL of water was added, extraction was performed with ethyl acetate (20 mL. times.3), and the organic phases were combined. Saturated brine (10mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate: petroleum ether ═ 1: 4) to give the product 5-chloro-4-iodo-N- (tetrahydro-2H-pyran-4-yl) pyridin-2-amine 36(160mg, yellow solid), yield: 40.4 percent
LCMS：m/z338.9，340.9(M+H)；RT＝4.1min(9min)。
Synthesis of 1- (5- (5-chloro-2- (tetrahydro-2H-pyran-4-ylamino) pyridin-4-yl) -2, 3-dihydropyrrolo [2, 3-b ] pyridin-1-yl) -2- (2-chlorophenyl) ethanone (A52)
Figure GPA0000243696240000491
5-chloro-4-iodo-N- (tetrahydro-2H-pyran-4-yl) pyridin-2-amine 2(120mg, 0.354mmol), 1, 4-dioxane (4mL) and water (0.5mL), GE010-04(112mg, 0.354mmol) (see GE010 for the synthesis of this compound), Pd (dppf) were added sequentially at room temperature in a dry 25mL round bottom flask2Cl2CH2Cl2(28mg, 0.0354mmol), sodium hydrogencarbonate (59mg, 0.708mmol), and nitrogen gas were purged 3 times. Heating to 105 ℃, stirring for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 10mL of water was added, extraction was performed with ethyl acetate (30 mL. times.3), and the organic phases were combined. Washing with saturated brine (10mL × 1), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the resulting residue by silica gel column chromatography with an eluent system (ethyl acetate: petroleum ether ═ 1: 4 to ethyl acetate: petroleum ether ═ 10: 1) to give the product 1- (5- (5-chloro-2- (tetrahydro-2H-pyran-4-ylamino) pyridin-4-yl) -2, 3-dihydropyrrolo [2, 3-b ] p]Pyridin-1-yl) -2- (2-chlorophenyl) ethanone a52(33mg, light yellow solid), yield: 19.3 percent.
LCMS：m/z483.1，485.1(M+H)；RT＝4.78min(9min).
1H-NMR(CDCL3，400MHz)：δ8.18(d，J＝2.0Hz，1H)，8.12(s，1H)，7.61(d，J＝1.1Hz，1H)，7.41-7.33(m，1H)，7.28(dd，J＝6.3，3.0Hz，1H)，7.21(dd，J＝6.1，2.1Hz，2H)，6.31(s，1H)，4.64(s，2H)，4.47(s，1H)，4.21(t，J＝8.6Hz，2H)，3.99(d，J＝11.6Hz，2H)，3.85(s，1H)，3.59-3.46(m，2H)，3.15(t，J＝8.6Hz，2H)，2.03(t，J＝5.3Hz，2H)，1.55-1.46(m，2H).
Example 53: synthesis of 2- (2-chlorophenyl) -1- (5- (2, 5-dichloropyridin-4-yl) -2, 3-dihydropyrrolo [2, 3-b ] pyridin-1-yl) ethanone (37)
Figure GPA0000243696240000492
In a dry 25mL round bottom flask, compound 32(700mg, 1.99mmol) (see GE010 for Synthesis of Compound 1), 2, 5-dichloropyridine-4-boronic acid (420mg, 2.19mmol), 1, 4-dioxane (5mL) and water (1.0mL), Pd (dppf) were added sequentially at room temperature2Cl2(147mg, 0.199mmol), potassium carbonate (328mg, 2.387mmol), and nitrogen was purged 3 times. The mixture was heated to 105 ℃ with stirring and reacted for 3 hours. After the reaction result was checked by TLC plate, 10mL of water was added, extraction was performed with ethyl acetate (20 mL. times.3), and the organic phases were combined. Washing with saturated brine (10 mL. times.1), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the resulting residue by column chromatography (ethyl acetate: petroleum ether: 4: 6) to obtainTo the product 2- (2-chlorophenyl) -1- (5- (2, 5-dichloropyridin-4-yl) -2, 3-dihydropyrrolo [2, 3-b]Pyridin-1-yl) ethanone 37(410mg, yellow solid), yield: 49.2 percent.
LCMS：m/z418.6，420.6(M+H)；RT＝5.53min(9min)。
Synthesis of 1- (5- (5-chloro-2- (1-methyl-1H-pyrazol-5-ylamino) pyridin-4-yl) -2, 3-dihydropyrrolo [2, 3-b ] pyridin-1-yl) -2- (2-chlorophenyl) ethanone (A53)
Figure GPA0000243696240000501
2- (2-chlorophenyl) -1- (5- (2, 5-dichloropyridin-4-yl) -2, 3-dihydropyrrolo [2, 3-b ] was added sequentially at room temperature to a dry 10mL microwave tube]Pyridin-1-yl) ethanone 37(150mg, 0.36mmol), THF (3mL), 1-methyl-1H-pyrazol-5-amine (35mg, 0.36mmol), Pd2(dba)3(33mg, 0.036mmol), Xtanphos (21mg, 0.036mmol), cesium carbonate (126mg, 0.396mmol), and nitrogen replaced 3 times. The temperature was raised to 155 ℃ and stirred for 4 hours. After the reaction was completed, flash filtration was performed using a small amount of silica gel, the solid was washed with THF (5mL × 3), the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (DCM: MeOH ═ 30: 1), separated by a preparative column, and freeze-dried to obtain the product 1- (5- (5-chloro-2- (1-methyl-1H-pyrazol-5-ylamino) pyridin-4-yl) -2, 3-dihydropyrrolo [2, 3-b ] of the product]Pyridin-1-yl) -2- (2-chlorophenyl) ethanone a53(26mg, light yellow solid), yield: 15 percent.
LCMS：m/z479.0，481.0(M+H)；RT＝4.65min(9min).
1H-NMR(CDCL3，400MHz)：δ10.95(s，1H)，8.15(d，J＝28.3Hz，2H)，7.55(d，J＝14.4Hz，2H)，7.48-7.33(m，1H)，7.26(d，J＝9.4Hz，1H)，7.24-7.17(m，2H)，6.84(s，1H)，6.21(s，1H)，4.60(s，2H)，4.23(d，J＝8.4Hz，2H)，3.84(s，3H)，3.17(t，J＝8.4Hz，2H).
The following 54-64 compounds were prepared using a similar procedure as example 53:
example 54: synthesis of (4- {1- [2- (2-chloro-phenyl) -ethyl ] -1H-pyrrolo [2, 3-b ] pyridin-5-yl } -pyrimidin-2-yl) - (2-methyl-2H-pyrazol-3-yl) -amine (A54)
Figure GPA0000243696240000502
LCMS：m/z430.1(M+H)；RT＝4.59min(9min).
1H-NMR(CDCL3，400MHz)：δ8.99(d，J＝1.8Hz，1H)，8.52(d，J＝1.8Hz，1H)，8.43(d，J＝5.3Hz，1H)，7.50(d，J＝1.6Hz，1H)，7.35(d，J＝7.8Hz，1H)，7.32-7.21(m，2H)，7.15(t，J＝7.0Hz，1H)，7.06(t，J＝7.2Hz，1H)，6.99-6.84(m，3H)，6.41(dd，J＝22.0，2.4Hz，2H)，4.58(t，J＝7.0Hz，2H)，3.82(s，3H)，3.30(t，J＝7.0Hz，2H).
Example 55: synthesis of 2- (2-chloro-4-fluoro-phenyl) -N- { 2-cyano-4- (2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -phenyl } -acetamide (A55)
Figure GPA0000243696240000503
LCMS：m/z462.0(M+H)；RT＝4.01min(9min).
1H-NMR(DMSO，400MHz)：δ10.59(s，1H)，9.51(s，1H)，8.51(dd，J＝9.8，3.5Hz，2H)，8.36(dd，J＝8.7，1.8Hz，1H)，7.80(d，J＝8.7Hz，1H)，7.58-7.37(m，3H)，7.34(d，J＝1.8Hz，1H)，7.26-7.13(m，1H)，6.25(d，J＝1.5Hz，1H)，3.92(s，2H)，3.66(s，3H).
Example 56: synthesis of 2- (2-fluoro-phenyl) -N- { 2-cyano-4- (2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -phenyl } -acetamide (A56)
Figure GPA0000243696240000511
LCMS：m/z428.1(M+H)；RT＝3.75min(9min).
1H-NMR(DMSO，400MHz)：δ10.57(s，1H)，9.51(s，1H)，8.63-8.44(m，2H)，8.37(d，J＝8.5Hz，1H)，7.81(d，J＝8.8Hz，1H)，7.51(d，J＝5.1Hz，1H)，7.46-7.23(m，3H)，7.23-7.05(m，2H)，6.25(s，1H)，3.84(s，2H)，3.66(s，3H).
Example 57: synthesis of 1- {5- [ 5-chloro-2- (2-methyl-2H-pyrazol-3-ylamine) -pyridin-4-yl ] -2, 3-dihydropyrrolo [2, 3-b ] pyridin-1-yl } -2- (2-chloro-pyridin-3-yl) -ethanone (A57)
Figure GPA0000243696240000512
LCMS：m/z480.1，482.1(M+H)；RT＝4.11min(9min).
1H NMR(400MHz，dmso)：δ8.35-8.24(m，2H)，8.19-8.03(m，2H)，7.90-7.80(m，2H)，7.63(d，J＝2.3Hz，1H)，7.39(dd，J＝7.3，4.8Hz，1H)，7.28(d，J＝1.2Hz，1H)，5.95(s，1H)，4.59(s，2H)，4.06(t，J＝8.4Hz，2H)，3.55(s，3H)，3.12(t，J＝8.3Hz，2H).
Example 58: synthesis of 2- (2-chloro-phenyl) -N- { 2-cyano-4- [ 5-fluoro-2- (2-methyl-2H-pyrazol-3-ylamine) -pyrimidin-4-yl ] -phenyl } -acetamide (A58)
Figure GPA0000243696240000513
LCMS：m/z462.1(M+H)；RT＝4.18min(9min).
1H NMR(400MHz，dmso)：δ10.64(s，1H)，9.61(s，1H)，8.63(d，J＝3.3Hz，1H)，8.31(s，1H)，8.23(d，J＝9.8Hz，1H)，7.86(d，J＝8.8Hz，1H)，7.55-7.38(m，2H)，7.37-7.21(m，3H)，6.24(d，J＝1.5Hz，1H)，3.94(s，2H)，3.66(s，3H).
Example 59: synthesis of 2- (2-chloro-3-fluoro-phenyl) -N- { 2-cyano-4- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -phenyl } acetamide (A59)
Figure GPA0000243696240000514
LCMS：m/z462.1(M+H)；RT＝3.98min(9min).
1H-NMR(DMSO-d6，400MHz)：10.64(s，1H)，9.50(s，1H)，8.52(dd，J＝4.0Hz，2H)，8.37(d，J＝8.0Hz，1H)，7.81(d，J＝8.0Hz，1H)，7.51(d，J＝8.0Hz，1H)，7.34-7.32(m，4H)，6.25(s，1H)，4.00(s，2H)，3.67(s，3H).
Example 60: synthesis of 1- {5- [ 5-chloro-2- (2-chloro-4-fluoro-phenylamino) -pyridin-4-yl ] -2, 3-dihydropyrrolo [2, 3-b ] pyridin-1-yl } -2- (2-chloro-phenyl) -ethanone (A60)
Figure GPA0000243696240000521
LCMS：m/z527.9(M+H)；RT＝6.16min(9min).
1H NMR(400MHz，dmso)：δ8.71(s，1H)，8.20(d，J＝18.5Hz，2H)，7.91-7.74(m，2H)，7.44(ddd，J＝9.2，7.1，3.3Hz，2H)，7.36(dd，J＝5.6，3.7Hz，1H)，7.27(dd，J＝5.7，3.5Hz，2H)，7.22-7.14(m，1H)，6.94(s，1H)，4.56(s，2H)，4.05(t，J＝8.4Hz，2H)，3.13(t，J＝8.4Hz，2H).
Example 61: synthesis of 1- {5- [2- (2-chloro-4-fluoro-phenylamino) -pyrimidin-4-yl ] -2, 3-dihydropyrrolo [2, 3-b ] pyridin-1-yl } -2- (2-chloro-phenyl) -ethanone (A61)
Figure GPA0000243696240000522
LCMS：m/z494.1，496.1(M+H)；RT＝7.46min(9min).
1H NMR(400MHz，CDCL3)：δ8.81(s，1H)，8.58-8.39(m，2H)，8.16(s，1H)，7.48(s，1H)，7.39(dd，J＝6.0，3.1Hz，1H)，7.33-7.25(m，1H)，7.18(ddd，J＝16.5，8.4，4.8Hz，4H)，7.06(dd，J＝11.5，5.5Hz，1H)，4.66(s，2H)，4.22(t，J＝8.6Hz，2H)，3.18(t，J＝8.5Hz，2H).
Example 62: synthesis of N- (2-cyano-4- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) phenyl) -2- (pyridin-3-yl) acetamide Compound (A62)
Figure GPA0000243696240000523
LCMS：m/z411.2(M+H)；RT＝2.22min(9min).
1H NMR(dmso，400MHz)δ10.61(s，1H)，9.50(s，1H)，8.57-8.42(m，4H)，8.36(d，J＝8.7Hz，1H)，7.82-7.71(m，2H)，7.50(d，J＝5.2Hz，1H)，7.39-7.29(m，2H)，6.25(s，1H)，3.81(s，2H)，3.66(s，3H).
Example 63: synthesis of 2- (2-chlorophenyl) -N- (2-cyano-4- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) phenyl) acetamide Compound (A63
Figure GPA0000243696240000524
LCMS：m/z443.1(M+H)；RT＝3.02min(9min).
1H NMR(dmso，400MHz)δ10.57(s，1H)，9.16(s，1H)，8.22-8.12(m，2H)，7.99(dd，J＝8.6，2.0Hz，1H)，7.77(d，J＝8.6Hz，1H)，7.49-7.40(m，2H)，7.38(d，J＝1.7Hz，1H)，7.33-7.24(m，2H)，7.19(d，J＝5.0Hz，1H)，7.08(s，1H)，6.30(d，J＝1.8Hz，1H)，3.92(s，2H)，3.67(s，3H).
Example 64: synthesis of N- {4- [ 5-chloro-2- (2-methyl-2H-pyrazol-3-ylamine) -pyridin-4-yl ] -2-cyano-phenyl } -2- (2-chloro-phenyl) -acetamide (A64)
Figure GPA0000243696240000531
LCMS：m/z477(M+H)；RT＝4.50min(9min).
1H-NMR(CD3OD，400MHz)：8.06(s，1H)，7.92(s，1H)，7.83(d，J＝8.0Hz，1H)，7.60(d，J＝8.0Hz，1H)，7.46(dd，J＝4.0Hz，1H)，7.43-7.40(m，3H)，7.29(d，J＝8.0Hz，2H)，6.11(s，1H)，3.97(s，2H)，3.66(s，3H)
Example 65: 5-bromo-2, 3-dihydro-1H-indole-7-carbonitrile (39)
Figure GPA0000243696240000532
In a dry 100mL round bottom flask was added sequentially 7-cyanoindoline compound 38(600mg, 4.161mmol), DCM (10mL) at room temperature and NBS (756mg, 4.244mmol) slowly at low temperature zero. The mixture was heated to 25 ℃ with stirring and reacted for 1 hour. After completion of the reaction by TLC plate, it was filtered, extracted with DCM (20mL) and the organic phases were combined. Saturated aqueous sodium bicarbonate (10mL × 2) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 5-bromo-2, 3-dihydro-1H-indole-7-carbonitrile 39(900mg, brown solid), yield: 96.9 percent
LCMS：m/z223.0，225.0(M+H)；RT＝4.96min(9min)。
Synthesis of 5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -2, 3-dihydro-1H-indole-7-carbonitrile (40)
Figure GPA0000243696240000533
The compound 5-bromo-2, 3-dihydro-1H-indole-7-carbonitrile 39(700mg, 3.14mmol), pinacol diboron (1595mg, 6.28mmol), Pd (dppf) Cl, was added sequentially at room temperature in a dry 50mL single-necked flask2(230mg, 0.314mmol), potassium acetate (617mg, 6.28mmol) and 1, 4-dioxane (16mL), with nitrogen being replaced 3 times. The mixture was stirred and heated to 110 ℃ to react for 3 hours. After LCMS detection reaction is finished, filtering is carried out, filtrate is decompressed and concentrated, and the obtained residue is purified by comilash (EA/PE is 10% -30%) to obtain the product, namely the product 5- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -2, 3-dihydro-1H-indole-7-carbonitrile 3(700mg, yellow solid), yield: 82.5% and purity about 90%。
LCMS：m/z271.2(M+H)；RT＝4.86min(9min).
4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (42)
Figure GPA0000243696240000534
1-methyl-1H-pyrazol-5-amine (600mg, 4.67mmol) and THF (2mL) are added sequentially in a dry 50mL single-neck flask at room temperature, the temperature is reduced to-78 ℃, LiHDMS (11.7mL, 11.7mmol) is slowly added dropwise, and the mixture is stirred for 30 min. 4-chloro-2- (methylsulfonyl) pyrimidine (1.17g, 6.07mmol) was dissolved in 13mL THF and added dropwise to the reaction mixture, which was stirred at-78 deg.C for 30min and then at room temperature for 30 min. After completion of the LCMS detection reaction, 20mL of water was added to quench and extracted with EA, and after concentration under reduced pressure, the crude product was purified with combiflash (EA/PE 0% -50%) to give the product 4-chloro-N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine (42) (740mg, yellow solid).
5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl]Synthesis of (41) 2, 3-dihydro-1H-indole-7-carbonitrile
Figure GPA0000243696240000541
In a dry 50mL round bottom flask, 5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] was added sequentially at room temperature]Bioxaborolan-2-yl) -2, 3-dihydro-1H-indole-7-carbonitrile 40(300mg, 1.11mmol), 1, 4-dioxane (5mL) and water (1mL), Compound 42(240mg, 0.89mmol), Pd (dppf) Cl2(81mg, 0.111mmol), potassium carbonate (184mg, 1.33mmol), and nitrogen substitution 3 times. The temperature was raised to 100 ℃ and stirred for 1 hour. After the reaction is complete, filtration is carried out, the filtrate is concentrated under reduced pressure and the residue obtained is purified by column chromatography on silica gel with the eluent system (ethyl acetate to DCM: MeOH ═ 20: 1) to give 5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl]-2, 3-dihydro-1H-indole-7-carbonitrile 41(308mg, light yellow solid), yield: 87.5 percent.
LCMS：m/z 318.2(M+H)；RT＝3.26min(9min).
Synthesis of 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A65)
Figure GPA0000243696240000542
In a dry 50mL round bottom flask 5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile 41(250mg, 0.788mmol), DMF (6mL), 2-chloropyridine-3-acetic acid (162mg, 0.945mmol), EDCI (454mg, 2.364mmol), HOBt (319mg, 2.364mmol), triethylamine (399mg, 3.94mmol), nitrogen substitution 3 times were added in this order at room temperature. Heating to 35 ℃, and stirring for 24-48 hours. After completion of the reaction, filtration was performed, extraction was performed with EA (40mL × 2), and the organic phases were combined. Saturated aqueous sodium chloride (10mL) was washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography with an eluent system (ethyl acetate to DCM: MeOH ═ 20: 1) and purified by preparative chromatography to give the product 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile a65(39mg, light yellow solid) in yield: 10.5 percent.
LCMS：m/z471.2(M+H)；RT＝3.36min(9min).
1H NMR(400MHz，dmso)：δ9.47(s，1H)，8.47(d，J＝5.2Hz，1H)，8.37-8.19(m，3H)，7.82(d，J＝6.1Hz，1H)，7.49-7.37(m，2H)，7.32(s，1H)，6.22(s，1H)，4.31(t，J＝8.1Hz，2H)，4.09(s，2H)，3.63(s，3H)，3.23(t，J＝7.7Hz，2H).
Example 66: synthesis of 1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A66)
Figure GPA0000243696240000551
In a dry 50mL round bottom flask, 5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile 41(100mg, 0.315mmol), DMF (4mL), compound 43(119mg, 0.63mmol) (see GE053 for the synthesis of this compound), DIPEA (163mg, 1.26mmol) was added in succession under nitrogen 3 times at room temperature. The temperature was raised to 30 ℃ and stirred for 18 hours. EA (50mL × 2), washed with saturated brine (10mL), dried, filtered, the filtrate concentrated under reduced pressure and the resulting residue purified by silica gel column chromatography with an eluent system (ethyl acetate to DCM: MeOH ═ 20: 1) to give the crude product which, after purification on a preparative column, gave the product 1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile a66(49mg, light yellow solid) in yield: 33.1 percent.
LCMS：m/z470.2，472.2(M+H)；RT＝4.10min(9min).
1H NMR(400MHz，dmso)：δ9.46(s，1H)，8.47(d，J＝5.2Hz，1H)，8.25(d，J＝4.8Hz，2H)，7.52-7.39(m，2H)，7.42-7.18(m，4H)，6.22(d，J＝1.7Hz，1H)，4.29(t，J＝8.2Hz，2H)，4.05(s，2H)，3.64(s，3H)，3.22(t，J＝8.1Hz，2H).
The following 67-69 compounds were prepared using a similar procedure to that used in example 66:
example 67: synthesis of 1- [2- (2-chloro-4-fluoro-phenyl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamine) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A67)
Figure GPA0000243696240000552
LCMS：m/z488.2(M+H)；RT＝4.18min(9min).
1H NMR(400MHz，dmso)：δ9.49(s，1H)，8.50(d，J＝5.3Hz，1H)，8.28(d，J＝4.5Hz，2H)，7.54-7.40(m，3H)，7.35(d，J＝1.8Hz，1H)，7.25-7.17(m，1H)，6.25(d，J＝1.7Hz，1H)，4.32(t，J＝8.2Hz，2H)，4.07(s，2H)，3.67(s，3H)，3.25(t，J＝8.2Hz，2H).
Example 68: synthesis of 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (tetrahydro-pyran-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A68)
Figure GPA0000243696240000553
LCMS：m/z475.2(M+H)；RT＝3.31min(9min).
1H-NMR(DMSO-d6，400MHz)：8.34(d，J＝4.0Hz，2H)，8.28(d，J＝4.0Hz，2H)，7.86(d，J＝4.0Hz，1H)，7.44(br，1H)，7.41(d，J＝4.0Hz，1H)，7.25(s，1H)，4.35-4.32(m，2H)，4.12(s，2H)，4.01-3.97(m，1H)，3.87-3.83(m，2H)，3.38(t，2H)，3.25(t，2H)，1.85-1.82(m，2H)，1.52-1.50(m，2H).
Example 69: synthesis of 2- (2-chlorophenyl) -N- (2-cyano-4- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) phenyl) acetamide Compound (A69)
Figure GPA0000243696240000561
LCMS：m/z448.2(M+H)；RT＝4.05min(9min).
1H NMR(dmso，400MHz)1H NMR(400MHz，dmso)δ10.57(s，1H)，8.50(d，J＝2.0Hz，1H)，8.37(d，J＝5.4Hz，2H)，7.80(d，J＝8.7Hz，1H)，7.54-7.35(m，3H)，7.34-7.18(m，3H)，4.00(s，1H)，3.93(s，2H)，3.85(d，J＝11.0Hz，2H)，3.38(s，2H)，1.83(d，J＝11.4Hz，2H)，1.58-1.43(m，2H).
Example 70: synthesis of 4-bromo-2-fluoro-6-iodo-aniline Compound (45)
Figure GPA0000243696240000562
In a dry 100mL single-neck flask, compound 44(3000mg, 15.79mmol), Ag was added sequentially at room temperature2SO4(5.4g，17.32mmol)，I2(4.4g, 17.32mmol) and EtOH (100mL) and stirred at room temperature for 6 hours. After completion of the reaction by LCMS, it was filtered and concentrated under reduced pressure, and ethyl acetate (200mL) was added thereto, followed by saturation with sodium thiosulfate (50 mL. times.3)) Saturated sodium carbonate solution (50mL × 2) and water (50mL) were washed, the organic phase was dried over anhydrous sodium sulfate, the filtrate was filtered, concentrated under reduced pressure, and the resulting residue was purified with comiflash (EA/PE ═ 0% to 100%) to give the product which was purified with comiflash (EA/PE ═ 0% to 4%) to give the product 4-bromo-2-fluoro-6-iodo-aniline 45(3.8g, violet solid) in yield: 76 percent.
LCMS：m/z315.9(M+H)；RT＝4.86min(9min).
Synthesis of 2-amino-5-bromo-3-fluoro-benzonitrile Compound (46)
Figure GPA0000243696240000563
In a dry 50mL single neck flask, compound 45(1500mg, 4.75mmol), ZnCN was added sequentially at room temperature2(279mg，2.37mmol)，Pd2(dpa)3(435mg, 0.475mmol), dppf (263mg, 0.475mmol) and DMF (15mL), H2O (0.15mL) was purged with nitrogen 3 times. The reaction was heated to 110 ℃ and allowed to react for 1 hour. After completion of the LCMS detection reaction, filtration and concentration of the filtrate under reduced pressure, the resulting residue was purified with comiflash (EA/PE 0% -20%) to give the product which was purified with comiflash (EA/PE 0% -4%) to give the product 2-amino-5-bromo-3-fluoro-benzonitrile 46(700mg, yellow solid) in yield: 68 percent of
LCMS：m/z215(M+H)；RT＝3.90min(9min).
Synthesis of N- (4-bromo-2-amino-6-fluoro-phenyl) -2- (2-chlorophenyl) -acetamide Compound (47)
Figure GPA0000243696240000564
In a dry 50mL single-necked flask, compound 46(270mg, 1.26mmol), 43(1429mg, 7.56mmol), pyridine (993mg, 12.6mmol) and DMF (5mL) were added in this order at room temperature and reacted at room temperature for 3 hours. After completion of the reaction by LCMS, the reaction was quenched by addition of water (30ML), extracted with EA (30ML × 2), the organic phases were combined, washed with saturated brine (30ML), and after concentration of the organic phase under reduced pressure, the resulting residue was purified with comiwash (MeOH/0.5% aqueous TFA ═ 10% to 80%) to give the product N- (4-bromo-2-amino-6-fluoro-phenyl) -2- (2-chlorophenyl) -acetamide 47(165mg, white solid) in yield: 36 percent
LCMS：m/z367(M+H)；RT＝4.33min(9min).
Synthesis of 2- (2-chloro-phenyl) -N- [ 2-cyano-6-fluoro-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaboron-2-yl) -phenyl ] acetamide Compound (48)
Figure GPA0000243696240000571
In a dry 50mL single-neck flask, compound 47(134mg, 0.365mmol), pinacol diboron (278mg, 1.094mmol), Pd (dppf) Cl were added in succession at room temperature2(40mg, 0.0548mmol), potassium acetate (107mg, 1.094mmol) and 1, 4-dioxane (8mL), and nitrogen was purged 3 times. The mixture was heated to 115 ℃ with stirring and reacted for 5 hours. After LCMS detection, filtration and concentration of the filtrate under reduced pressure purified with comiflash (EA/PE 0% to 80%) to give the product 2- (2-chloro-phenyl) -N- [ 2-cyano-6-fluoro-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxyboropent-2-yl) -phenyl]Acetamide 48(45mg, yellow solid), yield: 30 percent of
LCMS：m/z 333.1(M+H)；RT＝3.39min(9min).
Synthesis of 2- (2-chloro-phenyl) -N- { 2-cyano-6-fluoro-4- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -phenyl } acetamide Compound (A70)
Figure GPA0000243696240000572
48(15mg, 0.109mmol), 42(28mg, 0.134mmol), Pd (dppf) were added successively at room temperature to a dry 50mL microwave tube2Cl2(8mg, 0.0109mmol), sodium hydrogencarbonate (18mg, 0.218mmol), 1, 4-dioxane (2mL) and water (0.5mL), and nitrogen gas was purged 3 times. The reaction was heated to 80 ℃ for 1 hour. After the LCMS detection reaction is finished, the reaction solution is filtered, the filtrate is decompressed and concentrated, and the obtained residue is purified by prep-HPLC to obtain the product 2- (2-chloro-phenyl) -N- { 2-cyano-6-fluoro-4-, [2- (2-chloro-phenyl) -N- { 2-cyano-6-fluoro-4 ], [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl]-phenyl } acetamide a70(38mg, yellow solid), yield: 76 percent of
LCMS：m/z462.2(M+H)；RT＝3.84min(9min).
1H NMR(dmso，400MHz)δ10.67(s，1H)，9.59(s，1H)，8.58(d，J＝5.2Hz，1H)，8.42(s，1H)，8.30(d，J＝10.8Hz，1H)，7.58(d，J＝5.2Hz，1H)，7.48-7.40(m，2H)，7.36(d，J＝1.7Hz，1H)，7.32-7.26(m，2H)，6.26(d，J＝1.5Hz，1H)，3.92(s，2H)，3.67(s，3H).
Example 71: synthesis of 2- (2-chlorophenyl) -N- (2-cyano-5-fluoro-4- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) phenyl) acetamide Compound (A71)
Figure GPA0000243696240000573
Prepared in a similar manner to example 70.
LCMS：m/z 462.2(M+H)；RT＝4.24min(9min).
1H NMR(dmso，400MHz)1H NMR(400MHz，dmso)δ10.72(s，1H)，9.58(s，1H)，8.54(d，J＝5.2Hz，1H)，8.39(d，J＝8.2Hz，1H)，7.80(d，J＝13.3Hz，1H)，7.48-7.38(m，2H)，7.34(d，J＝1.8Hz，1H)，7.32-7.27(m，2H)，7.25(dd，J＝5.1，1.8Hz，1H)，6.25(d，J＝1.7Hz，1H)，3.97(s，2H)，3.66(s，3H).
Example 72: synthesis of 1- [2- (2-chlorophenyl) -ethyl ] -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole-7-carbonitrile (50)
Figure GPA0000243696240000581
5-bromo-1- [2- (2-chlorophenyl) -ethyl ] was added sequentially at room temperature in a dry 10mL microwave tube]-1H-indole-7-carbonitrile (49) (147mg, 0.41mmol), bis (pinacolato) diboron (208mg, 0.82mmol), Pd (dppf) Cl2(10mg, cat.), potassium acetate (80mg, 0.82mmol) and 1, 4-Dioxane (2mL) was replaced with nitrogen 3 times. The reaction is carried out for 2 hours by microwave heating to 120 ℃. After completion of the reaction by LCMS, the catalyst was removed by filtration, 20mL of water was added, extracted with ethyl acetate (30 mL. times.3), and the organic phases were combined. The residue was purified by silica gel column chromatography using an eluent system (ethyl acetate: petroleum ether ═ 3: 2) to give the product 1- [2- (2-chlorophenyl) -ethyl ] -ethyl]-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole-7-carbonitrile (50) (128mg, light yellow solid), yield: 76.6 percent.
LCMS：m/z408(M+H)；RT＝6.14min(9min).
Synthesis of 1- [2- (2-chloro-phenyl) -ethyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -1H-indole-7-carbonitrile (A72)
Figure GPA0000243696240000582
1- [2- (2-chlorophenyl) -ethyl ] was added successively at room temperature to a dry 10mL microwave tube]-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole-7-carbonitrile (50) (128mg, 0.31mmol), 2- (4-chloropyrimidine) -3- (2-methyl-2H-pyrazole) amine GE001-04(66mg, 0.31mmol), Pd (dppf) Cl2(10mg, cat.), potassium carbonate (85mg, 0.62mmol), 1, 4-dioxane (2mL) and water (0.5mL), and nitrogen was purged 3 times. The reaction is carried out for 1 hour by microwave heating to 100 ℃. After completion of the reaction by LCMS, the catalyst was removed by filtration, 20mL of water was added, extracted with ethyl acetate (30 mL. times.3), and the organic phases were combined. Saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the resulting residue purified by silica gel column chromatography with eluent system (100% ethyl acetate) and then by prep-HPLC with eluent (acetonitrile/water containing 0.5% trifluoroacetic acid ═ 50%) to give the product 1- [2- (2-chloro-phenyl) -ethyl ] -ethyl ester]-5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl]-1H-indole-7-carbonitrile (a72) (29mg, pale solid), yield: 20.7 percent.
LCMS：m/z455(M+H)；RT＝4.658min(9min).
1H-NMR(DMSO-d6，400MHz)：9.51(s，1H)，8.88(s，1H)，8.62(s，1H)，8.52(d，J＝4Hz，1H)，8.44(s，1H)，7.57(d，J＝8.0Hz，1H)，7.37-7.35(m，2H)，7.20-7.08(m，3H)，6.28(s，1H)，4.89(t，2H)，3.69(s，3H)，3.32(t，2H).
Compounds 73-94 were prepared using a method analogous to example 72:
example 73: synthesis of 2- (2-chlorophenyl) -N- (2-cyano-4- (2- (pyridin-4-ylamino) pyrimidin-4-yl) phenyl) acetamide (A73)
Figure GPA0000243696240000591
LCMS：m/z441.2(M+H)；RT＝2.92min(9min).
1H NMR(dmso，400MHz)1H NMR(400MHz，dmso)δ11.42(s，1H)，10.66(s，1H)，8.83(d，J＝5.3Hz，1H)，8.67-8.55(m，3H)，8.50(dd，J＝8.7，2.2Hz，1H)，8.23(d，J＝5.6Hz，2H)，7.95-7.83(m，2H)，7.50-7.39(m，2H)，7.35-7.26(m，2H)，3.96(s，2H).
Example 74: 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (pyridin-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A74)
Figure GPA0000243696240000592
LCMS：m/z468.2(M+H)；RT＝2.69min(9min).
1H NMR(400MHz，dmso)：δ11.42(s，1H)，8.81(d，J＝5.3Hz，1H)，8.60(d，J＝6.9Hz，2H)，8.37(dd，J＝21.2，5.3Hz，3H)，8.24(s，2H)，7.87(t，J＝5.7Hz，2H)，7.44(dd，J＝7.3，4.9Hz，1H)，4.38(t，J＝8.1Hz，2H)，4.14(s，2H)，3.30(t，J＝8.0Hz，2H).
Example 75: synthesis of 1- [2- (2, 5-dichlorophenyl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A75)
Figure GPA0000243696240000593
LCMS：m/z504.2(M+H)；RT＝4.399min(9min).
1H NMR(400MHz，dmso)：δ9.50(s，1H)，8.50(d，J＝5.2Hz，1H)，8.28(d，J＝4.5Hz，2H)，7.67-7.44(m，3H)，7.44-7.26(m，2H)，6.26(d，J＝1.7Hz，1H)，4.33(t，J＝8.2Hz，2H)，4.10(s，2H)，3.67(s，3H)，3.26(t，J＝8.1Hz，2H).
Example 76: synthesis of 1- [2- (2-methoxy-phenyl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A76)
Figure GPA0000243696240000594
LCMS：m/z466.3(M+H)；RT＝3.96min(9min).
1H NMR(400MHz，dmso)：δ9.50(s，1H)，8.49(d，J＝5.2Hz，1H)，8.26(d，J＝10.8Hz，2H)，7.49(d，J＝5.3Hz，1H)，7.36(d，J＝1.7Hz，1H)，7.29-7.13(m，2H)，6.98(d，J＝8.2Hz，1H)，6.90(t，J＝7.4Hz，1H)，6.25(s，1H)，4.23(t，J＝8.2Hz，2H)，3.85(s，2H)，3.74(s，3H)，3.67(s，3H)，3.20(t，J＝8.1Hz，2H).
Example 77: 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-methyl-pyridin-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A77)
Figure GPA0000243696240000601
LCMS：m/z482.2(M+H)；RT＝2.81min(9min).
1H NMR(400MHz，dmso)：δ11.31(s，1H)，8.80(d，J＝5.4Hz，1H)，8.39(ddd，J＝16.0，6.5，4.4Hz，4H)，8.16(s，1H)，7.98(s，1H)，7.86(d，J＝5.5Hz，2H)，7.44(dd，J＝7.5，4.8Hz，1H)，4.38(t，J＝8.2Hz，2H)，4.14(s，2H)，3.28(t，J＝8.1Hz，2H)，2.60(s，3H).
Example 78: synthesis of 1- (2- (2, 3-dichlorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indole-7-carbonitrile Compound (A78)
Figure GPA0000243696240000602
LCMS：m/z504.1(M+H)；RT＝4.43min(9min).
1H NMR(dmso，400MHz)1H NMR(400MHz，dmso)δ9.48(s，1H)，8.50(d，J＝5.2Hz，1H)，8.28(d，J＝4.0Hz，2H)，7.58(dd，J＝7.8，1.6Hz，1H)，7.49(d，J＝5.3Hz，1H)，7.42-7.31(m，3H)，6.24(d，J＝1.6Hz，1H)，4.33(t，J＝8.2Hz，2H)，4.16(s，2H)，3.66(s，3H)，3.25(t，J＝8.1Hz，2H).
Example 79: synthesis of 1- (2- (2-chloro-5-fluorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indole-7-carbonitrile Compound (A79)
Figure GPA0000243696240000603
LCMS：m/z488.1(M+H)；RT＝4.23min(9min).
1H NMR(dmso，400MHz)1H NMR(400MHz，dmso)δ9.49(s，1H)，8.50(d，J＝5.3Hz，1H)，8.28(d，J＝4.8Hz，2H)，7.55-7.45(m，2H)，7.39-7.27(m，2H)，7.25-7.15(m，1H)，6.25(d，J＝1.7Hz，1H)，4.32(t，J＝8.2Hz，2H)，4.09(s，2H)，3.67(s，3H)，3.25(t，J＝8.0Hz，2H).
Example 80: synthesis of 5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -1- (2-pyrazol-1-yl-acetyl) -2, 3-dihydro-1H-indole-7-carbonitrile (A80)
Figure GPA0000243696240000604
LCMS：m/z426.2(M+H)；RT＝2.98min(9min).
1H NMR(400MHz，dmso)：δ9.51(s，1H)，8.51(d，J＝3.4Hz，1H)，8.29(d，J＝6.5Hz，2H)，7.70(s，1H)，7.59-7.39(m，2H)，7.35(s，1H)，6.39-6.14(m，2H)，5.37(s，2H)，4.24(d，J＝7.9Hz，2H)，3.67(d，J＝2.3Hz，3H)，3.25(t，J＝7.8Hz，2H).
Example 81: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (4-chloro-3-fluorophenyl) acetyl) indoline-7-carbonitrile (A81)
Figure GPA0000243696240000611
LCMS：m/z488(M+H)；RT＝4.24min(8min).
1H-NMR(DMSO，400MHz)δ9.48(s，1H)，8.50(d，J＝5.2Hz，1H)，8.27(d，J＝9.5Hz，2H)，7.63-7.42(m，2H)，7.42-7.24(m，2H)，7.16(d，J＝8.2Hz，1H)，6.24(s，1H)，4.27(t，J＝8.2Hz，2H)，4.02(s，2H)，3.66(s，3H)，3.22(t，J＝8.0Hz，2H).
Example 82: synthesis of 1- (2- (2-chlorophenyl) acetyl) -5- (2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) indole-7-carbonitrile Compound (A82)
Figure GPA0000243696240000612
LCMS：m/z474.1(M+H)；RT＝4.48min(9min).
1H NMR(dmso，400MHz)δ8.39(d，J＝5.4Hz，1H)，8.31(s，2H)，7.57(s，1H)，7.52-7.46(m，1H)，7.45-7.39(m，1H)，7.37-7.31(m，2H)，7.28(d，J＝5.3Hz，1H)，4.35(t，J＝8.2Hz，2H)，4.11(s，2H)，3.89(d，J＝11.3Hz，2H)，3.41(s，2H)，3.27(t，J＝8.1Hz，2H)，1.86(d，J＝11.5Hz，2H)，1.64-1.42(m，2H).
Example 83: 5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1- (2- (pyridin-3-yl) acetyl) indoline-7-carbonitrile
Figure GPA0000243696240000613
LCMS：m/z 474.1(M+H)；m/z437.2(M+H)；RT＝2.36min(10min).
1H NMR(dmso，400MHz)δ9.53(s，1H)，8.78(d，J＝4.3Hz，2H)，8.55(d，J＝5.3Hz，1H)，8.31(d，J＝16.0Hz，2H)，8.28(d，J＝7.9Hz，1H)，7.89(dd，J＝7.9，5.6Hz，1H)，7.54(d，J＝5.3Hz，1H)，7.39(d，J＝1.9Hz，1H)，6.29(d，J＝1.8Hz，1H)，4.37(d，J＝8.3Hz，2H)，4.25(s，2H)，3.71(s，3H)，3.31(t，J＝8.2Hz，2H).
Example 84: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2- (nitrile) phenyl) acetyl) indoline-7-carbonitrile (A84)
Figure GPA0000243696240000614
In a dry 100mL round-bottomed flask, compound 51(151.9mg, 0.943mmol), acetic anhydride (96.5mg, 0.945mml), DMF (1mL), N were added sequentially at room temperature2Protected and stirred for 2 hours at 30 ℃. Compound 41(100mg, 0.315mmol), N-morpholine (103mg, 1.018mmol), and DMF (4ml) were added. The reaction mixture was purged with nitrogen 3 times, and stirred at room temperature for 24 hours. After the LC/MS detection reaction was completed, the product 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2- (nitrile) phenyl) acetyl) indoline-7-carbonitrile a84(54mg, pale yellow solid) was obtained by preparative separation and purification, yield Y: 12 percent.
LCMS：m/z472(M+H)；RT＝3.36min(8min)
1H-NMR(DMSO，400MHz)：δ9.48(s，1H)，8.50(d，J＝5.2Hz，1H)，8.27(d，J＝13.8Hz，2H)，7.42(ddd，J＝27.5，26.0，3.5Hz，3H)，6.99(d，J＝5.0Hz，2H)，6.25(d，J＝1.7Hz，1H)，4.27(t，J＝8.2Hz，2H)，4.21(s，2H)，3.67(s，3H)，3.21(t，J＝8.0Hz，2H)。
Example 85: synthesis of 1- (2- (2-chloropyridin-3-yl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile Compound (A85)
Figure GPA0000243696240000621
LCMS：m/z471.1(M+H)；RT＝3.52min(9min).
1H NMR(dmso，400MHz)1H NMR(400MHz，dmso)δ9.54(s，1H)，8.46(d，J＝5.1Hz，1H)，8.40-8.25(m，3H)，7.94-7.81(m，2H)，7.52(s，1H)，7.47-7.39(m，1H)，7.34(d，J＝5.3Hz，1H)，4.35(t，J＝8.2Hz，2H)，4.12(s，2H)，3.79(s，3H)，3.28(t，J＝8.2Hz，2H).
Example 86: synthesis of 1- (2- (2-bromophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indole-7-carbonitrile Compound (A86)
Figure GPA0000243696240000622
LCMS：m/z514.1(M+H)；RT＝4.25min(9min).
1H NMR(dmso，400MHz)1H NMR(400MHz，dmso)δ9.45(s，1H)，8.46(d，J＝5.2Hz，1H)，8.23(d，J＝5.5Hz，2H)，7.58(d，J＝8.0Hz，1H)，7.45(d，J＝5.3Hz，1H)，7.39-7.26(m，3H)，7.23-7.13(m，1H)，6.22(d，J＝1.8Hz，1H)，4.28(t，J＝8.2Hz，2H)，4.03(s，2H)，3.63(s，3H)，3.21(t，J＝8.0Hz，2H).
Example 87: synthesis of 1- [3- (2-chloro-phenyl) -propionyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamine) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A87)
Figure GPA0000243696240000623
LCMS：m/z484.2(M+H)；RT＝4.65min(9min).
1H NMR(400MHz，dmso)：δ8.61(d，J＝5.5Hz，1H)，8.03(s，1H)，7.89(d，J＝1.3Hz，1H)，7.77(d，J＝5.5Hz，1H)，7.45-7.33(m，3H)，7.30-7.05(m，3H)，6.15(d，J＝2.0Hz，1H)，3.65(t，J＝8.7Hz，2H)，3.56(s，3H)，3.13-2.97(m，6H).
Example 88: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (thiophen-2-yl) acetyl) indoline-7-carbonitrile (A88)
Figure GPA0000243696240000631
LCMS：m/z442(M+H)；RT＝3.878min(8min).
1H-NMR(DMSO，400MHz)：δ9.48(s，1H)，8.50(d，J＝5.2Hz，1H)，8.27(d，J＝13.8Hz，2H)，7.42(ddd，J＝27.5，26.0，3.5Hz，3H)，7.04-6.92(m，2H)，6.25(d，J＝1.7Hz，1H)，4.27(t，J＝8.2Hz，2H)，4.21(s，2H)，3.67(s，3H)，3.21(t，J＝8.0Hz，2H)
Example 89: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2, 3-fluorophenyl) acetyl) indoline-7-carbonitrile) (A89)
Figure GPA0000243696240000632
LCMS：m/z472(M+H)；RT＝4.468min(8min).
1H-NMR(DMSO，400MHz)：δ9.48(s，1H)，8.49(d，J＝5.3Hz，1H)，8.27(d，J＝5.1Hz，2H)，7.48(d，J＝5.3Hz，1H)，7.34(d，J＝1.9Hz，2H)，7.20-7.12(m，2H)，6.24(d，J＝1.8Hz，1H)，4.31(s，2H)，4.09(s，2H)，3.66(s，3H)，3.24(s，2H)，
Example 90: synthesis of 1- (2, 2-difluoro-2-phenyl-acetyl) -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A90)
Figure GPA0000243696240000633
LCMS：m/z472.2(M+H)；RT＝4.25min(9min).
1H NMR(400MHz，dmso)：δ9.51(s，1H)，8.52(d，J＝5.2Hz，1H)，8.35(d，J＝25.2Hz，2H)，7.76-7.53(m，5H)，7.51(d，J＝5.2Hz，1H)，7.34(d，J＝1.9Hz，1H)，6.25(d，J＝1.8Hz，1H)，4.15(t，J＝7.8Hz，2H)，3.66(s，3H)，3.14(t，J＝7.9Hz，2H).
Example 91: synthesis of 5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -1- (2-phenyl-propionyl) -2, 3-dihydro-1H-indole-7-carbonitrile (A91)
Figure GPA0000243696240000634
LCMS：m/z450.2(M+H)；RT＝4.31min(9min).
1H NMR(400MHz，dmso)δ8.60(d，J＝5.5Hz，1H)，7.97(s，1H)，7.79(dd，J＝10.0，3.4Hz，2H)，7.39(d，J＝1.9Hz，1H)，7.26-7.13(m，3H)，7.05-6.96(m，2H)，6.16(d，J＝1.9Hz，1H)，4.42(d，J＝6.9Hz，1H)，3.65(t，J＝8.8Hz，2H)，3.32(s，3H)，3.05(t，J＝8.6Hz，2H)，1.40(d，J＝6.9Hz，3H).
Example 92: synthesis of 1- [2- (3-chloro-pyridin-4-yl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A92)
Figure GPA0000243696240000641
LCMS：m/z471.1(M+H)；RT＝3.47min(9min).
1H NMR(400MHz，dmso)δ9.46(s，1H)，8.62(s，1H)，8.49(dd，J＝5.0，3.2Hz，2H)，8.28(d，J＝3.4Hz，2H)，7.47(dd，J＝11.6，5.1Hz，2H)，7.34(d，J＝1.8Hz，1H)，6.24(d，J＝1.8Hz，1H)，4.33(t，J＝8.2Hz，2H)，4.16(s，2H)，3.66(s，3H)，3.26(s，2H).
Example 93: 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2, 6-dimethylpyridin-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A93)
Figure GPA0000243696240000642
LCMS：m/z496.2(M+H)；RT＝2.86min(9min).
1H NMR(400MHz，dmso)：δ10.00(s，1H)，8.62(d，J＝5.2Hz，1H)，8.36(d，J＝15.1Hz，3H)，7.86(d，J＝6.2Hz，1H)，7.67-7.21(m，4H)，4.36(t，J＝8.1Hz，2H)，4.12(s，2H)，3.27(d，J＝7.8Hz，2H)，2.35(s，6H).
Example 94: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) indole-7-carbonitrile Compound (A94)
Figure GPA0000243696240000643
LCMS：m/z454.0(M+H)；RT＝4.05min(9min).
1H NMR(dmso，400MHz)δ9.51(s，1H)，8.46(d，J＝5.1Hz，1H)，8.29(s，2H)，7.86(s，1H)，7.52(s，1H)，7.42-7.26(m，3H)，7.23-7.09(m，2H)，4.31(t，J＝8.2Hz，2H)，4.02(s，2H)，3.79(s，3H)，3.26(t，J＝8.1Hz，2H).
Example 95: synthesis of 4-chloro-N- (oxetan-3-yl) pyrimidin-2-amine Compound (54)
Figure GPA0000243696240000644
In a dry 10mL single neck flask, compound 52(2.0g, 27.36mmol), 53(4.08g, 27.36mmol), TEA (3.3g, 32.83mmol) and ethanol (50mL) were added sequentially at room temperature, warmed to 50 ℃ and stirred for 16 h. After LCMS detection reaction was completed, the crude product was dissolved in 50mL of EA after concentration under reduced pressure, washed with water and saturated brine, respectively, and purified with combiflash (EA/PE 0% -80%) after concentration to give 4-chloro-N- (oxetan-3-yl) pyrimidin-2-amine 54(900mg, white solid) as a product with yield: 17.8 percent.
LCMS：m/z186.5(M+H)；RT＝2.46min(9min).
Synthesis of 5- (2- (oxetan-3-ylamino) pyrimidin-4-yl) indole-7-carbonitrile Compound (55)
Figure GPA0000243696240000651
In a dry 50mL single-neck flask 54(400mg, 2.16mmol), 40(582mg, 2.16mmol), Pd (dppf) Cl were added in succession at room temperature2(158mg, 0.216mmol), potassium carbonate (596mg, 4.31mmol), 1, 4-dioxane (6mL) and water (1.5mL), and nitrogen was purged 3 times. The reaction was heated to 100 ℃ for 3 hours. After completion of the LCMS check reaction, filtration and concentration of the filtrate under reduced pressure, the resulting residue was purified with combiflash (EA/PE 0% -100%) to give the product 5- (2- (oxetan-3-ylamino) pyrimidin-4-yl) indole-7-carbonitrile 55(155mg, yellow solid) in yield: 24.5 percent
LCMS：m/z294.1(M+H)；RT＝2.97min(9min).
Synthesis of 1- (2- (2-chloropyridin-3-yl) acetyl) -5- (2- (oxetan-3-ylamino) pyrimidin-4-yl) indoline-7-carbonitrile Compound (A95)
Figure GPA0000243696240000652
In a dry 50mL single-necked flask, compound 55(155mg, 0.528mmol), compound 56(363mg, 2.11mmol), EDCI (607mg, 3.17mmol), HOBt (428mg, 3.17mmol), TEA (534mg, 5.28mmol) and DMF (4mL) were added in this order at room temperature and stirred at 40 ℃ for 16 hours. After completion of the LCMS check reaction, purification with combiflash (MeOH/DCM 0% -5%) afforded the product 1- (2- (2-chloropyridin-3-yl) acetyl) -5- (2- (oxetan-3-ylamino) pyrimidin-4-yl) indoline-7-carbonitrile a95(20mg, yellow solid) in yield: 8 percent.
LCMS：m/z447.3(M+H)；RT＝3.39min(9min).
1H NMR(dmso，400MHz)δ8.40-8.30(m，2H)，8.27(d，J＝6.2Hz，2H)，7.98(d，J＝6.0Hz，1H)，7.85(dd，J＝7.5，1.8Hz，1H)，7.43(dd，J＝7.5，4.8Hz，1H)，7.26(d，J＝5.2Hz，1H)，4.99(s，1H)，4.77(t，J＝6.5Hz，2H)，4.52(t，J＝6.2Hz，2H)，4.34(t，J＝8.2Hz，2H)，4.12(s，2H)，3.26(s，2H).
Example 96: synthesis of 1- (2- (2-chloropyridin-3-yl) acetyl) -5- (2- ((2-chloropyridin-4-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile Compound (A96)
Figure GPA0000243696240000653
Prepared by a similar method to example 95.
LCMS：m/z502.1(M+H)；RT＝4.11min(9min).
1H NMR(dmso，400MHz)δ10.44(s，1H)，8.68(d，J＝5.3Hz，1H)，8.43-8.26(m，3H)，8.17(d，J＝5.7Hz，1H)，8.07(d，J＝1.7Hz，1H)，7.86(dd，J＝7.6，1.8Hz，1H)，7.70-7.59(m，2H)，7.43(dd，J＝7.5，4.8Hz，1H)，4.37(t，J＝8.2Hz，2H)，4.13(s，2H)，3.29(t，J＝8.1Hz，2H).
Example 97: (2-chlorophenyl) -difluoro-acetic acid ethyl ester (59)
Figure GPA0000243696240000661
1-chloro-2-iodobenzene 57(906mg, 3.8mmol) and DMF (8mL) were added sequentially to a dry 100mL round bottom flask at room temperature, copper powder (600mg, 9.44mmol) was added slowly under nitrogen protection at room temperature, 1-bromo-1, 1-difluoro-acetic acid ethyl ester 58(853mg, 4.2mmol) was added, and the reaction was stirred at 96 ℃ for 18 hours. After completion of the reaction by TLC plate detection, extraction was performed with EA (100mL) and the organic phases were combined. Saturated aqueous sodium bicarbonate (10mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product, and the resulting residue was purified by silica gel column chromatography with an eluent system (ethyl acetate/petroleum ether ═ 1/20) to give (2-chlorophenyl) -difluoro-acetic acid ethyl ester 59(650mg, colorless liquid), yield: 72.9 percent
LCMS：m/z235.2(M+H)；RT＝5.24min(8min)。
(2-chlorophenyl) -difluoro-acetic acid (60)
Figure GPA0000243696240000662
In a dry 50mL round bottom flask were added successively (2-chlorophenyl) -difluoro-acetic acid ethyl ester 59(3.2g, 13.64mmol), MeOH (9mL), THF (6mL) and water (6mL), lithium hydroxide monohydrate (2.28g, 54.66mmol) at room temperature. Stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, adjusted to PH 5-6 with hydrochloric acid, extracted with EA (100mL × 4), and the organic phases were combined. Washed with saturated aqueous sodium bicarbonate (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give (2-chlorophenyl) -difluoro-acetic acid 60(2.5g, white solid), yield: 88.6 percent.
LCMS：m/z207.1(M+H)；RT＝0.64min(4min).
1- [2- (2-chloro-phenyl) -2, 2-difluoro-acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2-, 3-dihydro-1H-indole-7-carbonitrile (a97)
Figure GPA0000243696240000663
In a dry 50mL round bottom flask, (2-chlorophenyl) -difluoro-acetic acid 60(664mg, 3.214mmol), DCM (20mL), DMF (0.1mL), oxalyl chloride (4mL, 25.2mmol) were added sequentially at room temperature to 40 ℃ and stirred for 1 hour, evaporated to dryness under reduced pressure, diluted with DCM (20mL) and evaporated to dryness under reduced pressure again, and the residue was slowly added to a mixed solvent of 5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (170mg, 0.536mmol) and triethylamine (489mg, 4.824mmol), DCM (30mL) and DMF (3mL) and replaced with nitrogen 3 times. The temperature was raised to 25 ℃ and stirred for 24 hours. After the reaction was complete, the solvent was evaporated to dryness, extracted with EA (50mL × 3) and the organic phases were combined. Saturated aqueous sodium chloride solution (10mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (ethyl acetate/PE ═ 1/4 to ethyl acetate) and then purified by preparative chromatography to give the product 1- [2- (2-chloro-phenyl) -2, 2-difluoro-acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2-, 3-dihydro-1H-indole-7-carbonitrile a97(44mg, light yellow solid) in yield: 16.2 percent.
LCMS：m/z506.2(M+H)；RT＝7.85min(15min).
1H NMR(400MHz，dmso)：δ9.51(s，1H)，8.53(d，J＝5.2Hz，1H)，8.36(d，J＝15.9Hz，2H)，7.86(d，J＝7.3Hz，1H)，7.71-7.44(m，4H)，7.35(d，J＝1.8Hz，1H)，6.25(d，J＝1.7Hz，1H)，4.13(t，J＝7.9Hz，2H)，3.67(s，3H)，3.24(t，J＝7.7Hz，2H).
The following 98-100 compounds were prepared in analogy to example 97:
example 98: synthesis of 1-benzoyl-5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indole-7-carbonitrile Compound (A98)
Figure GPA0000243696240000671
LCMS：m/z422.2(M+H)；RT＝3.91min(9min).
1H NMR(dmso，400MHz)δ8.50(d，J＝5.4Hz，1H)，7.64-7.53(m，3H)，7.51-7.42(m，4H)，7.38(t，J＝7.3Hz，2H)，7.31(s，1H)，6.26(d，J＝2.0Hz，1H)，3.68(s，3H)，3.61(t，J＝8.8Hz，2H)，2.97(t，J＝8.6Hz，2H).
Example 99: 1- [2- (2-fluoro-phenyl) -2, 2-difluoro-acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2-, 3-dihydro-1H-indole-7-carbonitrile (a99)
Figure GPA0000243696240000672
LCMS：m/z490.1(M+H)；RT＝7.58min(15min).
1H NMR(400MHz，dmso)：δ9.52(s，1H)，8.53(d，J＝5.2Hz，1H)，8.37(d，J＝14.3Hz，2H)，7.81-7.63(m，2H)，7.52(d，J＝5.2Hz，1H)，7.48-7.29(m，3H)，6.26(d，J＝1.7Hz，1H)，4.20(t，J＝7.7Hz，2H)，3.67(s，3H)，3.23(t，J＝7.8Hz，2H).
Example 100: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2, 6-difluorophenyl) acetyl) indoline-7-carbonitrile (A100)
Figure GPA0000243696240000673
LCMS：m/z472(M+H)；RT＝7.071min(15min).
1H-NMR(DMSO，400MHz)：δ9.46(s，1H)，8.49(d，J＝5.3Hz，1H)，8.28(s，2H)，7.49(d，J＝5.2Hz，1H)，7.34(d，J＝1.9Hz，1H)，7.11(t，J＝7.8Hz，2H)，6.24(d，J＝1.8Hz，1H)，4.36(t，J＝8.1Hz，2H)，4.03(s，2H)，3.66(s，3H)，
Example 101: synthesis of 2, 6-difluoro-4-nitrophenylacetic acid (62)
Figure GPA0000243696240000674
To a solution of compound 61(1.0g, 5.71mmol) in DCM (8mL) in a dry 100mL round bottom flask at room temperature was added Et3N (1.732g, 17.13 mmol). Acetyl chloride (896.68Mg, 11.42mmol) was slowly added dropwise at zero degrees Celsius and the reaction stirred at room temperature for 2 hours. After completion of the TLC detection reaction, EA was extracted three times (50ml × 3), washed with saturated brine (30ml), separated, and the resulting organic phase was concentrated by distillation under reduced pressure and purified by silica gel column chromatography using an eluent system (PE: EA ═ 4: 6) to give the product 2, 6-difluoro-4-nitrophenylacetic acid 62(1.23g, pale yellow solid) in yield Y: 97 percent.
LCMS：m/z218(M+H)；RT＝3.738min(5min)
Synthesis of 4-amino-2, 6-difluorophenethyl ester (63)
Figure GPA0000243696240000681
In a dry 100mL round-bottom flask, compound 62(1.23g, 5.66mmol) was dissolved in Me (8mL) at room temperature. Pd/C (2.0g) was carefully added, and the reaction solution was stirred under hydrogen atmosphere at room temperature for 14 hours. LC/MS, after TLC detection reaction, using diatomite to adsorb and suction-filter excessive palladium carbon, evaporating filtrate to dryness, dissolving and extracting with EA three times (50 ml. x 3), washing with saturated saline (30ml), separating liquid, distilling and concentrating the obtained organic phase under reduced pressure, purifying with silica gel column chromatography with eluent system (PE: EA ═ 3: 7) to obtain product 4-amino-2, 6-difluorophenethyl ester 63(700mg, light yellow solid, Y81.1%)
LCMS：m/z153(M+H)；RT＝3.256min(5min)
5- (2- (3, 5-difluoro-4-acetylesterylphenylamino) pyrimidin-4-yl) indole-7-carbonitrile (64)
Figure GPA0000243696240000682
To a dry 25ml microwave reaction tube were added compound 63(320mg, 1.247mmol), compound 65(282mg, 1.496mmol), Pd (dba) in that order3(171.3mmg，0.187mmol)，Se2(CO3) (1.218g, 3.741mmol), RuPhOS (174.56mg, 0.3741mmol), 1.4-dioxane (8ml), and microwave reaction at 120 ℃ for 2 hours. After completion of the LC/MS detection reaction, EA (50mL × 3) was extracted, washed with saturated brine (30mL), dried, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (ethyl acetate to DCM: 15: 1: 4: 6) to give the product 5- (2- (3, 5-difluoro-4-acetylesterylphenylamino) pyrimidin-4-yl) indole-7-carbonitrile 64(170mg, P: 90%, yellow solid).
LCMS：m/z408(M+H)；RT＝4.817min(10min)
Synthesis of 5- (2- (3, 5-difluoro-4-acetylesterylphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A101)
Figure GPA0000243696240000683
To a dry 100mL round bottom flask was added o-fluorophenylacetic acid (590.2mg, 3.383mmol), compound (COCl) in that order at room temperature2(5ml), DCM (30ml) and DMF (0.5ml) were stirred at room temperature for 10 minutes and the reaction was stirred at reflux for 1 hour at 40 ℃. The reaction solution was evaporated to dryness, DCM dissolved and evaporated to dryness twice, and the residue was dissolved in DCM (20ml) to give a solution of o-fluorobenzeneacetyl chloride in dichloromethane. Compound 64(120mg, 0.295mmol) was dissolved in DCM (20ml) and Et3N (446mg) was added in order, and the above-prepared o-fluorophenylacetyl chloride dichloromethane solution (10ml) was reacted at room temperature for 2 hours after completion of LC/MS detection reaction, followed by preparative isolation and purification to give the product 5- (2- (3, 5-difluoro-4-acetylesterylphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile a101(40mg, pale yellow solid) in yield Y: 25 percent.
LCMS：m/z544(M+H)；RT＝9.33min(15min)
1H-NMR(DMSO，400MHz)δ10.14(s，1H)，8.62(d，J＝5.3Hz，1H)，8.33(d，J＝9.4Hz，2H)，7.70(d，J＝10.8Hz，2H)，7.57(d，J＝5.3Hz，1H)，7.34(d，J＝7.4Hz，2H)，7.18(d，J＝7.9Hz，2H)，4.32(t，J＝8.1Hz，2H)，4.02(s，2H)，
Example 102: synthesis of 5- (2- (3, 5-difluoro-4-hydroxyphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A102)
Figure GPA0000243696240000691
In a dry 100mL round-bottomed flask, compound A101(30mg, 0.0552mmol), potassium carbonate (7.6mg, 0.0552mmol), and H were added sequentially at room temperature2O (1ml), MeOH (9ml) was stirred at room temperature for 40 min. After the reaction was completed by LC/MS detection, EA (10 mL. multidot.3) was extracted, washed with saturated brine (10mL), dried, filtered, and the filtrate was concentrated under reduced pressure to give a crude residue, which was dissolved in DMF (1mL),isolated by preparative isolation to give 5- (2- (3, 5-difluoro-4-hydroxyphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile a102(15mg, light yellow solid), yield Y: 50 percent.
LCMS：m/z502(M+H)；RT＝8.125min(15min).
1H-NMR(DMSO，400MHz)：δ9.75(s，1H)，9.59(s，1H)，8.55(d，J＝5.2Hz，1H)，8.31(d，J＝8.9Hz，2H)，7.49(t，J＝7.7Hz，3H)，7.34(d，J＝7.4Hz，2H)，7.18(d，J＝8.0Hz，2H)，4.31(d，J＝8.2Hz，2H)，4.02(s，2H)，3.25(t，J＝8.1Hz，2H)，
Example 103: synthesis of 2- (3-chloropyridin-2-yl) acetonitrile (66)
Figure GPA0000243696240000692
In a dry 250mL round bottom flask N2Protection, compound 67(2.3g, 54mmol), THF (100ml), LiHDMS (100ml, 100mmol) were added sequentially at zero degrees Centigrade. A50 ml tetrahydrofuran solution of acetonitrile (4.0g, 28mmol) was slowly added, nitrogen gas was substituted 3 times, and the reaction was stirred at room temperature for 2 hours. After completion of the LC/MS detection reaction, 50mL of ice water was quenched, EA (50mL × 3) was extracted, washed with saturated brine (30mL), dried, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (PE: EA ═ 5: 1) to give 2- (3-chloropyridin-2-yl) acetonitrile 66(6.0g, pale yellow solid) in yield Y: 100 percent and 85 percent of purity, and continuously feeding the mixture to the next step for reaction.
LCMS：153(M+H)；RT＝4.25min(10min).
Synthesis of 2- (3-chloropyridin-2-yl) acetic acid hydrochloride (68)
Figure GPA0000243696240000693
In a dry 250mL round bottom flask, compound 66(4.0g, 25.3mmol) and concentrated hydrochloric acid (15mL) were added sequentially at room temperature and the reaction was heated to 90 ℃ and stirred for 4 hours. After the LC/MS detection reaction was completed, the reaction solution was directly evaporated to dryness to obtain 2- (3-chloropyridin-2-yl) acetic acid hydrochloride 68(6.7g, pale yellow solid) in yield Y: 100 percent.
LCMS：172(M+H)；RT＝1.81min(5min)
1- (2- (3-Chloropyridin-2-yl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A103)
Figure GPA0000243696240000701
In a dry 100mL round-bottomed flask, compound 41(80mg0.252mmol), compound 68(259.5mg, 1.52mmol), HATU (718.9mg, 1.890mmol), DIPEA (244.4mg, 1.890mmol), DMF (20mL) N was added sequentially at room temperature2Protected and stirred at room temperature for 72 hours. After completion of the LC/MS detection reaction, EA (50mL × 3) was extracted, washed with saturated brine (30mL), dried, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (DCM: MeOH: 15: 1: 4: 1) and recrystallized from ethanol to give the product 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (3-chloropyridin-2-yl) acetyl) indoline-7-carbonitrile a103(33mg, pale yellow solid) in yield Y: 23 percent.
LCMS：472(M+H)；RT＝6.128min(15min).
1H-NMR(DMSO，400MHz)：δ9.47(s，1H)，8.48(dd，J＝9.3，5.0Hz，2H)，8.28(d，J＝6.6Hz，2H)，7.99-7.83(m，1H)，7.49(d，J＝5.2Hz，1H)，7.42-7.22(m，2H)，6.24(d，J＝1.5Hz，1H)，4.42-4.14(m，4H)，3.66(s，3H)，3.24(d，J＝8.1Hz，2H).
The following compounds 104-121 were prepared in analogy to example 103:
example 104: 5- [2- (4-bromo-2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -1- [2- (2-fluoro-phenyl) -acetyl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A104)
Figure GPA0000243696240000702
LCMS：m/z532.0，534.0(M+H)；RT＝3.66min(10min).
1H NMR(400MHz，dmso)：δ9.22(s，1H)，8.63(s，1H)，8.43(d，J＝5.5Hz，1H)，8.09(s，1H)，7.67-7.44(m，2H)，7.39(d，J＝6.4Hz，1H)，7.29-7.19(m，2H)，6.23(s，2H)，4.21(t，J＝6.4Hz，2H)，3.65(s，2H)，3.37(t，J＝6.2Hz，2H).
Example 105: synthesis of tert-butyl 4- (4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indol-5-yl) pyrimidin-2-ylamino) -1H-pyrazole-1-carboxylate Compound (A105)
Figure GPA0000243696240000703
LCMS：m/z540.1(M+H)；RT＝4.99min(9min).
1H NMR(dmso，400MHz)δ9.88(s，1H)，8.56(d，J＝4.4Hz，1H)，8.39(s，1H)，8.28(s，2H)，7.88(s，1H)，7.44(d，J＝5.2Hz，1H)，7.39-7.28(m，2H)，7.23-7.12(m，2H)，4.32(t，J＝8.2Hz，2H)，4.02(s，2H)，3.25(t，J＝8.2Hz，2H)，1.56(s，9H).
Example 106: synthesis of 5- (2- (1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile Compound (A106)
Figure GPA0000243696240000704
In a dry 50mL single neck flask, compound 5(65mg, 0.120mmol), TFA (250mg, 2.19mmol) and DCM (10mL) were added sequentially at room temperature and stirred at room temperature for 5 h. Upon completion of the LCMS detection reaction, saturated sodium bicarbonate solution was quenched, extracted with DCM, washed sequentially with water, brine, concentrated and the crude product was purified by prep-HPLC to give the product 5- (2- (1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile GE109-12(30mg, yellow solid), yield: 57.7 percent.
LCMS：m/z440.1(M+H)；RT＝4.37min(9min).
1H NMR(400MHz，dmso)δ9.53(s，1H)，8.47(d，J＝5.2Hz，1H)，8.30(s，2H)，7.77(s，2H)，7.40-7.28(m，3H)，7.28-6.98(m，3H)，4.32(t，J＝8.2Hz，2H)，4.03(s，2H)，3.26(t，J＝8.2Hz，2H).
Example 107: 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamine) -pyridin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A107)
Figure GPA0000243696240000711
LCMS：m/z470.1(M+H)；RT＝4.49min(10min).
1H NMR(400MHz，dmso)：δ8.82(s，1H)，8.35(dd，J＝4.7，1.6Hz，1H)，8.16(d，J＝5.3Hz，1H)，7.96-7.73(m，3H)，7.44(dd，J＝7.5，4.8Hz，1H)，7.32(d，J＝1.6Hz，1H)，7.11(d，J＝4.4Hz，1H)，7.02(s，1H)，6.26(d，J＝1.6Hz，1H)，4.34(t，J＝8.1Hz，2H)，4.12(s，2H)，3.66(s，3H)，3.26(t，J＝8.1Hz，2H).
Example 108: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyridin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A108)
Figure GPA0000243696240000712
LCMS：m/z469(M+H)；RT＝3.573min(10min).
1H-NMR(DMSO，400MHz)：δ9.08(s，1H)，8.15(d，J＝5.6Hz，1H)，7.89(d，J＝19.3Hz，2H)，7.43(ddd，J＝16.8，9.4，5.6Hz，3H)，7.32(dd，J＝5.8，3.5Hz，2H)，7.19(s，1H)，7.08(s，1H)，6.30(s，1H)，4.31(t，J＝8.2Hz，2H)，4.08(s，2H)，3.67(s，3H)，3.24(t，J＝8.1Hz，2H)
Example 109: 5- [2- (3-fluoro-4-methoxyphenylamino) -pyrimidin-4-yl ] -1- [2- (2-fluoro-phenyl) -acetyl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A109)
Figure GPA0000243696240000713
LCMS：m/z498.1(M+H)；RT＝5.00min(10min)
1H NMR(400MHz，dmso)：δ9.69(s，1H)，8.53(d，J＝5.2Hz，1H)，8.32(d，J＝5.3Hz，2H)，7.79(dd，J＝14.3，2.5Hz，1H)，7.49-7.29(m，4H)，7.19(d，J＝8.0Hz，2H)，7.11(d，J＝9.5Hz，1H)，4.32(t，J＝8.2Hz，2H)，4.03(s，2H)，3.78(s，3H)，3.26(t，J＝8.5Hz，2H).
Example 110: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyridin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A110)
Figure GPA0000243696240000721
LCMS：(M+H)+/m/z＝453；RT＝3.421min(10min)
1H-NMR(DMSO，400MHz)：δ8.80(s，1H)，8.15(d，J＝5.3Hz，1H)，7.85(d，J＝24.8Hz，2H)，7.32(d，J＝1.6Hz，3H)，7.18(d，J＝7.8Hz，2H)，7.10(d，J＝5.2Hz，1H)，7.01(s，1H)，6.26(d，J＝1.4Hz，1H)，4.29(s，2H)，4.01(s，2H)，3.66(s，3H)，3.23(s，2H)
Example 111: 5- [2- (3-fluoro-4-methoxyphenylamino) -pyrimidin-4-yl ] -1- [2- (2-fluoro-phenyl) -acetyl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A111)
Figure GPA0000243696240000722
LCMS：m/z498.1(M+H)；RT＝5.00min(10min).
1H NMR(400MHz，dmso)：δ9.69(s，1H)，8.53(d，J＝5.2Hz，1H)，8.32(d，J＝5.3Hz，2H)，7.79(dd，J＝14.3，2.5Hz，1H)，7.49-7.29(m，4H)，7.19(d，J＝8.0Hz，2H)，7.11(d，J＝9.5Hz，1H)，4.32(t，J＝8.2Hz，2H)，4.03(s，2H)，3.78(s，3H)，3.26(t，J＝8.5Hz，2H).
Example 112: 1- [2- (2, 6-difluoro-phenyl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamine) -pyridin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A112)
Figure GPA0000243696240000723
LCMS：m/z471.1(M+H)；RT＝3.74min(10min).
1H NMR(400MHz，dmso)：δ8.81(s，1H)，8.15(d，J＝5.4Hz，1H)，7.86(d，J＝26.7Hz，2H)，7.43-7.37(m，1H)，7.32(d，J＝1.8Hz，1H)，7.16-7.06(m，3H)，7.02(s，1H)，6.26(d，J＝1.8Hz，1H)，4.35(t，J＝8.1Hz，2H)，4.04(s，2H)，3.66(s，3H)，3.25(t，J＝8.0Hz，2H).
Example 113: synthesis of 5- (2- (3, 5-difluoro-4-methoxyphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile Compound (A113)
Figure GPA0000243696240000724
In a dry 50mL single-necked flask, compound 71(50mg, 0.114mmol), compound 72(55mg, 0.343mmol), DCM (2mL) and DMSO (0.1mL) were added sequentially at room temperature and stirred at 90 ℃ for 16 hours. After LCMS detection reaction was complete, the crude product was purified by prep-HPLC to give the product 5- (2- (3, 5-difluoro-4-methoxyphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile a113(25mg, yellow solid) in yield: 42.4 percent.
LCMS：m/z516.1(M+H)；RT＝5.32min(9min).
1H NMR(400MHz，dmso)δ9.97(s，1H)，8.59(d，J＝5.3Hz，1H)，8.32(d，J＝8.2Hz，2H)，7.65-7.49(m，3H)，7.41-7.27(m，2H)，7.23-7.12(m，2H)，4.32(t，J＝8.2Hz，2H)，4.02(s，2H)，3.83(s，3H)，3.26(t，J＝7.5Hz，2H).
Example 114: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A114)
Figure GPA0000243696240000731
LCMS：m/z472(M+H)；RT＝3.90min(8min).
1H-NMR(DMSO，400MHz)：δ9.42(s，1H)，8.46(d，J＝5.2Hz，1H)，8.24(d，J＝6.0Hz，2H)，7.50-7.17(m，5H)，7.15(d，J＝7.8Hz，2H)，6.21(d，J＝1.6Hz，1H)，4.27(t，J＝8.2Hz，2H)，3.98(s，2H)，3.63(s，3H)。
Example 115: synthesis of 4- (4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indol-5-yl) pyrimidin-2-ylamino) -N, N-dimethylbenzoyl compound (A115)
Figure GPA0000243696240000732
LCMS：m/z521.2(M+H)；RT＝4.34min(9min).
1H NMR(400MHz，dmso)δ9.91(s，1H)，8.57(d，J＝5.3Hz，1H)，8.34(d，J＝4.8Hz，2H)，7.83(d，J＝8.7Hz，2H)，7.51(d，J＝5.3Hz，1H)，7.40-7.28(m，4H)，7.23-7.14(m，2H)，4.32(t，J＝8.2Hz，2H)，4.02(s，2H)，3.26(t，J＝8.3Hz，2H)，2.94(s，6H).
Example 116: synthesis of 5- (2- (4-methoxyphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A116)
Figure GPA0000243696240000733
LCMS：m/z480.1(M+H)；RT＝4.92min(9min).
1H NMR(400MHz，dmso)δ9.47(s，1H)，8.47(d，J＝5.2Hz，1H)，8.30(d，J＝2.2Hz，2H)，7.63(d，J＝9.0Hz，2H)，7.41-7.29(m，3H)，7.18(dd，J＝15.7，7.8Hz，2H)，6.87(d，J＝9.1Hz，2H)，4.31(t，J＝8.2Hz，2H)，4.02(s，2H)，3.70(s，3H)，3.26(t，J＝8.1Hz，2H).
Example 117: synthesis of 5- (2- (4-fluoro-3-methoxyphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A117)
Figure GPA0000243696240000741
LCMS：m/z 498.1(M+H)；RT＝5.057min(9min).
1H NMR(dmso，400MHz)δ9.71(s，1H)，8.54(d，J＝5.2Hz，1H)，8.34(s，2H)，7.91(d，J＝7.5Hz，1H)，7.46(d，J＝5.2Hz，1H)，7.34(dt，J＝7.7，6.6Hz，2H)，7.15(dq，J＝19.8，9.1Hz，4H)，4.32(t，J＝8.1Hz，2H)，4.02(s，2H)，3.86(s，3H)，3.24(t，J＝8.2Hz，2H).
Example 118: synthesis of methyl 4- (4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indol-5-yl) pyrimidin-2-ylamino) benzoate Compound (A118)
Figure GPA0000243696240000742
LCMS：m/z522.1(M+H)；RT＝5.28min(9min).
1H NMR(400MHz，dmso)δ10.14(s，1H)，8.61(d，J＝5.3Hz，1H)，8.35(d，J＝3.5Hz，2H)，7.91(q，J＝9.0Hz，4H)，7.57(d，J＝5.3Hz，1H)，7.40-7.30(m，2H)，7.23-7.14(m，2H)，4.37-4.20(m，4H)，4.03(s，2H)，3.29-3.22(m，2H)，1.28(t，J＝7.1Hz，3H).
Example 119: synthesis of 5- (2- (3-cyanophenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile Compound (A119)
Figure GPA0000243696240000743
LCMS：m/z475.1(M+H)；RT＝5.01min(9min).
1H NMR(400MHz，dmso)δ10.08(s，1H)，8.61(d，J＝5.3Hz，1H)，8.34(d，J＝3.9Hz，3H)，7.99(d，J＝9.6Hz，1H)，7.56(d，J＝5.3Hz，1H)，7.50(t，J＝8.0Hz，1H)，7.41-7.28(m，3H)，7.24-7.14(m，2H)，4.33(t，J＝8.2Hz，2H)，4.02(s，2H)，3.26(t，J＝6.2Hz，2H).
Example 120: synthesis of 4- (4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indol-5-yl) pyridin-2-ylamino) phenyl) (pyrrolidin-1-yl) methanone Compound (A120)
Figure GPA0000243696240000744
LCMS：m/z547.1(M+H)；RT＝4.54min(9min).
1H NMR(400MHz，dmso)δ9.92(s，1H)，8.57(d，J＝5.3Hz，1H)，8.35(d，J＝5.4Hz，2H)，7.83(d，J＝8.7Hz，2H)，7.50(dd，J＝9.4，7.0Hz，3H)，7.39-7.27(m，2H)，7.23-7.14(m，2H)，4.32(t，J＝8.2Hz，2H)，4.02(s，2H)，3.44(s，4H)，3.29-3.21(m，2H)，1.80(s，4H).
Example 121: synthesis of 5- (2- (5-cyano-1-methyl-1H-pyrrol-3-ylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A121)
Figure GPA0000243696240000751
LCMS：m/z 478.0(M+H)；RT＝4.60min(9min).
1H NMR(dmso，400MHz)δ9.62(s，1H)，8.48(d，J＝5.1Hz，1H)，8.29(s，2H)，7.46(d，J＝1.7Hz，1H)，7.38-7.30(m，3H)，7.22-7.15(m，2H)，6.88(s，1H)，4.32(t，J＝8.3Hz，2H)，4.02(s，2H)，3.73(s，3H)，3.26(s，2H).
Example 122: 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (tetrahydrofuran-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A122)
Figure GPA0000243696240000752
In a dry 5mL microwave tube, 5- (2-bromo-pyridin-4-yl) -1- [2- (2-fluoro-phenyl) -acetyl ] -2, 3-dihydro-1H-indole-7-carbonitrile 1(125mg, 0.286mmol), DCM (2mL) and DMSO (0.1mL), 3-aminotetrahydrofuran hydrochloride 2(212mg, 0.123.58mmol) and triethylamine (347mg, 3.43mmol) were added sequentially at room temperature. After warming to 45 ℃ and stirring for 0.5H, after DCM was allowed to evaporate, warming to 90 ℃ and further stirring for 18H, preparative neutral preparative purification by preparative chromatography gave the product 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (tetrahydrofuran-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile GE148(62mg, light yellow solid) in yield: 49.2 percent.
LCMS：m/z444.1(M+H)；RT＝3.69min(10min).
1H NMR(400MHz，dmso)：δ8.35(d，J＝5.1Hz，1H)，8.26(s，2H)，7.48(d，J＝6.2Hz，1H)，7.40-7.27(m，2H)，7.26-7.06(m，3H)，4.44(s，1H)，4.30(t，J＝8.2Hz，2H)，4.01(s，2H)，3.90(s，1H)，3.82(dd，J＝15.2，7.6Hz，1H)，3.71(dd，J＝13.8，8.0Hz，1H)，3.54(dd，J＝8.8，4.3Hz，1H)，3.23(t，J＝8.0Hz，2H)，2.15(dd，J＝12.5，7.4Hz，1H)，1.89(dd，J＝12.2，6.9Hz，1H).
The following 123-127 compounds were prepared using a method analogous to that of example 122:
example 123: 4- (4- { 7-cyano-1- [2- (2-fluoro-phenyl) -acetyl ] -2, 3-dihydro-1H-indol-5-yl } -pyrimidin-2-ylamino) -piperidine-1-carboxylic acid tert-butyl ester (A123)
Figure GPA0000243696240000753
LCMS：m/z579.1(M+Na)；RT＝4.52min(10min).
1H NMR(400MHz，dmso)：δ8.33(d，J＝5.0Hz，1H)，8.25(s，2H)，7.33(dt，J＝7.8，6.6Hz，2H)，7.28-6.99(m，4H)，4.30(t，J＝8.2Hz，2H)，4.01(s，2H)，3.99-3.72(m，3H)，3.24(dd，J＝15.0，7.0Hz，2H)，2.88(s，2H)，1.84(d，J＝10.4Hz，2H)，1.51-1.03(m，11H).
Example 124: synthesis of 5- (2- (3-methoxyphenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A124)
Figure GPA0000243696240000761
LCMS：m/z 480.1(M+H)；RT＝5.068min(9min).
1H NMR(DMSO-d6，400MHz)δ9.76(s，1H)，8.62(d，J＝5.2Hz，1H)，8.42(d，J＝5.2Hz，2H)，7.72(s，1H)，7.54(d，J＝5.2Hz，1H)，7.47-7.36(m，2H)，7.36-7.19(m，4H)，6.59(dd，J＝7.8，2.0Hz，1H)，4.39(t，J＝8.3Hz，2H)，4.09(s，2H)，3.82(s，3H)，3.32(t，J＝7.1Hz，2H).
Example 125: synthesis of 4- (4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indol-5-yl) pyrimidin-2-ylamino) benzamide Compound (A125)
Figure GPA0000243696240000762
LCMS：m/z493.1(M+H)；RT＝4.01min(9min).
1H NMR(400MHz，dmso)δ9.97(s，1H)，8.59(d，J＝5.3Hz，1H)，8.35(d，J＝4.4Hz，2H)，7.94-7.68(m，5H)，7.53(d，J＝5.3Hz，1H)，7.34(dt，J＝7.8，6.5Hz，2H)，7.23-7.04(m，3H)，4.33(t，J＝8.2Hz，2H)，4.03(s，2H)，3.28-3.22(m，2H).
Example 126: synthesis of 1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (2-deuterated methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H- -1H-indole-7-carbonitrile (A126)
Figure GPA0000243696240000763
1H-NMR(400MHz，DMSO-d6)δ9.47(s，1H)，8.49(d，J＝5.2Hz，1H)，8.27(d，J＝4.3Hz，2H)，7.54-7.43(m，2H)，7.39(s，1H)，7.36-7.19(m，3H)，6.24(d，J＝1.8Hz，1H)，4.31(t，J＝8.2Hz，2H)，4.08(s，2H)，3.27-3.19(m，2H).
LCMS：m/z473.1(M+H)；RT＝5.306min(10min)
Example 127: synthesis of 5- (2- (4-cyanophenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A127)
Figure GPA0000243696240000764
LCMS：m/z 475.0(M+H)；RT＝4.971min(9min).
1H NMR(dmso，400MHz)δ10.32(s，1H)，8.69(d，J＝5.2Hz，1H)，8.42(d，J＝5.3Hz，2H)，8.06(d，J＝8.8Hz，2H)，7.80(d，J＝8.8Hz，2H)，7.67(d，J＝5.3Hz，1H)，7.48-7.33(m，2H)，7.29-7.14(m，2H)，4.39(t，J＝8.2Hz，2H)，4.09(s，2H)，3.32(d，J＝5.3Hz，2H).
Example 128: 1- [2- (2-chloro-phenyl) -acetyl ] -5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -2, 3-dihydro-1H-indole-7-carbonitrile (73)
Figure GPA0000243696240000771
In a dry 100mL round bottom flask, 5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -2, 3-dihydro-1H-indole-7-carbonitrile 40(3.0g, 11.11mmol), THF (80mL) were added sequentially at room temperature, o-chlorophenylacetic acid (3.409g, 20mmol), HATU (7.605g, 20mmol) and Et3N (2.473g, 24.44mmol) were slowly added under nitrogen protection at room temperature, and the reaction was stirred at room temperature for 48 hours. After completion of the reaction by TLC plate detection, extraction was performed with EA (100mL) and the organic phases were combined. Saturated aqueous sodium bicarbonate (10mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product, which was purified by silica gel column chromatography with an eluent system (ethyl acetate/petroleum ether ═ 1/5 to ethyl acetate/petroleum ether ═ 1/1) to give (1- [2- (2-chloro-phenyl) -acetyl ] -5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaboropent-2-yl) -2, 3-dihydro-1H-indole-7-carbonitrile 3(1.0g, yellow solid) at a yield of 21.5%
LCMS：m/z423.1(M+H)；RT＝3.33min(5min)。
5- (2-bromo-pyridin-4-yl) -1- [2- (2-chloro-phenyl) -acetyl ] -2, 3-dihydro-1H-indole-7-carbonitrile (74)
Figure GPA0000243696240000772
(1- [2- (2-chloro-phenyl) -acetyl ] was added sequentially to a dry 50mL round-bottomed flask at room temperature]-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxyboropent-2-yl) -2, 3-dihydro-1H-indole-7-carbonitrile 73(1.2g, 2.839mmol), 2, 4-dibromopyrimidine (675mg, 2.839mmol), Pd (dppf) Cl2(249mg, 0.34mmol), sodium hydrogencarbonate (596mg, 7.1mmol), 1, 4-dioxane (10mL) and water (3mL), and nitrogen gas was substituted 3 times. The reaction was heated to 78 ℃ for 2 hours. After LCMS check reaction was complete, filtration and filtrate was concentrated under reduced pressure and the resulting residue was purified with comiflash (EA/PE ═ 1/1, DCM/MeOH ═ 30/1) to afford the product 5- (2-bromo-pyridin-4-yl) -1- [2- (2-chloro-phenyl) -acetyl-)]-2, 3-dihydro-1H-indole-7-carbonitrile 74(840mg, yellow solid), yield: 65.6 percent
LCMS：m/z454.0(M+H)；RT＝4.96min(10min).
1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (2-cyanopyridin-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A128)
Figure GPA0000243696240000773
In a dry 5mL aliquotInto the wave tube, 5- (2-bromo-pyridin-4-yl) -1- [2- (2-chloro-phenyl) -acetyl ] was added sequentially at room temperature]-2, 3-dihydro-1H-indole-7-carbonitrile 74(85mg, 0.187mmol), DMF (1.5mL), Ruphos (13mg, 0.028mmol), 2-cyano-4-aminopyridine 75(45mg, 0.374mmol) and Et3N (57mg, 0.56mmol), Pd2(dba)3(26mg, 0.028mmol), nitrogen gas was replaced 3 times. Heating to 80 ℃, and stirring and reacting for 80min in a microwave reactor. After the reaction is complete, filtration and purification by preparative chromatography gives 1- [2- (2-chloro-phenyl) -acetyl]-5- [2- (2-cyanopyridin-4-ylamino) -pyrimidin-4-yl]-2, 3-dihydro-1H-indole-7-carbonitrile a128(23mg, light yellow solid), yield: 25 percent.
LCMS：m/z492.1(M+H)；RT＝4.82min(10min).
1H NMR(400MHz，dmso)：δ10.60(s，1H)，8.71(d，J＝5.3Hz，1H)，8.50(d，J＝5.8Hz，1H)，8.38(dd，J＝14.1，4.3Hz，3H)，7.96(dd，J＝5.7，2.0Hz，1H)，7.70(d，J＝5.3Hz，1H)，7.50-7.38(m，2H)，7.36-7.24(m，2H)，4.34(t，J＝8.2Hz，2H)，4.09(s，2H)，3.26(t，2H).
Example 129: 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (1-methanesulfonyl-1H-pyrazol-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A129)
Figure GPA0000243696240000781
In a dry 25mL round bottom flask, 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (1H-pyrazol-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile A106(50mg, 0.114mmol), DCM (5mL) and triethylamine (58mg, 0.57mmol) were added sequentially at room temperature, MsCl (40mg, 0.342mmol) was added dropwise, and nitrogen was replaced 3 times. The temperature is raised to 30 ℃, and the reaction is stirred for 3 hours. After completion of the reaction, quenched with MeOH (1mL) and water (0.5mL), concentrated under reduced pressure and purified by preparative chromatography neutral prep. to give the product 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (1-methanesulfonyl-1H-pyrazol-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile a129(33mg, as a light yellow solid) in yield: 55.9 percent.
LCMS：m/z518.0(M+H)；RT＝4.39min(10min).
1H NMR(400MHz，dmso)：δ9.98(s，1H)，8.59(d，J＝5.0Hz，1H)，8.44(s，1H)，8.31(s，2H)，8.03(s，1H)，7.48(d，J＝5.3Hz，1H)，7.42-7.26(m，2H)，7.25-7.09(m，2H)，4.33(t，J＝8.2Hz，2H)，4.02(s，2H)，3.47(s，3H)，3.26(dd，J＝10.5，5.8Hz，2H).
Example 130: synthesis of 5- (2- (1-methoxypropan-2-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A130)
Figure GPA0000243696240000782
LCMS：m/z 462.1(M+H)；RT＝4.535min(9min).
1H NMR(dmso，400MHz)δ8.39(d，J＝4.8Hz，1H)，8.33(s，2H)，7.56-7.44(m，2H)，7.42-7.31(m，2H)，7.24(d，J＝5.2Hz，1H)，7.10(d，J＝8.1Hz，1H)，4.38(t，J＝8.2Hz，2H)，4.28(s，1H)，4.15(s，2H)，3.50-3.45(m，1H)，3.35-3.25(m，6H)，1.20(d，J＝6.4Hz，3H).
Example 131: synthesis of 5- (2- (1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A131)
Figure GPA0000243696240000783
Compound 74(65mg, 0.143mmol) and 4-aminopyrazole (30mg, 0.358mmol) were added to a dry reaction tube in this order at room temperature, and after dissolving with 2mL of dichloromethane and 0.1mL of dimethylsulfoxide, the reaction tube was slowly heated to 80 ℃ to gradually volatilize the solvent, and the reaction tube was stirred at that temperature for 18 hours. After LCMS detection reaction was complete, purification by prep-HPLC afforded the product 5- (2- (1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile a131(8.9mg, green solid), yield: 13.7 percent.
LCMS：m/z 456.0(M+H)；RT＝4.012min(9min).
1H NMR(dmso，400MHz)δ12.56(s，1H)，9.56(s，1H)，8.53(d，J＝5.0Hz，1H)，8.36(s，2H)，7.97(s，1H)，7.67(s，1H)，7.55-7.46(m，2H)，7.39(dt，J＝3.5，2.5Hz，3H)，4.40(t，J＝8.2Hz，2H)，4.16(s，2H)，3.33(d，J＝8.4Hz，2H).
The following 132-140 compounds were prepared using a procedure analogous to that of example 131:
example 132: synthesis of 5- (2- ((1H-pyrazol-3-yl) amino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A132)
Figure GPA0000243696240000791
LCMS：t＝1.67min，ESI：[M+H]+m/z 456.
1H NMR(400MHz，DMSO)δ9.81(s，1H)，8.51(d，J＝5.3Hz，1H)，8.34(s，2H)，7.62(s，1H)，7.49(dd，J＝5.7，3.6Hz，1H)，7.46-7.40(m，2H)，7.35(dd，J＝5.7，3.6Hz，2H)，6.58(s，1H)，4.35(t，J＝8.1Hz，2H)，4.11(s，2H)，3.32-3.25(m，2H).
Example 133: synthesis of 5- (2- (2-hydroxypropylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A133)
Figure GPA0000243696240000792
LCMS：m/z 432.1(M+H)；RT＝4.171min(9min).
1H NMR(dmso，400MHz)δ8.38(d，J＝5.4Hz，1H)，8.32(s，2H)，7.46-7.29(m，3H)，7.29(d，J＝5.1Hz，1H)，7.25-7.16(m，2H)，4.34(t，J＝8.2Hz，2H)，4.05(s，2H)，3.85-3.83(m，1H)，3.27(t，J＝8.1Hz，3H)，1.10(d，J＝6.2Hz，3H).
Example 134: synthesis of 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-cyanopyridin-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile Compound (A134)
Figure GPA0000243696240000793
LCMS：m/z493.0(M+H)；RT＝4.11min(10min).
1H NMR(dmso，400MHz)δ10.61(s，1H)，8.72(d，J＝5.3Hz，1H)，8.51(d，J＝5.8Hz，1H)，8.45-8.28(m，4H)，7.97(dd，J＝5.8，2.1Hz，1H)，7.86(d，J＝7.7Hz，1H)，7.71(d，J＝5.3Hz，1H)，7.44(dd，J＝7.4，4.8Hz，1H)，4.37(t，J＝8.3Hz，2H)，4.14(s，2H)，3.27(s，2H).
Example 135: synthesis of 5- (2- (1-acetamido-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile Compound (A135)
Figure GPA0000243696240000801
LCMS：m/z482.1(M+H)；RT＝4.6min(9min).
1H NMR(400MHz，dmso)δ9.97(s，1H)，8.57(d，J＝12.7Hz，2H)，8.31(s，2H)，7.97(s，1H)，7.47(d，J＝5.2Hz，1H)，7.39-7.29(m，2H)，7.18(dd，J＝15.9，8.3Hz，2H)，4.37-4.26(m，2H)，4.02(s，2H)，3.28-3.20(m，2H)，2.59(s，3H).
Example 136: synthesis of 5- (2- (1-isopropyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A136)
Figure GPA0000243696240000802
LCMS：m/z 498.1(M+H)；RT＝4.595min(9min).
1H NMR(dmso，400MHz)δ9.38(s，1H)，8.54(d，J＝5.3Hz，1H)，8.33(s，2H)，7.56-7.51(m，2H)，7.48(t，J＝4.8Hz，2H)，7.39(dd，J＝5.9，3.5Hz，2H)，6.24(s，1H)，4.60-4.55(m，1H)，4.39(t，J＝8.2Hz，2H)，4.15(s，2H)，3.30(d，J＝8.2Hz，2H)，1.37(d，J＝6.5Hz，6H).
Example 137: 3- (4- {1- [2- (2-chloro-phenyl) -acetyl ] -7-cyano-2, 3-dihydro-1H-indol-5-yl } -pyrimidin-2-ylamino) -azetidine-1-carboxylic acid tert-butyl ester (A137)
Figure GPA0000243696240000803
LCMS：m/z 545.1(M+H)；RT＝5.018min(10min).
1H NMR(dmso，400MHz)δ8.36(d，J＝5.2Hz，1H)，8.27(d，J＝6.6Hz，2H)，7.89(d，J＝6.1Hz，1H)，7.44(ddd，J＝17.5，7.5，4.7Hz，2H)，7.37-7.24(m，3H)，4.62(s，1H)，4.31(t，J＝8.2Hz，2H)，4.13(s，2H)，4.08(s，2H)，3.77(s，2H)，3.25(dd，J＝14.1，6.0Hz，2H)，1.36(s，9H).
Example 138: synthesis of 5- (2- (3-chloro-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile Compound (A138)
Figure GPA0000243696240000804
LCMS：m/z474.0(M+H)；RT＝4.19min(9min).
1H NMR(400MHz，dmso)δ12.88(s，1H)，8.77(s，1H)，8.43(d，J＝5.3Hz，1H)，8.26(s，2H)，7.97(s，1H)，7.46-7.27(m，3H)，7.23-7.08(m，2H)，4.30(t，J＝8.2Hz，2H)，4.01(s，2H)，3.24(dd，J＝14.8，6.7Hz，2H).
Example 139: synthesis of 5- (2- (1-isopropyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile Compound (A139)
Figure GPA0000243696240000811
LCMS：m/z499.1(M+H)；RT＝3.88min(9min).
1H NMR(400MHz，dmso)δ9.30(s，1H)，8.47(d，J＝5.2Hz，1H)，8.34(dd，J＝4.8，1.9Hz，1H)，8.26(s，2H)，7.85(dd，J＝7.5，1.8Hz，1H)，7.51-7.37(m，3H)，6.17(d，J＝1.6Hz，1H)，4.55-4.45(m，1H)，4.34(t，J＝8.2Hz，2H)，4.12(s，2H)，3.26-3.20(m，2H)，1.30(d，J＝6.6Hz，6H).
Example 140: synthesis of 5- (2- (3, 5-difluoro-4-methoxyphenylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile Compound (A140)
Figure GPA0000243696240000812
LCMS：m/z533.1(M+H)；RT＝4.90min(9min).
1H NMR(400MHz，dmso)δ9.96(s，1H)，8.59(d，J＝5.3Hz，1H)，8.41-8.27(m，3H)，7.86(dd，J＝7.5，1.8Hz，1H)，7.59(d，J＝11.4Hz，2H)，7.53(d，J＝5.3Hz，1H)，7.43(dd，J＝7.5，4.8Hz，1H)，4.36(t，J＝8.2Hz，2H)，4.13(s，2H)，3.83(s，3H)，3.27(s，2H).
Example 141: synthesis of 1- (2- (2-chloropyridin-3-yl) acetyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline-7-carbonitrile Compound (3)
Figure GPA0000243696240000813
In a dry 100mL single neck flask, compound 40(1.83g, 6.77mmol), compound 2-chloropyridine-3-acetic acid (1.86g, 10.8mmol), HATU (5.6g, 14.8mmol), TEA (1.6g, 16.3mmol) and DMF (20mL) were added sequentially at room temperature and stirred at room temperature for 16 h. After LCMS detection reaction was complete, 40mL of water was added and extracted with EA, finally washed with saturated brine, separated, concentrated and the crude product was purified with combiflash (EA/PE 0-70%) to give the product 1- (2- (2-chloropyridin-3-yl) acetyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline-7-carbonitrile 76(2.2g, yellow solid) in yield: 76.7 percent.
LCMS：m/z424.1(M+H)；RT＝3.06min(4min).
Synthesis of 5- (2-bromopyridin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile Compound (77)
Figure GPA0000243696240000814
In a dry 100mL single-neck flask at room temperature were added sequentially compound 76(1.98g, 4.67mmol), compound 2, 4-dibromopyrimidine (1.45g, 6.08mmol), Pd (dppf) Cl2(342mg, 0.467mmol), TEA (945mg, 9.34mmol) and dioxane (40mL), H2O (10mL), stirred at 60 ℃ for 50 min. After LCMS detection reaction was complete, filtration, concentration and purification of the crude product with combiflash (EA/PE 0-100%) gave the product 5- (2-bromopyridin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile 77(1.08g, yellow solid) in yield: 51 percent.
LCMS：m/z454(M+H)；RT＝2.79min(4min).
Synthesis of 5- (2- (1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile (A141)
Figure GPA0000243696240000821
In a dry 50mL one-neck flask, compound 77(75mg, 0.165mmol), compound 78(91mg, 0.495mmol) and DCM (2mL) were added sequentially at room temperature and stirred at 90 ℃ for 16 h. After LCMS detection reaction was complete, the crude product was purified by prep-HPLC to give the product 5- (2- (1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile a141(13mg, yellow solid) in yield: 17.3 percent.
LCMS：m/z457(M+H)；RT＝3.33min(9min).
1H NMR(400MHz，dmso)δ12.49(s，1H)，9.49(s，1H)，8.47(d，J＝5.2Hz，1H)，8.39-8.22(m，3H)，7.97-7.81(m，2H)，7.60(s，1H)，7.43(dd，J＝7.5，4.8Hz，1H)，7.32(d，J＝5.2Hz，1H)，4.35(t，J＝8.2Hz，2H)，4.13(s，2H)，3.28-3.21(m，2H).
The following 142-146 compounds were prepared using a method similar to that of example 141:
example 142: synthesis of 5- (2- (1-hydroxypropan-2-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A142)
Figure GPA0000243696240000822
LCMS：m/z 448.0(M+H)；RT＝3.854min(9min).
1H NMR(dmso，400MHz)δ8.39(d，J＝4.8Hz，1H)，8.32(d，J＝3.3Hz，2H)，7.55-7.50(m，1H)，7.49-7.45(m，1H)，7.38(dd，J＝5.5，3.7Hz，2H)，7.23(d，J＝5.2Hz，1H)，6.95(d，J＝7.4Hz，1H)，4.72(t，J＝5.6Hz，1H)，4.38(t，J＝8.2Hz，2H)，4.14(s，2H)，4.12-3.99(m，1H)，3.57-3.50(m，1H)，3.34(s，1H)，3.30(d，J＝8.5Hz，2H)，1.19(d，J＝6.6Hz，3H).
Example 143: 1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (tetrahydrofuran-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A143)
Figure GPA0000243696240000823
LCMS：m/z460.1(M+H)；RT＝3.75min(10min).
1H NMR(400MHz，dmso)：δ8.35(d，J＝5.1Hz，1H)，8.26(s，2H)，7.46(t，J＝7.7Hz，2H)，7.43-7.36(m，1H)，7.36-7.24(m，2H)，7.21(d，J＝5.2Hz，1H)，4.43(s，1H)，4.31(t，J＝8.2Hz，2H)，4.07(s，2H)，3.90(s，1H)，3.85-3.78(m，1H)，3.75-3.67(m，1H)，3.54(dd，J＝8.7，4.1Hz，1H)，3.24(t，J＝8.1Hz，2H)，2.14(s，1H)，1.88(d，J＝5.5Hz，1H).
Example 144: synthesis of 5- (2- (1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2, 6-difluorophenyl) acetyl) indoline-7-carbonitrile (A144)
Figure GPA0000243696240000831
LCMS：m/z 458.1(M+H)；RT＝3.502min(9min).
1H NMR(dmso，400MHz)δ12.57(s，1H)，9.56(s，1H)，8.54(d，J＝5.1Hz，1H)，8.37(d，J＝5.2Hz，2H)，7.97(s，1H)，7.67(s，1H)，7.47(dd，J＝15.1，6.8Hz，1H)，7.39(d，J＝5.2Hz，1H)，7.19(t，J＝7.8Hz，2H)，4.44(t，J＝8.1Hz，2H)，4.12(s，2H)，3.34(d，J＝8.7Hz，2H).
Example 145: synthesis of 5- (2- (4- (methylsulfonyl) phenylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A145)
Figure GPA0000243696240000832
LCMS：m/z 528.1(M+H)；RT＝4.105min(9min).
1H NMR(dmso，400MHz)δ10.32(s，1H)，8.70(d，J＝5.3Hz，1H)，8.43(d，J＝3.1Hz，2H)，8.11(d，J＝8.9Hz，2H)，7.90(d，J＝8.8Hz，2H)，7.67(d，J＝5.3Hz，1H)，7.46-7.37(m，2H)，7.30-7.20(m，2H)，4.40(t，J＝8.2Hz，2H)，4.10(s，2H)，3.34(d，J＝8.1Hz，2H)，3.20(s，3H).
Example 146: 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (pyridin-3-yl) acetyl) indoline-7-carbonitrile (A146)
Figure GPA0000243696240000833
LCMS：m/z437.2(M+H)；RT＝2.36min(10min).
1H NMR(400MHz，dmso)δ9.53(s，1H)，8.78(d，J＝4.3Hz，2H)，8.55(d，J＝5.3Hz，1H)，8.31(d，J＝16.0Hz，2H)，8.28(d，J＝7.9Hz，1H)，7.89(dd，J＝7.9，5.6Hz，1H)，7.54(d，J＝5.3Hz，1H)，7.39(d，J＝1.9Hz，1H)，6.29(d，J＝1.8Hz，1H)，4.37(d，J＝8.3Hz，2H)，4.25(s，2H)，3.71(s，3H)，3.31(t，J＝8.2Hz，2H).
Example 147: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-cyclopropylpyridin-3-yl) acetyl) indoline-7-carbonitrile Compound (A147)
Figure GPA0000243696240000834
In a dry 50mL single neck flask, compound 80(90mg, 0.508mmol), Ac was added sequentially at room temperature20(49mg, 0.476mmol), DMF (1mL) was stirred at 60 ℃ for 1h, A8(50mg, 0.158mmol), NMP (55mg, 0.54mmol) were added and stirred at 50 ℃ for 1.5 h. Upon completion of LCMS check reaction, purification with combiflash (MeOH/DCM 0% -3%) afforded the product 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-cyclopropylpyridin-3-yl) acetyl) indoline-7-carbonitrile a147(7mg, white solid) in yield: 10 percent.
LCMS：m/z477.2(M+H)；RT＝2.22min(9min).
1H NMR(dmso，400MHz)δ9.46(s，1H)，8.49(d，J＝5.2Hz，1H)，8.33-8.23(m，3H)，7.53(dd，J＝7.7，1.6Hz，1H)，7.49(d，J＝5.3Hz，1H)，7.34(d，J＝1.9Hz，1H)，7.09(dd，J＝7.6，4.8Hz，1H)，6.24(d，J＝1.8Hz，1H)，4.31(t，J＝8.2Hz，2H)，4.14(s，2H)，3.66(s，3H)，3.24(t，J＝8.1Hz，2H)，2.17-2.09(m，1H)，0.96-0.84(m，4H).
The following 148-151 compounds were prepared using a method analogous to example 147:
example 148: synthesis of 4- (4- (1- (2- (2-chloropyridin-3-yl) acetyl) -7-cyanoindol-5-yl) pyrimidin-2-ylamino) -N, N-dimethylbenzamide Compound (A148)
Figure GPA0000243696240000841
LCMS：m/z538.1(M+H)；RT＝3.45min(9min).
1H NMR(400MHz，dmso)δ9.91(s，1H)，8.57(d，J＝5.2Hz，1H)，8.35(dd，J＝6.4，2.1Hz，3H)，7.85(dd，J＝14.0，5.3Hz，3H)，7.51(d，J＝5.3Hz，1H)，7.43(dd，J＝7.5，4.8Hz，1H)，7.36(d，J＝8.6Hz，2H)，4.36(t，J＝8.3Hz，2H)，4.13(s，2H)，3.27(s，2H)，2.94(s，6H).
Example 149: synthesis of 1- (2- (2-chlorophenyl) acetyl) -5- (2- (pyridazin-4-ylamino) pyrimidin-4-yl) indoline-7-carbonitrile (A149)
Figure GPA0000243696240000842
LCMS：t＝1.58min，ESI：[M+H]+m/z 468.
1H NMR(400MHz，DMSO-d6)δ9.92(d，J＝7.8Hz，1H)，9.57(d，J＝20.8Hz，2H)，9.10(d，J＝5.4Hz，1H)，8.75(d，J＝2.9Hz，1H)，8.60(d，J＝14.9Hz，2H)，8.38(d，J＝5.4Hz，1H)，7.50(dd，J＝5.7，3.6Hz，1H)，7.44(dd，J＝5.6，3.7Hz，1H)，7.39-7.33(m，2H)，7.27(dd，J＝8.2，2.6Hz，1H)，4.39(t，J＝8.1Hz，2H)，4.14(s，2H)，3.36-3.30(m，2H).
Example 150: synthesis of 4- ((4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indolin-5-yl) pyrimidin-2-yl) amino) -N-methylbenzamide (A150)
Figure GPA0000243696240000843
LCMS：m/z507(M+H)；RT＝1.67min.
1H-NMR(DMSO，400MHz)：δ10.00(s，1H)，8.62(d，J＝5.2Hz，1H)，8.38(d，J＝3.9Hz，2H)，8.28(d，J＝4.5Hz，1H)，7.88(d，J＝8.9Hz，2H)，7.80(d，J＝8.8Hz，2H)，7.57(s，1H)，7.39(s，2H)，7.31-7.13(m，2H)，4.35(s，3H)，4.06(s，3H)，3.30(t，J＝8.2Hz，3H)，2.77(d，J＝4.5Hz，3H).
Example 151: synthesis of 1- (2- (2-chlorophenyl) acetyl) -5- (2- ((3-cyano-4-fluorophenyl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A151)
Figure GPA0000243696240000851
LCMS：t＝1.86min，ESI：[M+H]+m/z 493.
1H NMR(400MHz，DMSO-d6)δ10.12(s，1H)，8.63(d，J＝5.3Hz，1H)，8.49-8.23(m，2H)，8.03(dd，J＝8.2，3.8Hz，1H)，7.59(d，J＝5.3Hz，1H)，7.51(t，J＝9.1Hz，1H)，7.38(dd，J＝16.2，9.2Hz，1H)，7.29-7.15(m，1H)，4.36(t，J＝8.2Hz，2H)，4.06(s，2H)，3.31-3.14(m，2H).
Example 152: 1- [2- (2-chloro-phenyl) -acetyl ] -5- (2-fluoropyridin-4-yl) -2, 3-dihydro-1H-indole-7-carbonitrile (82)
Figure GPA0000243696240000852
(1- [2- (2-chloro-phenyl) -acetyl ] was added sequentially to a dry 50mL round-bottomed flask at room temperature]-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxoboropent-2-yl) -2, 3-dihydro-1H-indole-7-carbonitrile 73(850g, 2.01mmol), 2-fluoro-4-bromopyridine 81(531mg, 3.01mmol), Pd (dppf) Cl2(147mg, 0.201mmol), sodium hydrogencarbonate (591mg, 7.04mmol), 1, 4-dioxane (6mL) and water (1.5mL), and nitrogen gas was substituted 3 times. The reaction was heated to 70 ℃ for 1 hour. After LCMS detection, filtration and concentration of the filtrate under reduced pressure, the resulting residue was purified with comilash (EA/PE 1/2, EA/PE 3/1) to give the product 1- [2- (2-chloro-phenyl) -acetyl]-5- (2-fluoropyridin-4-yl) -2, 3-dihydro-1H-indole-7-carbonitrile 82(540mg, yellow solid), yield: 68.6 percent of
LCMS：m/z392.0(M+H)；RT＝4.18min(10min).
1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (1H-pyrazol-4-ylamino) -pyridin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A152)
Figure GPA0000243696240000853
To a dry 5mL microwave tube, 82(120mg, 0.306mmol), DCM (2mL) and DMSO (0.2mL), 1-Boc-4-amino-pyrazole (168mg, 0.918mmol) were added sequentially at room temperature. After warming to 60 ℃ and stirring for 0.5H, after DCM was allowed to evaporate, warming to 105 ℃ and stirring for 18H, purification was performed by preparative chromatography neutral prep. to give the product 1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (1H-pyrazol-4-ylamino) -pyridin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile a152(20mg, yellow solid) in yield: 14.3 percent.
LCMS：m/z455.1(M+H)；RT＝2.79min(10min).
1H NMR(400MHz，dmso)：δ12.42(s，1H)，8.73(s，1H)，8.12(d，J＝5.3Hz，1H)，7.92(s，1H)，7.82(d，J＝29.8Hz，2H)，7.50(s，1H)，7.48-7.38(m，2H)，7.32(dd，J＝5.5，3.8Hz，2H)，6.92(d，J＝5.4Hz，1H)，6.86(s，1H)，4.30(t，J＝8.2Hz，2H)，4.07(s，2H)，3.24(dd，J＝13.9，5.6Hz，2H).
The following 153-171 compounds were prepared using a method analogous to example 152:
example 153: synthesis of 5- (2- (1H-pyrazol-5-ylamino) pyridin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A153)
Figure GPA0000243696240000861
LCMS：m/z 455.0(M+H)；RT＝2.951min(9min).
1H NMR(dmso，400MHz)δ12.17(s，1H)，9.30(s，1H)，8.21(d，J＝5.3Hz，1H)，7.93(s，1H)，7.84(s，1H)，7.64(d，J＝24.8Hz，2H)，7.53(dd，J＝5.6，3.8Hz，1H)，7.49-7.45(m，1H)，7.41-7.35(m，2H)，7.09(d，J＝4.8Hz，1H)，6.34(s，1H)，4.37(t，J＝8.1Hz，2H)，4.14(s，2H)，3.30(d，J＝8.0Hz，2H).
Example 154: synthesis of 5- (2- (1H-pyrazol-4-ylamino) pyridin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile Compound (A154)
Figure GPA0000243696240000862
LCMS：m/z439.1(M+H)；RT＝2.66min(9min).
1H NMR(400MHz，dmso)δ12.43(s，1H)，8.74(s，1H)，8.12(d，J＝5.4Hz，1H)，7.93(s，1H)，7.85(s，1H)，7.78(s，1H)，7.50(s，1H)，7.39-7.28(m，2H)，7.23-7.12(m，2H)，6.91(d，J＝5.5Hz，1H)，6.86(s，1H)，4.29(t，J＝8.1Hz，2H)，4.01(s，2H)，3.22(t，J＝8.1Hz，2H).
Example 155: 4- (4- { 7-cyano-1- [2- (2-fluoro-phenyl) -acetyl ] -2, 3-dihydro-1H-indol-5-yl } -pyrimidin-2-ylamino) -2-fluoro-N, N-dimethylbenzamide (A155)
Figure GPA0000243696240000863
LCMS：m/z539.0(M+H)；RT＝4.107min(10min).
1H NMR(400MHz，dmso)：δ10.10(s，1H)，8.61(d，J＝5.2Hz，1H)，8.34(d，J＝9.7Hz，2H)，7.90(d，J＝13.2Hz，1H)，7.55(d，J＝5.8Hz，2H)，7.32(dd，J＝20.4，7.8Hz，3H)，7.18(d，J＝7.7Hz，2H)，4.32(t，J＝8.2Hz，2H)，4.02(s，2H)，3.25(d，J＝8.2Hz，2H)，2.96(s，3H)，2.86(s，3H).
Example 156: synthesis of 4- (4- (1- (2- (2-chloropyridin-3-yl) acetyl) -7-cyanoindol-5-yl) pyrimidin-2-ylamino) benzamide Compound (A156)
Figure GPA0000243696240000864
LCMS：m/z510.0(M+H)；RT＝3.23min(9min).
1H NMR(400MHz，dmso)δ9.96(s，1H)，8.58(d，J＝5.3Hz，1H)，8.38-8.28(m，3H)，7.91-7.74(m，6H)，7.52(d，J＝5.3Hz，1H)，7.42(dd，J＝7.5，4.8Hz，1H)，7.13(s，1H)，4.35(t，J＝8.3Hz，2H)，4.12(s，2H)，3.26(s，2H).
Example 157: synthesis of 3- (2- (2-fluorophenyl) acetyl) -6- (2- (pyridazin-4-ylamino) pyrimidin-4-yl) -2, 3-dihydro-1H-indene-4-carbonitrile (A157)
Figure GPA0000243696240000871
LCMS：t＝1.88min，ESI：[M+H]+m/z 468.
1H NMR(400MHz，DMSO-d6)δ9.75(s，1H)，8.55(d，J＝5.3Hz，1H)，8.35(d，J＝3.4Hz，2H)，7.86-7.74(m，2H)，7.49(d，J＝5.3Hz，1H)，7.44-7.32(m，2H)，7.19(dt，J＝17.8，9.4Hz，4H)，4.35(t，J＝8.2Hz，2H)，4.05(s，2H)，3.29(dd，J＝10.8，6.1Hz，2H).
Example 158: synthesis of 1- (2- (2-chlorophenyl) acetyl) -5- (2- ((4-fluorophenyl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A158)
Figure GPA0000243696240000872
LCMS：t＝1.93min，ESI：[M+H]+m/z 484.
1H NMR(400MHz，DMSO-d6)δ9.75(s，1H)，8.55(d，J＝5.2Hz，1H)，8.35(d，J＝3.0Hz，2H)，7.79(dd，J＝9.0，5.0Hz，2H)，7.54-7.47(m，2H)，7.46-7.40(m，1H)，7.35(dd，J＝5.7，3.5Hz，2H)，7.16(t，J＝8.9Hz，2H)，4.36(t，J＝8.2Hz，2H)，4.12(s，2H)，3.30(t，J＝7.6Hz，2H).
Example 159: synthesis of tert-butyl 4- (4- ((4- (7- (cyano-1- (2- (2-fluorophenyl) acetyl) indolin-5-yl) pyrimidin-2-yl) amino) benzoyl) piperazine-1-carboxylate (159)
Figure GPA0000243696240000873
LCMS：m/z661(M+H)；RT＝1.85min.
1H-NMR：(DMSO，400MHz)δ9.97(s，1H)，8.61(d，J＝5.3Hz，1H)，8.38(d，J＝4.9Hz，2H)，7.88(d，J＝8.6Hz，2H)，7.55(d，J＝5.3Hz，1H)，7.40(d，J＝8.6Hz，3H)，7.21(d，J＝7.9Hz，2H)，4.34(d，J＝8.2Hz，2H)，4.05(s，2H)，3.48(s，3H)，3.37(d，J＝7.0Hz，3H)，3.29(d，J＝9.0Hz，3H)，1.41(s，8H).
Example 160: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((4- (piperazine-1-carbonyl) phenyl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A160)
Figure GPA0000243696240000874
LCMS：m/z563(M-100+H)；RT＝1.58min.
1H-NMR：(400MHz，DMSO)δ9.94(s，2H)，8.60(d，J＝5.2Hz，1H)，8.38(d，J＝4.1Hz，2H)，7.86(d，J＝8.8Hz，2H)，7.54(d，J＝5.3Hz，1H)，7.37(t，J＝8.2Hz，2H)，7.21(dd，J＝16.3，8.5Hz，1H)，4.35(t，J＝8.0Hz，2H)，4.05(s，2H)，2.67(s，4H).
Example 161: 1- [2- (2-fluoro-phenyl) -acetyl ] -5- {2- [4- (3-hydroxy-pyrrolidine-1-carbonyl) -phenylamino ] -pyrimidin-4-yl } -2, 3-dihydro-1H-indole-7-carbonitrile (A161)
Figure GPA0000243696240000881
LCMS：m/z563.2(M+H)；RT＝3.62min(10min).
1H NMR(400MHz，dmso)：δ9.93(s，1H)，8.57(d，J＝5.3Hz，1H)，8.35(d，J＝5.8Hz，2H)，7.84(d，J＝8.7Hz，2H)，7.50(dd，J＝12.5，6.7Hz，3H)，7.34(dt，J＝7.6，6.5Hz，2H)，7.24-7.10(m，2H)，4.92(d，J＝31.5Hz，1H)，4.32(t，J＝8.2Hz，2H)，4.20(s，1H)，4.02(s，2H)，3.71-3.39(m，4H)，3.25(s，2H)，1.94-1.74(m，2H).
Example 162: synthesis of 4- (4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indol-5-yl) pyrimidin-2-ylamino) -2, 5-difluoro-N, N-dimethylbenzamide (A162)
Figure GPA0000243696240000882
LCMS：m/z 557.1(M+H)；RT＝4.220min(9min).
1H NMR(dmso，400MHz)δ9.58(s，1H)，8.66(d，J＝5.3Hz，1H)，8.41(d，J＝10.8Hz，2H)，8.13(dd，J＝11.6，6.5Hz，1H)，7.65(d，J＝5.3Hz，1H)，7.45-7.34(m，3H)，7.29-7.20(m，2H)，4.39(t，J＝8.2Hz，2H)，4.09(s，2H)，3.30(d，J＝8.1Hz，2H)，3.04(s，3H)，2.95(s，3H)..
Example 163: synthesis of 4- (4- (1- (2- (2-chloropyridin-3-yl) acetyl) -7-cyanoindol-5-yl) pyridin-2-ylamino) -2-fluorobenzamide (A163)
Figure GPA0000243696240000883
LCMS：m/z 528.1(M+H)；RT＝3.407min(9min).
1H NMR(dmso，400MHz)δ10.26(s，1H)，8.71(d，J＝5.3Hz，1H)，8.42(dd，J＝6.9，4.0Hz，3H)，7.99-7.91(m，2H)，7.73(d，J＝8.7Hz，1H)，7.67-7.61(m，2H)，7.51(dd，J＝7.4，4.8Hz，2H)，7.45(s，1H)，4.44(t，J＝8.2Hz，2H)，4.21(s，2H)，3.34(s，2H).
Example 164: 4- (4- { 7-cyano-1- [2- (2-fluoro-phenyl) -acetyl ] -2, 3-dihydro-1H-indol-5-yl } -pyrimidin-2-ylamino) -2-fluoro-benzamide (a164)
Figure GPA0000243696240000884
LCMS：m/z511.1(M+H)；RT＝3.89min(10min).
1H NMR(400MHz，dmso)：δ10.16(s，1H)，8.61(d，J＝5.3Hz，1H)，8.33(d，J＝8.2Hz，2H)，7.88(dd，J＝14.5，1.8Hz，1H)，7.65(t，J＝8.7Hz，1H)，7.60-7.47(m，2H)，7.47-7.23(m，4H)，7.18(t，J＝8.6Hz，2H)，4.31(t，J＝8.2Hz，2H)，4.01(s，2H)，3.24(d，J＝8.4Hz，2H).
Example 165: synthesis of 5- (2- ((2, 4-difluorophenyl) amino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A165)
Figure GPA0000243696240000891
LCMS：t＝1.92min，ESI：[M+H]+m/z 486.
1H NMR(400MHz，DMSO-d6)δ9.78(s，1H)，9.23(s，1H)，8.48(d，J＝5.3Hz，1H)，8.29(d，J＝4.9Hz，2H)，8.13(s，1H)，7.71(dd，J＝15.4，9.1Hz，2H)，7.47(d，J＝5.3Hz，1H)，7.21(d，J＝8.0Hz，3H)，7.09-7.01(m，1H)，4.33(t，J＝8.4Hz，4H)，4.04(s，2H)，3.92(s，1H)，3.26(t，J＝8.7Hz，3H).
Example 166: synthesis of 5- (2- ((4-fluoro-3-methylphenyl) amino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A166)
Figure GPA0000243696240000892
LCMS：m/z482(M+H)；RT＝1.96min.
1H-NMR(DMSO，400MHz)：δ9.67(s，1H)，8.55(d，J＝5.2Hz，1H)，8.36(d，J＝8.1Hz，2H)，7.78(d，J＝6.5Hz，1H)，7.52(d，J＝4.1Hz，1H)，7.48(d，J＝5.2Hz，1H)，7.43-7.30(m，2H)，7.28-7.15(m，2H)，7.08(t，J＝9.2Hz，1H)，4.35(t，J＝8.2Hz，2H)，4.05(s，2H)，3.31-3.25(m，2H)，2.25(s，3H).
Example 167: synthesis of 5- ((4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indolin-5-yl) pyrimidin-2-yl) amino) -N, N-dimethylpyridinamide (A167)
Figure GPA0000243696240000893
LCMS：t＝1.83min，ESI：[M+H]+m/z 522.
1H NMR(400MHz，DMSO-d6)δ10.16(s，1H)，8.94(d，J＝2.2Hz，1H)，8.64(d，J＝5.3Hz，1H)，8.36(dd，J＝10.8，4.5Hz，3H)，7.64-7.53(m，2H)，7.38(t，J＝7.4Hz，2H)，7.27-7.15(m，2H)，4.35(t，J＝8.1Hz，2H)，4.06(s，2H)，3.29(t，J＝6.1Hz，2H)，3.04(s，3H)，3.00(s，3H).
Example 168: synthesis of 5- (2- ((3, 4-difluorophenyl) amino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A168)
Figure GPA0000243696240000901
LCMS：t＝1.95min，ESI：[M+H]+m/z 486.
1H NMR(400MHz，DMSO-d6)δ9.96(s，1H)，8.60(d，J＝5.3Hz，1H)，8.36(d，J＝6.2Hz，2H)，8.03(ddd，J＝14.0，7.4，2.5Hz，1H)，7.55(d，J＝5.3Hz，1H)，7.49(d，J＝9.3Hz，1H)，7.42-7.33(m，3H)，7.26-7.17(m，2H)，4.35(t，J＝8.3Hz，2H)，4.05(s，2H)，3.31-3.26(m，2H).
Example 169: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((5-fluoropyridin-2-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A169)
Figure GPA0000243696240000902
LCMS：t＝1.65min，ESI：[M+H]+m/z 469.
1H NMR(400MHz，DMSO-d6)δ10.05(s，1H)，8.62(d，J＝5.3Hz，1H)，8.38(d，J＝5.3Hz，2H)，8.34-8.26(m，2H)，7.82-7.70(m，1H)，7.60(d，J＝5.2Hz，1H)，7.44-7.29(m，2H)，7.29-7.15(m，2H)，4.35(t，J＝8.3Hz，2H)，4.05(s，2H)，3.32-3.26(m，2H).
Example 170: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((1- (2-hydroxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A170)
Figure GPA0000243696240000903
LCMS：t＝1.76min，ESI：[M+H]+m/z 498.
1H NMR(400MHz，DMSO-d6)δ9.55(s，1H)，8.49(s，1H)，8.33(d，J＝8.1Hz，2H)，7.96(s，1H)，7.55(s，1H)，7.38(dd，J＝13.1，6.3Hz，3H)，7.29-7.15(m，2H)，4.91(s，1H)，4.35(t，J＝8.2Hz，2H)，4.05(s，2H)，3.98(s，3H)，3.29(t，J＝7.6Hz，2H)，1.04(d，J＝5.4Hz，3H).
Example 171: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((1- (2-hydroxypropyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A171)
Figure GPA0000243696240000904
LCMS：t＝1.74min，ESI：[M+H]+m/z 498.
1H NMR(400MHz，DMSO-d6)δ9.55(s，1H)，8.49(s，1H)，8.33(d，J＝8.1Hz，2H)，7.96(s，1H)，7.55(s，1H)，7.38(dd，J＝13.1，6.3Hz，3H)，7.29-7.15(m，2H)，4.91(s，1H)，4.35(t，J＝8.2Hz，2H)，4.05(s，2H)，3.98(s，3H)，3.29(t，J＝7.6Hz，2H)，1.04(d，J＝5.4Hz，3H).
Example 172: 1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (1H-pyrazol-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carboxylic acid amide (A172)
Figure GPA0000243696240000911
In a dry 50mL reaction flask, 1(50mg, 0.11mmol), DCM (14mL) and water (0.8mL), TFA (4.56g, 40mmol) were added sequentially at room temperature. The reaction was stirred for 18H at 50 ℃ and purified by preparative chromatography neutral prep to give the product 1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (1H-pyrazol-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carboxylic acid amide a172(6.5mg, yellow solid) in yield: 12.5 percent
LCMS：m/z474.1(M+H)；RT＝3.45min(10min).
1H NMR(400MHz，dmso)：δ12.47(s，1H)，9.45(s，1H)，8.42(d，J＝5.2Hz，1H)，8.06(s，2H)，7.91(s，1H)，7.59(s，2H)，7.45-7.33(m，2H)，7.31-7.16(m，3H)，7.08(s，1H)，4.22(t，J＝7.8Hz，2H)，3.94(s，2H)，3.16(t，J＝7.6Hz，2H).
The following 173-compounds were prepared analogously to example 172:
example 173: 1- [2- (2-chloro-phenyl) -acetyl ] -5- [2- (1H-pyrazol-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carboxylic acid (A173)
Figure GPA0000243696240000912
LCMS：m/z475.0(M+H)；RT＝3.64min(10min).
1H NMR(400MHz，dmso)：δ12.52(s，2H)，9.46(s，1H)，8.42(d，J＝5.0Hz，1H)，8.13(d，J＝30.3Hz，2H)，7.74(s，2H)，7.37(dd，J＝12.1，7.4Hz，2H)，7.30-7.09(m，3H)，4.25(s，2H)，3.98(s，2H)，3.19(s，2H).
Example 174: synthesis of 4- ((4- (1- (2- (2-chlorophenyl) acetyl) -7-cyanoindolin-5-yl) pyrimidin-2-yl) amino) benzoic acid (A174)
Figure GPA0000243696240000913
LCMS：t＝1.55min，ESI：[M+H]+m/z 494.
1H NMR(400MHz，DMSO-d6)δ10.06(s，1H)，8.63(d，J＝5.2Hz，1H)，8.39(d，J＝4.1Hz，2H)，8.29(d，J＝9.3Hz，1H)，8.23-8.17(m，1H)，7.89(s，3H)，7.57(d，J＝5.3Hz，1H)，7.45-7.28(m，2H)，7.27-7.15(m，2H)，4.35(t，J＝8.1Hz，3H)，4.06(s，2H)，3.55-3.10(m，17H)，2.10-1.86(m，1H)，0.85(s，1H).
Example 175: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((4- (4-methylpiperazine-1-carbonyl) phenyl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A175)
Figure GPA0000243696240000914
LCMS：t＝1.87min，ESI：[M+H]+m/z 576.
1H NMR(400MHz，DMSO-d6)δ9.84-9.64(m，1H)，8.62(d，J＝5.2Hz，1H)，8.38(d，J＝7.7Hz，2H)，7.92(d，J＝8.7Hz，2H)，7.57(d，J＝5.2Hz，1H)，7.46(d，J＝8.6Hz，3H)，7.42-7.32(m，2H)，7.21(d，J＝7.9Hz，3H)，4.36(s，2H)，4.06(s，3H)，3.29(d，J＝7.8Hz，4H)，3.13-3.05(m，2H)，2.83(s，4H)，2.67(s，1H).
Example 176: synthesis of benzyl 4- ((4- (7-cyano-1- (2- (2-fluorophenyl) acetyl) indolin-5-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (A176)
Figure GPA0000243696240000921
LCMS：t＝2.18min，ESI：[M+H]+m/z 591.
1H NMR(400MHz，DMSO-d6)δ8.36(s，1H)，8.28(s，2H)，7.37(d，J＝5.9Hz，5H)，7.29(d，J＝8.0Hz，1H)，7.26-7.17(m，3H)，5.09(s，2H)，4.33(t，J＝8.3Hz，2H)，4.04(s，2H)，3.98(d，J＝13.2Hz，2H)，3.30(s，1H)，3.26(t，J＝8.2Hz，2H)，3.13-2.89(m，3H)，1.90(d，J＝9.8Hz，2H)，1.50-1.32(m，2H).
Example 177: synthesis of 5- (2- (1-cyano-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A177)
Figure GPA0000243696240000922
LCMS：m/z 465.1(M+H)；RT＝4.119min(9min).
1H NMR(dmso，400MHz)δ10.72(s，1H)，8.67(d，J＝5.3Hz，1H)，8.60(d，J＝2.9Hz，1H)，8.41(d，J＝2.1Hz，2H)，7.67(d，J＝5.3Hz，1H)，7.47-7.38(m，2H)，7.32-7.24(m，2H)，7.22(d，J＝2.9Hz，1H)，4.41(t，J＝8.2Hz，2H)，4.11(s，2H)，3.36-3.31(m，2H).
Example 178: synthesis of 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (2-methyl-2H- [1, 2, 3] triazol-4-ylamino) -pyrimidin-4-yl ] -6-oxo-2, 3-dihydro-1H-indole-7-carbonitrile (A178)
Figure GPA0000243696240000923
LCMS：m/z 455.1(M+H)；RT＝4.809min(10min).
1H NMR(dmso，400MHz)δ10.31(s，1H)，8.57(d，J＝5.2Hz，1H)，8.34(s，2H)，8.01(s，1H)，7.51(d，J＝5.3Hz，1H)，7.44-7.30(m，2H)，7.28-7.13(m，2H)，4.34(t，J＝8.2Hz，2H)，4.07(s，3H)，4.05(s，2H)，3.28d，J＝8.1Hz，2H).
Example 179: 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carboxylic acid amide (a179)
Figure GPA0000243696240000924
LCMS：m/z472.1(M+H)；RT＝4.43min(10min).
1H NMR(400MHz，dmso)：δ9.44(s，1H)，8.45(d，J＝5.3Hz，1H)，8.03(s，2H)，7.49(s，1H)，7.42-7.21(m，4H)，7.21-6.99(m，3H)，6.26(d，J＝1.6Hz，1H)，4.22(t，J＝7.9Hz，2H)，3.87(s，2H)，3.64-3.58(m，3H)，3.15(t，J＝7.8Hz，2H).
Example 180: 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carboxylic acid (A180)
Figure GPA0000243696240000931
LCMS：m/z473.1(M+H)；RT＝4.64min(10min).
1H NMR(400MHz，dmso)：δ12.55(s，1H)，9.44(s，1H)，8.44(d，J＝5.2Hz，1H)，8.12(d，J＝11.4Hz，2H)，7.40(d，J＝5.3Hz，1H)，7.30(q，J＝6.5Hz，3H)，7.21-7.07(m，2H)，6.23(d，J＝1.5Hz，1H)，4.26(t，J＝8.1Hz，2H)，3.92(s，2H)，3.66(s，3H)，3.20(t，J＝7.9Hz，2H).
Example 181: synthesis of 1- (5-bromo-7-methoxyindol-1-yl) -2- (2-chlorophenyl) ethanone Compound (84)
Figure GPA0000243696240000932
In a dry 50mL single-necked flask, compound 83(310mg, 1.36mmol), o-chlorophenylacetic acid (927mg, 5.44mmol), HATU (2.07g, 5.44mmol), TEA (826mg, 8.16mmol) and DMF (3mL) were added in this order at room temperature and reacted for 16 hours at room temperature. After LCMS detection of reaction completion, the reaction was quenched by addition of water (10ML), extracted with EA, the organic phases were combined, washed with saturated brine, concentrated under reduced pressure and the resulting residue was purified with comiwash (EA/PE ═ 0% to 30%) to give the product 1- (5-bromo-7-methoxyindol-1-yl) -2- (2-chlorophenyl) ethanone 84(500mg, yellow solid) in yield: 96.7 percent
LCMS：m/z380.8(M+H)；RT＝6.10min(9min).
Synthesis of (2-chlorophenyl) -1- (7-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indol-1-yl) ethanone Compound (85)
Figure GPA0000243696240000933
In a dry 50mL single-necked flask at room temperature were added compound 84(120mg, 0.315mmol), pinacol diboron (160mg, 0.63mmol), Pd (dppf) Cl2(23mg, 0.0315mmol), potassium acetate (62mg, 0.63mmol) and 1, 4-dioxane (2mL), and the nitrogen gas was replaced 3 times. The mixture was stirred and heated to 110 ℃ to react for 3 hours. After LCMS check reaction was complete, filtration and concentration of filtrate under reduced pressure purified the resulting residue with comiflash (EA/PE 0% -20%) to give the product (2-chlorophenyl) -1- (7-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indol-1-yl) ethanone 85(110mg, yellow solid), yield: 81.5 percent
LCMS：m/z 428.1(M+H)；RT＝6.19min(9min).
Synthesis of 1- (5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -7-methoxyindol-1-yl) -2- (2-chlorophenyl) ethanone Compound (A181)
Figure GPA0000243696240000941
85(50mg, 0.117mmol), 86(32mg, 0.152mmol), Pd (dppf) were added successively at room temperature to a dry 50mL microwave tube2Cl2(9mg, 0.0117mmol), potassium carbonate (32mg, 0.234mmol), 1, 4-dioxane (1mL) and water (0.25mL), and nitrogen was substituted 3 times. The reaction was heated to 90 ℃ for 1 hour. LCMS detection reaction is completed, filtration is carried out, filtrate is decompressed and concentrated, and then the product is purified by prep-HPLCThe product, 1- (5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -7-methoxyindol-1-yl) -2- (2-chlorophenyl) ethanone a182(25mg, yellow solid) was obtained after residue (yield): 45 percent of
LCMS：m/z475.1(M+H)；RT＝5.44min(9min).
1H NMR(dmso，400MHz)δ9.45(s，1H)，8.47(d，J＝5.3Hz，1H)，7.69(s，2H)，7.45(d，J＝5.3Hz，1H)，7.41-7.30(m，3H)，7.29-7.21(m，2H)，6.28(d，J＝1.7Hz，1H)，4.12(t，J＝7.5Hz，2H)，3.88(s，2H)，3.86(s，3H)，3.67(s，3H)，3.01(t，J＝7.4Hz，2H).
The following 182-197 compounds were prepared using a similar procedure to that used in example 181.
Example 182: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- (((1s, 3s) -3-hydroxycyclobutyl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A182)
Figure GPA0000243696240000942
LCMS：t＝1.76min，ESI：[M+H]+m/z 444.
1H NMR(400MHz，DMSO-d6)δ8.36(s，1H)，8.28(s，2H)，7.57(d，J＝6.4Hz，1H)，7.38(s，2H)，7.25-7.16(m，3H)，4.99(s，1H)，4.33(t，J＝8.0Hz，2H)，4.04(s，2H)，3.30(s，2H)，3.30-3.23(m，2H)，2.21(s，4H).
Example 183: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- (((1r, 3r) -3-hydroxycyclobutyl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A183)
Figure GPA0000243696240000943
LCMS：t＝1.78min，ESI：[M+H]+m/z 444.
1H NMR(400MHz，DMSO-d6)δ8.33(s，1H)，8.27(s，2H)，7.50(d，J＝7.2Hz，1H)，7.38(s，2H)，7.21(dd，J＝14.5，7.0Hz，3H)，5.05(d，J＝5.9Hz，1H)，4.33(t，J＝8.3Hz，2H)，4.04(s，2H)，3.87(s，2H)，3.29-3.23(m，3H)，2.60(s，2H)，1.84(s，2H).
Example 184: synthesis of 5- (2- ((1- (dimethylamino) propan-2-yl) amino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A184)
Figure GPA0000243696240000944
LCMS：t＝1.88min，ESI：[M+H]+m/z 459.
1H NMR(400MHz，DMSO-d6)δ8.34(d，J＝4.9Hz，1H)，8.29(s，2H)，7.38(t，J＝7.7Hz，2H)，7.25-7.16(m，3H)，6.99(d，J＝7.9Hz，1H)，4.33(t，J＝8.3Hz，2H)，4.16(s，1H)，4.04(s，2H)，3.25(t，J＝8.2Hz，2H)，2.37(dd，J＝19.1，12.2Hz，2H)，2.17(s，6H)，1.16(d，J＝8.0Hz，3H).
Example 185: synthesis of 5- (2- (2-hydroxypropylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile (A185)
Figure GPA0000243696240000951
LCMS：m/z 449.1(M+H)；RT＝4.164min(9min).
1H NMR(dmso，400MHz)δ8.32(dd，J＝13.3，11.2Hz，4H)，7.85(dd，J＝7.5，1.7Hz，1H)，7.42(dd，J＝7.5，4.8Hz，1H)，7.28(s，1H)，7.24(d，J＝5.4Hz，1H)，4.34(t，J＝8.2Hz，2H)，4.11(s，2H)，4.04-3.99(m，1H)，3.81(s，1H)，3.25(t，J＝8.1Hz，4H)，1.06(d，J＝6.2Hz，3H).
Example 186: synthesis of 5- (2- (2- (sulfonamido) ethylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A186)
Figure GPA0000243696240000952
LCMS：m/z 481.1(M+H)；RT＝4.822min(9min).
1H NMR(dmso，400MHz)δ8.51-8.30(m，3H)，7.54-7.32(m，4H)，7.29-7.17(m，2H)，6.99(s，2H)，4.37(t，J＝8.2Hz，2H)，4.08(s，2H)，3.79(s，2H)，3.30(t，J＝8.0Hz，4H).
Example 187: synthesis of 5- (2- (2- (methylsulfonyl) ethylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile Compound (A187)
Figure GPA0000243696240000953
LCMS：m/z497.1(M+H)；RT＝4.41min(9min).
1H NMR(400MHz，dmso)δ8.43-8.24(m，4H)，7.85(dd，J＝7.6，1.9Hz，1H)，7.51-7.38(m，2H)，7.29(d，J＝5.3Hz，1H)，4.34(t，J＝8.3Hz，2H)，4.11(s，2H)，3.74(s，2H)，3.38(t，J＝6.7Hz，2H)，3.25(t，J＝8.2Hz，2H)，3.00(s，3H).
Example 188: 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-methyl-2H- [1, 2, 3] triazol-4-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A188)
Figure GPA0000243696240000954
LCMS：m/z472.0(M+H)；RT＝4.87min(10min).
1H NMR(400MHz，dmso)δ10.28(s，1H)，8.53(d，J＝5.2Hz，1H)，8.40-8.25(m，3H)，7.97(s，1H)，7.85(dd，J＝7.5，1.9Hz，1H)，7.51-7.38(m，2H)，4.35(t，J＝8.2Hz，2H)，4.12(s，2H)，4.03(s，3H)，3.27(d，J＝8.3Hz，2H).
Example 189: synthesis of 5- (2- (2- (sulfonamido) ethylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile (A189)
Figure GPA0000243696240000961
LCMS：m/z 498.0(M+H)；RT＝4.204min(9min).
1H NMR(dmso，400MHz)δ8.51-8.38(m，3H)，8.35(s，1H)，7.92(dd，J＝7.6，1.9Hz，1H)，7.50(dd，J＝7.5，4.8Hz，1H)，7.41(s，1H)，7.35(d，J＝5.2Hz，1H)，6.99(s，2H)，4.41(t，J＝8.1Hz，2H)，4.19(s，2H)，3.80(s，2H)，3.32(t，J＝8.1Hz，4H).
Example 190: synthesis of 5- (2- (1-hydroxymethylcyclopropylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile Compound (A190)
Figure GPA0000243696240000962
LCMS：m/z444.1(M+H)；RT＝4.83min(9min).
1H NMR(dmso，400MHz)δ8.36(s，1H)，8.28(d，J＝5.7Hz，2H)，7.41-7.24(m，3H)，7.23-7.09(m，2H)，4.30(t，J＝8.2Hz，3H)，4.01(s，2H)，3.54(s，2H)，3.23(t，J＝8.2Hz，2H)，0.80(t，J＝5.7Hz，2H)，0.69(s，2H).
Example 191: 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carboxamide (A191)
Figure GPA0000243696240000963
LCMS：m/z488.1(M+H)；RT＝4.14min(9min).
1H NMR(400MHz，dmso)δ9.44(s，1H)，8.46(d，J＝5.3Hz，1H)，8.05(d，J＝2.8Hz，2H)，7.51(s，1H)，7.44-7.34(m，3H)，7.33(d，J＝1.9Hz，1H)，7.30-7.19(m，2H)，7.08(s，1H)，6.26(d，J＝1.8Hz，1H)，4.22(t，J＝7.9Hz，2H)，3.94(s，2H)，3.67(s，3H)，3.15(t，J＝7.8Hz，2H).
Example 192: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carboxylic acid (A192)
Figure GPA0000243696240000964
LCMS：m/z489.1(M+H)；RT＝4.06min(9min).
1H NMR(400MHz，dmso)δ12.56(s，1H)，9.44(s，1H)，8.45(d，J＝5.3Hz，1H)，8.12(d，J＝11.1Hz，2H)，7.44-7.39(m，2H)，7.38-7.34(m，1H)，7.32(d，J＝1.9Hz，1H)，7.30-7.24(m，2H)，6.23(d，J＝1.8Hz，1H)，4.27(t，J＝8.1Hz，2H)，4.00(s，2H)，3.66(s，3H)，3.21(t，J＝8.2Hz，2H).
Example 193: synthesis of 5- (2- (2- (sulfonamido) ethylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A193)
Figure GPA0000243696240000965
LCMS：m/z 497.1(M+H)；RT＝5.012min(9min).
1H NMR(dmso，400MHz)δ8.44(s，1H)，8.33(s，2H)，7.54-7.46(m，2H)，7.43-7.31(m，4H)，6.98(s，2H)，4.38(t，J＝8.2Hz，2H)，4.15(s，2H)，3.79(s，2H)，3.31(t，J＝7.4Hz，4H).
Example 194: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) -5-fluoropyridin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A194)
Figure GPA0000243696240000971
LCMS：m/z 472.1(M+H)；RT＝5.513min(9min).
1H NMR(dmso，400MHz)δ9.56(s，1H)，8.60(d，J＝3.6Hz，1H)，8.11(s，2H)，7.41-7.25(m，3H)，7.22-7.13(m，2H)，6.22(d，J＝1.8Hz，1H)，4.31(t，J＝8.3Hz，2H)，4.02(s，2H)，3.66(s，3H)，3.25(t，J＝8.3Hz，2H).
Example 195: synthesis of tert-butyl 4- (4- ((4- (7- (cyano-1- (2- (2-fluorophenyl) acetyl) indolin-5-yl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (A195)
Figure GPA0000243696240000972
LCMS：t＝2.13min，ESI：m/z 523，567.
1H NMR(400MHz，DMSO-d6)δ8.34(d，J＝4.9Hz，1H)，8.29(s，2H)，7.38(t，J＝7.7Hz，2H)，7.25-7.16(m，3H)，6.99(d，J＝7.9Hz，1H)，4.33(t，J＝8.3Hz，2H)，4.16(s，1H)，4.04(s，2H)，3.25(t，J＝8.2Hz，2H)，2.37(dd，J＝19.1，12.2Hz，2H)，2.17(s，6H)，1.16(d，J＝8.0Hz，3H).
Example 196: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((1- (piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) nitrile (A196)
Figure GPA0000243696240000973
LCMS：t＝1.50min，ESI：[M+H]+m/z 523.
1H NMR(400MHz，DMSO-d6)δ9.56(s，1H)，8.50(s，1H)，8.34(s，2H)，8.02(s，1H)，7.53(s，1H)，7.38(dd，J＝11.4，6.4Hz，3H)，7.28-7.17(m，2H)，4.35(t，J＝8.3Hz，2H)，4.21-4.11(m，1H)，4.05(s，2H)，3.32-3.28(m，2H)，3.04(d，J＝13.0Hz，2H)，2.58(t，J＝11.8Hz，2H)，1.98(dt，J＝19.6，10.6Hz，2H)，1.81-1.70(m，2H).
Example 197: synthesis of 1- (2-cyclohexylacetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A197)
Figure GPA0000243696240000974
LCMS：t＝2.07min，ESI：[M+H]+m/z 442.
1H NMR(400MHz，DMSO-d6)δ8.66(d，J＝5.4Hz，1H)，8.08(d，J＝1.6Hz，1H)，7.95(s，1H)，7.82(d，J＝5.5Hz，1H)，7.61(s，1H)，7.44(d，J＝1.9Hz，1H)，6.21(d，J＝1.9Hz，1H)，3.74-3.63(m，5H)，3.10(t，J＝8.5Hz，2H)，2.56(d，J＝6.8Hz，2H)，1.86-1.76(m，1H)，1.74-1.55(m，5H)，1.27-1.06(m，3H)，0.92(dd，J＝22.8，10.8Hz，2H).
Example 198: synthesis of 4- (tert-butyl-dimethyl-silanyloxy) -1, 2, 3, 4-tetrahydro-quinoline Compound (2)
Figure GPA0000243696240000981
In a dry 100mL one-neck flask, compound 87(800mg, 5.36mmol), DCM (12mL) were added sequentially at room temperature, after cooling to 0 deg.C TBSCl (1212mg, 8.04mmol), and imidazole (922mg, 9.112mmol) were added slowly and stirred at room temperature for 4 h. After completion of the reaction by LCMS, quench with 0.2mL of water, add ethyl acetate (20mL), wash with saturated sodium carbonate solution and brine respectively, dry the organic phase over anhydrous sodium sulfate, filter the filtrate and concentrate under reduced pressure to give a crude product which is purified with comiwash (EA/PE ═ 2% to 10%) to give the product 4- (tert-butyl-dimethyl-silanyloxy) -1, 2, 3, 4-tetrahydro-quinoline 88(1.2g, colorless liquid), yield: 88 percent.
LCMS：m/z264.1(M+H)；RT＝8.35min(10min).
Synthesis of 6-bromo-4- (tert-butyl-dimethyl-silanyloxy) -1, 2, 3, 4-tetrahydro-quinoline Compound (89)
Figure GPA0000243696240000982
In a dry 100mL single neck flask compound 88(300mg, 1.138mmol), DCM (10mL) was added sequentially at room temperature, cooled to 0 degrees and NBS (202mg, 1.138mmol) was added slowly, stirred at 0 degrees for 1 hour and at 10 degrees for 1 hour. After LCMS detection of reaction completion, 0.2mL of water was added for quenching, ethyl acetate (20mL) was added, washed with saturated sodium carbonate solution and brine, the organic phase was dried over anhydrous sodium sulfate, the filtrate was filtered and concentrated under reduced pressure to give a crude product which was purified with comiwash (EA/PE ═ 1% to 13%) to give the product 6-bromo-4- (tert-butyl-dimethyl-silanyloxy) -1, 2, 3, 4-tetrahydro-quinoline 89(250mg, colorless liquid), yield: 64 percent
LCMS：m/z343.1(M+H)；RT＝7.6min(10min).
Synthesis of 1- [ 6-bromo-4- (tert-butyl-dimethyl-silanyloxy) -3, 4-dihydro-2H-quinolin-1-yl ] -2- (2-chloro-phenyl) -ethanone (90)
Figure GPA0000243696240000983
In a dry 50mL one-necked flask, compound 89(230mg, 0.672mmol), 2-chlorophenylacetic acid (252mg, 1.478mmol), HATU (613mg, 1.613mmol), TEA (191mg, 1.882mmol) and DMF (3mL) were added in this order at room temperature and reacted for 16 hours at room temperature. After LCMS check reaction was complete, the reaction was quenched by addition of water (10ML), extracted with EA, the organic phases were combined, washed with saturated brine, and after organic phase concentration under reduced pressure, the resulting residue was purified with comiwash (EA/PE ═ 10% to 50%) to give the product 1- [ 6-bromo-4- (tert-butyl-dimethyl-silanyloxy) -3, 4-dihydro-2H-quinolin-1-yl ] -2- (2-chloro-phenyl) -ethanone 90(500mg, colorless liquid), yield: 66 percent
LCMS：m/z495.1(M+H)；RT＝6.8min(10min).
Synthesis of [4- (tert-butyl-dimethyl-silanyloxy) -6- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -3, 4-dihydro-2H-quinolin-1-yl ] -2- (2-chloro-phenyl) -ethanone Compound (91)
Figure GPA0000243696240000991
In a dry 50mL single-necked flask at room temperature were added sequentially compound 90(180mg, 0.364mmol), pinacol diboron (184mg, 0.728mmol), Pd (dppf) Cl2(40mg, 0.0546mmol), potassium acetate (72mg, 0.728mmol) and 1, 4-dioxane (4mL), and nitrogen was purged 3 times. The mixture was heated to 110 ℃ with stirring and reacted for 2 hours. After LCMS detection, filtration and concentration of the filtrate under reduced pressure purification of the resulting residue with comiwash (EA/PE 10% to 50%) gave the product 1- [4- (tert-butyl-dimethyl-silanyloxy) -6- (4, 4, 5, 5-tetramethyl- [1, 3, 2]]Dioxolane-2-yl) -3, 4-dihydro-2H-quinolin-1-yl]-2- (2-chloro-phenyl) -ethanone 91(110mg, colorless liquid), yield: 87 percent of
LCMS：m/z 500.1(M+H)；RT＝7.5min(10min).
{4- (tert-butyl-dimethyl-silanyloxy) -6- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -3, 4-dihydro-2H-quinolin-1-yl } -2- (2-chloro-phenyl) -ethanone (92)
Figure GPA0000243696240000992
91(100mg, 0.2mmol), 86(51mg, 0.24mmol), Pd (dppf) were added sequentially to a dry 50mL microwave tube at room temperature2Cl2(22mg, 0.03mmol), potassium carbonate (61mg, 0.44mmol), 1, 4-dioxane (3mL) and water (0.5mL), and nitrogen was replaced 3 times. The reaction was heated to 105 ℃ for 2 hours. After completion of the reaction by LCMS detection, filtration and concentration of the filtrate under reduced pressure, the resulting residue was purified by prep-HPLC to give the product 1- {4- (tert-butyl-dimethyl-silanyloxy) -6- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl]-3, 4-dihydro-2H-quinolin-1-yl } -2- (2-chloro-phenyl) -ethanone 92(95mg, yellow liquid), yield: 86 percent of the total weight
LCMS：m/z548.2(M+H)；RT＝7.18min(10min).
Synthesis of 2- (2-chloro-phenyl) -1- { 4-hydroxy-6- [2- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -3, 4-dihydro-2H-quinolin-1-yl } -ethanone Compound (A198)
Figure GPA0000243696240000993
92(100mg, 0.183mmol), Bu were added sequentially to a dry 50mL microwave tube at room temperature4NF (1mL, 1mol/L) solution, THF (2 mL). The reaction was stirred at room temperature for 18 hours. After LCMS detection, the reaction is filtered, the filtrate is decompressed and concentrated, and the obtained residue is purified by prep-HPLC to obtain the product 2- (2-chloro-phenyl) -1- { 4-hydroxy-6- [2- (2-methyl-2H-pyrazol-3-yl amino) -pyrimidine-4-yl]-3, 4-dihydro-2H-quinolin-1-yl } -ethanone a198(20mg, yellow solid), yield: 23.2 percent
LCMS：m/z475.1(M+H)；RT＝4.85min(10min).
1H NMR(dmso，400MHz)δ9.48(s，1H)，8.50(d，J＝5.3Hz，1H)，8.26(d，J＝1.8Hz，1H)，7.98(dd，J＝8.7，2.0Hz，1H)，7.78(s，1H)，7.47-7.24(m，5H)，6.30(d，J＝1.8Hz，1H)，4.70-4.63(m，1H)，4.10-4.00(m，3H)，3.71(s，3H)，3.67(s，1H)，2.23-2.11(m，1H)，1.84(d，J＝7.1Hz，1H).
Example 199: synthesis of 5- [ 5-chloro-2- (2-methyl-2H-pyrazol-3-ylamine) -pyridin-4-yl ] -1- [2- (2-chloro-pyridin-3-yl) -acetyl ] - -6-oxo-2, 3-dihydro-1H-indole-7-carbonitrile (A199)
Figure GPA0000243696240001001
LCMS：m/z 504.2，505.2(M+H)；RT＝5.043min(10min).
1H NMR(dmso，400MHz)δ9.07(s，1H)，8.37(dd，J＝4.7，1.8Hz，1H)，8.26(s，1H)，7.89(dd，J＝7.5，1.8Hz，1H)，7.72(s，1H)，7.67(d，J＝1.4Hz，1H)，7.46(dd，J＝7.5，4.7Hz，1H)，7.36(d，J＝1.9Hz，1H)，6.81(s，1H)，6.27(d，J＝1.8Hz，1H)，4.37(t，J＝8.1Hz，2H)，4.15(s，2H)，3.68(s，3H)，3.27(t，J＝8.0Hz，2H).
Example 200: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carboxamide (A200)
Figure GPA0000243696240001002
LCMS：m/z489.1(M+H)；RT＝3.86min(9min).
1H NMR(400MHz，dmso)δ9.43(s，1H)，8.46(d，J＝5.3Hz，1H)，8.29(dd，J＝4.7，1.8Hz，1H)，8.05(s，2H)，7.83(dd，J＝7.5，1.9Hz，1H)，7.51(s，1H)，7.42-7.35(m，2H)，7.32(d，J＝1.8Hz，1H)，7.08(s，1H)，6.25(d，J＝1.7Hz，1H)，4.25(t，J＝8.0Hz，2H)，3.98(s，2H)，3.67(s，3H)，3.17(t，J＝7.8Hz，2H).
Example 201: synthesis of 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((4- (piperazin-1-ylsulfonyl) phenyl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A201)
Figure GPA0000243696240001003
LCMS：t＝2.00min，ESI：[M+H]+m/z 598.
1H NMR(400MHz，DMSO-d6)1H NMR(400MHz，DMSO)δ8.42(d，J＝5.2Hz，1H)，8.32(s，1H)，8.28(s，1H)，7.36(d，J＝8.6Hz，3H)，7.30(d，J＝5.2Hz，1H)，7.21(d，J＝8.0Hz，2H)，6.62(d，J＝8.6Hz，2H)，6.09(s，2H)，4.32(t，J＝8.2Hz，2H)，4.04(s，2H)，3.91(s，4H)，3.25(t，J＝8.1Hz，2H)，2.88(s，4H).
Example 202: 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-hydroxy-2-methyl-propylamino) -pyrimidin-4-yl ] -1H-indole-7-carbonitrile (A202)
Figure GPA0000243696240001004
LCMS：m/z463.1(M+H)；RT＝4.52min(10min).
1H NMR(400MHz，dmso)δ8.43-8.20(m，4H)，7.85(dd，J＝7.5，1.8Hz，1H)，7.43(dd，J＝7.5，4.8Hz，1H)，7.24(d，J＝5.7Hz，1H)，7.11(s，1H)，4.34(t，J＝8.2Hz，2H)，4.12(s，2H)，3.35(s，3H)，3.26(t，J＝8.1Hz，2H)，1.11(s，6H).
Example 203: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) -5-fluoropyridin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile (A203)
Figure GPA0000243696240001011
LCMS：m/z 489.0(M+H)；RT＝4.955min(9min).
1H NMR(dmso，400MHz)δ9.64(s，1H)，8.67(d，J＝3.5Hz，1H)，8.41(dd，J＝4.8，1.9Hz，1H)，8.19(d，J＝4.6Hz，2H)，7.93(dd，J＝7.6，1.8Hz，1H)，7.50(dd，J＝7.5，4.8Hz，1H)，7.40(d，J＝1.9Hz，1H)，6.30(d，J＝1.9Hz，1H)，4.42(t，J＝8.2Hz，2H)，4.20(s，2H)，3.73(s，3H)，3.35(t，J＝8.1Hz，2H).
Example 204: synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile Compound (A204)
Figure GPA0000243696240001012
LCMS：m/z539.0(M+H)；RT＝5.62min(9min).
1H NMR(dmso，400MHz)δ10.22(s，1H)，8.85(s，1H)，8.34(dd，J＝4.8，1.9Hz，1H)，7.85(dd，J＝7.5，1.9Hz，1H)，7.68(d，J＝17.6Hz，2H)，7.43(dd，J＝7.5，4.8Hz，1H)，7.34(s，1H)，6.22(d，J＝1.8Hz，1H)，4.34(t，J＝8.2Hz，2H)，4.12(s，2H)，3.66(s，3H)，3.24(t，J＝8.3Hz，2H).
Example 205: synthesis of 1- (5-bromo-7-nitroindolin-1-yl) -2- (2-fluorophenyl) ethan-1-one (94)
Figure GPA0000243696240001013
To a solution of compound 93(1.0g, 4.1mmol) and o-fluorophenylacetic acid (950mg, 6.2mmol) in toluene was slowly added dropwise SOCl with stirring at 0 deg.C2(9.6g, 80.4mmol) and the reaction was left to react overnight at 75 ℃. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun dry. The crude product was isolated by column chromatography (PE: EA: 3: 1) to give the title compound (820mg, 2.16mmol, as a red-brown solid) in 53% yield.
LCMS：t＝2.21min，ESI：[M+H]+m/z 379.
Synthesis of 1- (7-amino-5-bromoindolin-1-yl) -2- (2-fluorophenyl) ethan-1-one (95)
Figure GPA0000243696240001014
To a solution of compound 94(100mg, 0.26mmol) in ethanol was slowly added SnCl with stirring2(251mg, 1.32mmol) and the reaction was left at 75 ℃ overnight. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun-dried. The crude product was isolated by column chromatography (PE: EA: 3: 1) to give the title compound 95(70mg, 0.2mmol, yellow solid) in 77% yield.
LCMS：t＝2.00min，ESI：[M+H]+m/z 349.
1H NMR(400MHz，DMSO-d6)δ8.66(d，J＝5.4Hz，1H)，8.08(d，J＝1.6Hz，1H)，7.95(s，1H)，7.82(d，J＝5.5Hz，1H)，7.61(s，1H)，7.44(d，J＝1.9Hz，1H)，6.21(d，J＝1.9Hz，1H)，3.74-3.63(m，5H)，3.10(t，J＝8.5Hz，2H)，2.56(d，J＝6.8Hz，2H)，1.86-1.76(m，1H)，1.74-1.55(m，5H)，1.27-1.06(m，3H)，0.92(dd，J＝22.8，10.8Hz，2H).
Synthesis of 1- (7-amino-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indolin-1-yl) -2- (2-fluorophenyl) ethan-1-one (96)
Figure GPA0000243696240001021
To a dry 25mL round bottom flask was added sequentially compound 95(182mg, 0.52mmol), B2Pin2(199mg，0.78mmol)，KOAc(153mg，1.56mmol)，Pd(dppf)2Cl2(38mg, 0.05mmol), DMSO (3.0mL), nitrogen substitution 3 times, the reaction was placed in a90 ℃ oil bath for 0.5 h. After completion of the reaction, extraction was performed with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was separated by column chromatography (PE: EA ═ 2: 1) to obtain the objective compound 96(265mg, 0.52mmol, white solid) with a yield of 99%.
LCMS：t＝1.93min，ESI：[M+H]+m/z 396.
Synthesis of 1- (7-amino-5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indolin-1-yl) -2- (2-fluorophenyl) -1-one (A205)
Figure GPA0000243696240001022
To a dry 25mL round bottom flask was added compound 96(215mg, 0.54mmol), 86(227mg, 1.08mmol), NaHCO in that order3(181mg，2.16mmol)，Pd(dppf)2Cl2(59mg，0.08mmol)，1，4-dioxane(2.0mL)，H2O (0.5mL), replaced with nitrogen 3 times, and the reaction was placed in an oil bath at 70 ℃ for 2 hours. After the reaction was completed, extraction was performed with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was isolated by HPLC to obtain the objective compound a205(84mg, 0.19mmol, white solid) with a yield of 35%.
LCMS：t＝1.65min，ESI：[M+H]+m/z 444.
1H NMR(400MHz，DMSO-d6)δ9.39(s，1H)，8.45(d，J＝5.2Hz，1H)，7.39-7.28(m，5H)，7.25-7.16(m，3H)，6.29(d，J＝1.6Hz，1H)，5.42(s，2H)，4.20(t，J＝7.8Hz，2H)，4.03(s，2H)，3.70(s，3H)，3.09(t，J＝7.6Hz，2H).
The following 206-224 compounds were prepared using a method analogous to that of example 205:
example 206: synthesis of 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-hydroxy-1-methyl-ethylamino) -pyrimidin-4-yl ] -1H-indole-7-carbonitrile Compound (A206)
Figure GPA0000243696240001023
LCMS：m/z449.0(M+H)；RT＝4.20min(10min).
1H NMR(dmso，400MHz)δ8.50-8.12(m，4H)，7.88(d，J＝7.7Hz，1H)，7.46(dd，J＝7.5，4.8Hz，1H)，7.24(s，1H)，7.10(s，1H)，4.37(t，J＝8.1Hz，2H)，4.15(s，2H)，3.57-3.54(m，3H)，3.28(t，J＝8.0Hz，2H)，1.15(d，J＝6.6Hz，3H).
Example 207: 1- (2- (2-chloro-3-fluorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A207)
Figure GPA0000243696240001031
1H NMR(400MHz，CDCl3)δ8.46(d，J＝5.3Hz，1H)，8.15(s，1H)，8.09(s，1H)，7.52(d，J＝1.7Hz，1H)，7.39(s，1H)，7.26-7.23(m，2H)，7.17(d，J＝5.4Hz，1H)，7.13-7.09(m，1H)，6.36(d，J＝1.7Hz，1H)，4.24(t，J＝8.2Hz，2H)，4.07(s，2H)，3.82(s，3H)，3.25(t，J＝8.2Hz，2H).
LC-MS：t＝1.69min，MS：[M+H]+m/z 488.1.
Example 208: 1- (2- (2, 6-dichlorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A208)
Figure GPA0000243696240001032
1H NMR(500MHz，CDCl3)δ8.45(d，J＝5.4Hz，1H)，8.15(s，1H)，8.11(s，1H)，7.52(d，J＝1.8Hz，1H)，7.37(s，1H)，7.35(s，1H)，7.21(d，J＝7.9Hz，1H)，7.18(d，J＝5.4Hz，1H)，6.36(d，J＝1.7Hz，1H)，4.35(t，J＝8.2Hz，2H)，4.25(s，2H)，3.83(s，3H)，3.32(t，J＝8.0Hz，2H).
LC-MS：t＝1.73min，MS：[M+H]+m/z 504.1.
Example 209: 1- (2- (2-chloro-6-fluorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A209)
Figure GPA0000243696240001033
1H NMR(400MHz，CDCl3)δ8.45(d，J＝5.3Hz，1H)，8.14(s，1H)，8.09(s，1H)，7.51(d，J＝1.9Hz，1H)，7.25-7.22(m，2H)，7.16(d，J＝5.3Hz，1H)，7.07-6.98(m，1H)，6.35(d，J＝1.9Hz，1H)，4.31(t，J＝8.2Hz，2H)，4.07(s，2H)，3.82(s，3H)，3.30(t，J＝8.2Hz，2H).
LC-MS：t＝1.69min，MS：[M+H]+m/z 488.1.
Example 210: 5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1- (2-phenylacetyl) indoline-7-carbonitrile (A210)
Figure GPA0000243696240001034
1H NMR(400MHz，CDCl3)δ8.42(d，J＝5.6Hz，1H)，8.15(s，1H)，8.05(s，1H)，7.53(d，J＝2.0Hz，1H)，7.38-7.36(m，4H)，7.31-7.30(m，1H)，7.21(d，J＝5.5Hz，1H)，6.38(d，J＝2.0Hz，1H)，4.15(t，J＝8.2Hz，2H)，3.95(s，2H)，3.84(s，3H)，3.17(t，J＝8.2Hz，2H).
LC-MS：t＝1.62min，MS：[SM+H]+m/z 426.2.
Example 211: 1- (2- (4-chlorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A211)
Figure GPA0000243696240001041
1H NMR(400MHz，CDCl3)δ8.46(d，J＝5.4Hz，1H)，8.15(s，1H)，8.06(s，1H)，7.51(d，J＝1.9Hz，1H)，7.36-7.28(m，4H)，7.17(d，J＝5.4Hz，1H)，6.36(d，J＝1.9Hz，1H)，4.16(t，J＝8.2Hz，2H)，3.82(s，3H)，3.20(t，J＝8.2Hz，2H).
LC-MS：t＝1.70min，MS：[SM+H]+m/z 470.1.
Example 212: 1- (2- (3-chlorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A212)
Figure GPA0000243696240001042
1H NMR(400MHz，CDCl3)δ8.47(d，J＝5.3Hz，1H)，8.15(s，1H)，8.07(s，1H)，7.51(d，J＝1.8Hz，1H)，7.36(s，1H)，7.33-7.27(m，3H)，7.15(d，J＝5.3Hz，1H)，7.00(s，1H)，6.34(d，J＝1.8Hz，1H)，4.17(t，J＝8.2Hz，2H)，3.91(s，2H)，3.81(s，3H)，3.20(t，J＝8.1Hz，2H).
LC-MS：t＝1.69min，MS：[SM+H]+m/z 470.1.
Example 213: 5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1- (2- (o-tolyl) acetyl) indoline-7-carbonitrile (A213)
Figure GPA0000243696240001043
1H NMR(400MHz，CDCl3)δ8.38(d，J＝5.9Hz，1H)，8.15(s，1H)，8.07(s，1H)，7.56(d，J＝1.7Hz，1H)，7.27-7.25(m，1H)，7.23-7.19(m，4H)，6.42(d，J＝1.8Hz，1H)，4.14(t，J＝8.2Hz，2H)，3.93(s，2H)，3.87(s，3H)，3.21(t，J＝8.1Hz，2H)，2.38(s，3H).
LC-MS：t＝1.68min，MS：[SM+H]+m/z 450.1
Example 214: 1- (2- (3, 4-dichlorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A214)
Figure GPA0000243696240001044
1H NMR(400MHz，DMSO-D6)δ8.53(d，J＝5.2Hz，1H)，8.32(s，1H)，8.30(s，1H)，7.63(d，J＝8.3Hz，1H)，7.60(d，J＝2.0Hz，1H)，7.52(d，J＝5.3Hz，1H)，7.37(d，J＝1.9Hz，1H)，7.32(dd，J＝8.3，2.0Hz，1H)，6.27(d，J＝1.7Hz，1H)，4.30(t，J＝8.1Hz，2H)，4.05(s，2H)，3.69(s，3H)，3.25(t，J＝8.1Hz，2H).
LC-MS：t＝1.76min，MS：[SM+H]+m/z 504.0.
Example 215: 1- ((2-chlorobenzyl) sulfonyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A215)
Figure GPA0000243696240001045
1H NMR(400MHz，CDCl3)δ8.45(d，J＝5.3Hz，1H)，8.13(s，1H)，8.04(s，1H)，7.66-7.63(m，1H)，7.52(d，J＝1.9Hz，1H)，7.45-7.41(m，1H)，7.39-7.31(m，2H)，7.18(d，J＝5.4Hz，1H)，6.38(d，J＝1.9Hz，1H)，5.03(s，2H)，3.84(s，3H)，3.71(t，J＝8.1Hz，2H)，3.07(t，J＝8.1Hz，2H).
LC-MS：t＝1.71min，MS：[SM+H]+m/z 506.0.
Example 216: 5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1- (2- (2- (trifluoromethyl) phenyl) acetyl) indoline-7-carbonitrile (A216)
Figure GPA0000243696240001051
1H NMR(400MHz，CD3OD)δ8.48(d，J＝5.3Hz，1H)，8.32(s，1H)，8.28(s，1H)，7.74(d，J＝8.1Hz，1H)，7.63(t，J＝7.9Hz，1H)，7.56-7.46(m，3H)，7.43(d，J＝5.4Hz，1H)，6.42(t，J＝2.0Hz，1H)，4.36(t，J＝8.2Hz，2H)，4.20(s，2H)，3.79(s，3H)，3.32(m，3H).
LC-MS：t＝1.72min，MS：[SM+H]+m/z 504.1.
Example 217: 1- (2- (2-fluoro-3- (trifluoromethyl) phenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -nitrile (A217)
Figure GPA0000243696240001052
1H NMR(400MHz，CDCl3)δ8.44(d，J＝5.5Hz，1H)，8.16(s，1H)，8.10(s，1H)，7.70(t，J＝7.1Hz，1H)，7.62-7.48(m，2H)，7.30-7.27(m，1H)，7.21(d，J＝5.5Hz，1H)，6.39(d，J＝1.9Hz，1H)，4.30(t，J＝8.2Hz，2H)，4.00(s，2H)，3.85(s，3H)，3.29(t，J＝8.3Hz，2H).
LC-MS：t＝1.74min，MS：[SM+H]+m/z 522.2.
Example 218: 1- (2- (6-Chloropyridin-3-yl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A218)
Figure GPA0000243696240001053
1H NMR(400MHz，CDCl3)δ8.50(d，J＝5.3Hz，1H)，8.33(d，J＝2.1Hz，1H)，8.16(s，1H)，8.10(s，1H)，7.79(dd，J＝8.3，2.5Hz，1H)，7.56(d，J＝2.0Hz，1H)，7.36(d，J＝8.2Hz，1H)，7.17(d，J＝5.3Hz，1H)，6.39(d，J＝2.0Hz，1H)，4.25(t，J＝8.2Hz，2H)，3.91(s，2H)，3.85(s，3H)，3.27(t，J＝8.3Hz，2H).
LC-MS：t＝1.55min，MS：[SM+H]+m/z 471.2.
Example 219: 5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1- (2- (pyrimidin-5-yl) acetyl) indoline-7-carbonitrile (A219)
Figure GPA0000243696240001054
LC-MS：t＝1.34min，MS：[SM+H]+m/z 438.2.
Example 220: 5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1- (2- (perfluorophenyl) acetyl) indoline-7-carbonitrile (A220)
Figure GPA0000243696240001061
1H NMR(400MHz，CDCl3)δ8.39(d，J＝5.6Hz，1H)，8.09(s，1H)，8.02(s，1H)，7.53(d，J＝2.0Hz，1H)，6.39(d，J＝1.9Hz，1H)，5.35-5.33(m，1H)，4.40(t，J＝8.0Hz，2H)，3.92(s，2H)，3.85(s，3H)，3.34(t，J＝8.1Hz，2H).
LC-MS：t＝1.74min，MS：[SM+H]+m/z 527.1.
Example 221: 1- (2- (2, 5-difluorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A221)
Figure GPA0000243696240001062
1H NMR(400MHz，CDCl3)δ8.42(d，J＝5.6Hz，1H)，8.15(s，1H)，8.09(s，1H)，7.54(d，J＝2.0Hz，1H)，7.23(d，J＝5.7Hz，1H)，7.20-7.14(m，1H)，7.10-7.02(m，1H)，7.01-6.94(m，1H)，6.40(d，J＝1.9Hz，1H)，4.26(t，J＝8.2Hz，2H)，3.92(s，2H)，3.86(s，3H)，3.27(t，J＝8.2Hz，2H).
LC-MS：t＝1.71min，MS：[SM+H]+m/z 472.2.
Example 222: 5- (2- ((2-cyanoethyl) amino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A222)
Figure GPA0000243696240001063
1H NMR(400MHz，DMSO-D6)δ8.40(d，J＝5.0Hz，1H)，8.30(s，1H)，7.65-7.58(m，1H)，7.42-7.32(m，2H)，7.29(d，J＝5.2Hz，1H)，7.25-7.15(m，2H)，4.33(t，J＝8.2Hz，2H)，4.04(s，2H)，3.65-3.55(m，2H)，3.26(t，J＝8.1Hz，2H)，2.85-2.75(m，2H).
LCMS：t＝1.63min，MS：[M+H]+m/z 427.3.
Example 223: 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A223)
Figure GPA0000243696240001064
1H NMR(400MHz，CDCl3)δ8.38(s，1H)，8.18(s，1H)，8.12(s，1H)，7.88(s，1H)，7.66(s，1H)，7.45(t，J＝7.4Hz，1H)，7.32-7.27(m，1H)，7.15(dd，J＝7.6Hz，1H)，7.09(ddt，J＝9.1Hz，1H)，7.04(d，J＝5.3Hz，1H)，4.55-4.45(m，6.7Hz，1H)，4.23(t，J＝8.1Hz，2H)，3.96(s，2H)，3.24(t，J＝8.1Hz，2H)，1.55(s，3H)，1.53(s，3H).
LCMS：t＝1.72min，MS：[M+H]+m/z 482.3.
Example 224: 1- (2- (2-fluorophenyl) acetyl) -5- (2- ((2-methylpyridin-4-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A224)
Figure GPA0000243696240001065
1H NMR(400MHz，DMSO-D6)δ11.34(s，1H)，8.82(d，J＝5.3Hz，1H)，8.50(d，J＝7.0Hz，1H)，8.43(s，1H)，8.40(s，1H)，8.18(s，1H)，8.02(s，1H)，7.88(d，J＝5.3Hz，1H)，7.42-7.32(m，2H)，7.26-7.17(m，2H)，4.37(t，J＝8.2Hz，2H)，4.06(s，2H)，3.30(t，J＝8.3Hz，2H)，2.63(s，3H).
LCMS：t＝1.59min，MS：[M+H]+m/z 461.1.
Example 225: synthesis of (6-chloro-pyrimidin-4-yl) - (2-methyl-2H-pyrazol-3-yl) -amine (99)
Figure GPA0000243696240001071
In a dry 50mL single neck flask compound 97(391mg, 4.027mmol), 98(400mg, 2.685mmol), Pd2(dba)3(246mg, 0.2685mmol), RuPhos (125mg, 0.2685mmol), TEA (326mg, 3.222mmol) and DMF (5mL) were added sequentially at room temperature, warmed to 90 ℃ and the reaction was stirred with a microwave for 2 hours. After completion of LCMS check reaction, the crude product was dissolved in 50mL EA and washed with water and saturated brine, respectively, concentrated and purified with combiflash (EA/PE 1/5-4/1) to give the product (6-chloro-pyrimidin-4-yl) - (2-methyl-2H-pyrazol-3-yl) -amine 99(170mg, yellow solid) in yield: 30.2 percent.
LCMS：m/z210.0(M+H)；RT＝1.48min(10min).
Synthesis of [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [6- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A225)
Figure GPA0000243696240001072
99(70 m) were added successively at room temperature in a dry 50mL single-necked flaskg，0.334mmol)，100(311mg，0.7346mmol)，Pd(dppf)Cl2(32mg, 0.0434mmol), NaHCO3(70mg, 0.835mmol), 1, 4-dioxane (3mL) and water (0.8mL), with 3 nitrogen sparges. The reaction was heated to 88 ℃ for 2.5 hours. After LCMS detection reaction is finished, filtering, decompressing and concentrating filtrate, purifying through a column to obtain a crude product, purifying the obtained residue by prep-HPLC, and obtaining the product 1- [2- (2-chloro-pyridine-3-yl) -acetyl]-5- [6- (2-methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl]-2, 3-dihydro-1H-indole-7-carbonitrile a225(28mg, yellow solid), yield: 17.8 percent.
LCMS：m/z471.0(M+H)；RT＝4.31min(10min).
1H NMR(dmso，400MHz)δ9.51(s，1H)，8.67(s，1H)，8.37(dd，J＝4.7，1.8Hz，1H)，8.20(d，J＝18.5Hz，2H)，7.88(dd，J＝7.6，1.8Hz，1H)，7.60-7.35(m，2H)，7.20(s，1H)，6.34(d，J＝1.9Hz，1H)，4.37(t，J＝8.2Hz，2H)，4.15(s，2H)，3.70(s，3H)，3.28(d，J＝8.1Hz，2H).
Example 226: synthesis of (2-chloro-5-methylpyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile Compound (102)
Figure GPA0000243696240001073
In a dry 50mL single-necked flask, compound 100(236mg, 0.558mmol), 101(100mg, 0.614mmol), Pd (dppf) Cl were added sequentially at room temperature2(40mg, 0.0558mmol) NaHCO3(94mg, 1.12mmol) and dioxane (3mL), H2O (0.75mL), replaced with nitrogen three times, warmed to 73 ℃ and stirred for 1.5 hours. After completion of the LCMS detection reaction, the crude product was purified by combiflash (EA/PE 0% -80%) to give the product (2-chloro-5-methylpyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile 102(110mg, yellow solid) in yield: and 55 percent.
LCMS：m/z424.0(M+H)；RT＝5.15min(9min).
Synthesis of 5- (2- (1-methyl-1H-pyrazol-5-ylamino) -5-methylpyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile Compound (A226)
Figure GPA0000243696240001081
In a dry 50mL single-necked flask, 102(90mg, 0.212mmol), 97(29mg, 0.299mmol), Pd2(dba)3(20mg, 0.0218mmol), RuPhos (27mg, 0.0579mmol), TEA (23mg, 0.0227mmol), DMF (2mL) and nitrogen were sequentially added 3 times at room temperature. The reaction was heated to 90 ℃ for 1.5 hours. After LCMS detection, filtration, concentration of the filtrate under reduced pressure and purification of the resulting residue by prep-HPLC gave the product 5- (2- (1-methyl-1H-pyrazol-5-ylamino) -5-methylpyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile a226(3mg, yellow solid) in yield: 1 percent of
LCMS：m/z485.0(M+H)；RT＝4.61min(9min).
1H NMR(dmso，400MHz)δ9.37(s，1H)，8.43-8.31(m，2H)，7.92-7.84(m，2H)，7.82(s，1H)，7.46(dd，J＝7.4，4.7Hz，1H)，7.32(d，J＝1.9Hz，1H)，6.23(d，J＝1.8Hz，1H)，4.37(t，J＝8.2Hz，2H)，4.15(s，2H)，3.68(s，3H)，3.28(t，J＝7.9Hz，2H)，2.23(s，3H).
227-237 compounds were prepared using a method analogous to example 226:
example 227: synthesis of 5- (2- (3-chloro-1-methyl-1H-pyrazol-4-ylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) nitrile Compound (A227)
Figure GPA0000243696240001082
1H NMR(400MHz，dmso)δ8.83(s，1H)，8.42(d，J＝5.2Hz，1H)，8.36-8.31(m，1H)，8.28(s，2H)，7.94(s，1H)，7.85(d，J＝6.2Hz，1H)，7.48-7.34(m，2H)，4.34(t，J＝8.2Hz，2H)，4.11(s，2H)，3.78(s，3H)，3.26(t，J＝8.0Hz，2H).
LCMS：m/z505.1(M+H)；RT＝4.74min(9min).
Example 228: synthesis of 5- (2- (1-hydroxypropan-2-ylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A228)
Figure GPA0000243696240001083
1H NMR(dmso，400MHz)δ8.31(d，J＝5.2Hz，1H)，8.25(d，J＝2.3Hz，2H)，7.32(dt，J＝7.8，6.6Hz，2H)，7.22-7.11(m，3H)，6.88(d，J＝8.1Hz，1H)，4.65(t，J＝5.7Hz，1H)，4.29(t，J＝8.2Hz，2H)，4.01(s，1H)，4.00(s，2H)，3.50-3.42(m，1H)，3.23(dd，J＝17.1，8.9Hz，3H)，1.11(d，J＝6.5Hz，3H).
LCMS：m/z 432.1(M+H)；RT＝4.063min(9min).
Example 229: synthesis of 1- [2- (2-fluoro-phenyl) -acetyl ] -5- [2- (2-methanesulfonyl-ethylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A229)
Figure GPA0000243696240001091
1H NMR(dmso，400MHz)δ8.38(d，J＝5.1Hz，1H)，8.28(s，2H)，7.49(s，1H)，7.38-7.22(m，3H)，7.22-7.10(m，2H)，4.30(s，2H)，4.00(s，2H)，3.75(s，2H)，3.38(t，J＝6.3Hz，2H)，3.22(t，J＝8.1Hz，2H)，3.00(s，3H).
LCMS：m/z480.1(M+H)；RT＝4.31min(10min).
Example 230: synthesis of 5- (2- (2-hydroxypropylamino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A230)
Figure GPA0000243696240001092
1H NMR(dmso，400MHz)δ8.38(d，J＝5.4Hz，1H)，8.32(s，2H)，7.46-7.29(m，3H)，7.29(d，J＝5.1Hz，1H)，7.25-7.16(m，2H)，4.34(t，J＝8.2Hz，2H)，4.05(s，2H)，3.85-3.83(m，1H)，3.27(t，J＝8.1Hz，3H)，1.10(d，J＝6.2Hz，3H).
LCMS：m/z 432.1(M+H)；RT＝4.171min(9min).
Example 231: synthesis of 1- [2- (2-chloropyridin-3-yl) -acetyl ] -5- {2- [1- (2, 2, 2-trifluoro-ethyl) -1H-pyrazol-4-ylamino ] -pyrimidin-4-yl } -2, 3-dihydro-1H-indole-7-carbonitrile (A231)
Figure GPA0000243696240001093
1H-NMR(500MHz，DMSO-d6)δ9.69(s，1H)，8.53(s，1H)，8.38(dd，J＝4.8，1.9Hz，1H)，8.36(d，J＝10.8Hz，2H)，8.13(s，1H)，7.89(dd，J＝7.6，1.8Hz，1H)，7.69(s，1H)，7.47(dd，J＝7.4，4.8Hz，1H)，7.42(d，J＝5.2Hz，1H)，5.12(d，J＝9.2Hz，2H)，4.39(t，J＝8.2Hz，2H)，4.16(s，2H)，3.31(t，J＝8.2Hz，2H).
LCMS：m/z 539.0(M+H)；RT＝5.45min(10min)
Example 232: synthesis of 1- [2- (2-fluoro-phenyl) -acetyl ] -5- {2- [1- (2, 2, 2-trifluoro-ethyl) -1H-pyrazol-4-ylamino ] -pyrimidin-4-yl } -2, 3-dihydro-1H-indole-7-carbonitrile (A232)
Figure GPA0000243696240001094
1H-NMR(500MHz，DMSO-d6)δ9.69(s，1H)，8.54(s，1H)，8.34(s，2H)，8.13(s，1H)，7.68(s，1H)，7.47-7.32(m，3H)，7.21(dd，J＝16.7，9.3Hz，2H)，5.12(d，J＝9.3Hz，2H)，4.35(t，J＝8.2Hz，2H)，4.05(s，2H)，3.29(t，J＝8.1Hz，2H).
LCMS：m/z 522.1(M+H)；RT＝6.00min(10min)
Example 233: synthesis of 1- [2- (2-chloro-phenyl) -acetyl ] -5- {2- [1- (2, 2, 2-trifluoro-ethyl) -1H-pyrazol-4-ylamino ] -pyrimidin-4-yl } -2, 3-dihydro-1H-indole-7-carbonitrile (A233)
Figure GPA0000243696240001101
1H-NMR(500MHz，DMSO-d6)δ9.68(s，1H)，8.52(d，J＝4.9Hz，1H)，8.33(s，2H)，8.12(s，1H)，7.68(s，1H)，7.48(dd，J＝5.6，3.7Hz，1H)，7.44-7.36(m，2H)，7.34(dd，J＝5.8，3.5Hz，2H)，5.12(d，J＝9.0Hz，2H)，4.35(t，J＝8.2Hz，2H)，4.11(s，2H)，3.28(d，J＝8.0Hz，2H).
LCMS：m/z 538.1(M+H)；RT＝5.77min(10min)
Example 234: synthesis of 5- (2- (1-deuteromethyl-1H-pyrazol-3-ylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile (A234)
Figure GPA0000243696240001102
1H-NMR(500MHz，DMSO-d6)δ9.77(s，1H)，8.47(d，J＝5.2Hz，1H)，8.38-8.25(m，3H)，7.85(dd，J＝7.5，1.9Hz，1H)，7.56(d，J＝2.1Hz，1H)，7.47-7.35(m，2H)，6.57(d，J＝2.2Hz，1H)，4.35(t，J＝8.2Hz，2H)，4.12(s，2H)，3.27(t，J＝8.1Hz，2H).
LCMS：m/z474.0(M+H)；RT＝4.48min(10min)
Example 235: synthesis of 5- (2- (1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-3-ylamino) pyrimidin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7 carbonitrile (A235)
Figure GPA0000243696240001103
1H-NMR(500MHz，DMSO-d6)δ9.97(s，1H)，8.49(d，J＝5.2Hz，1H)，8.38-8.20(m，3H)，7.86(dd，J＝7.6，1.9Hz，1H)，7.74(d，J＝2.3Hz，1H)，7.48-7.35(m，2H)，6.75(d，J＝2.4Hz，1H)，4.99(q，J＝9.0Hz，2H)，4.35(t，J＝8.3Hz，2H)，4.12(s，2H)，3.27(d，J＝8.0Hz，2H).
LCMS：m/z539.0(M+H)；RT＝5.11min(10min)
Example 236: synthesis of 5- (2- (1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-3-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A236)
Figure GPA0000243696240001104
1H-NMR(500MHz，DMSO-d6)δ9.97(s，1H)，8.49(d，J＝5.2Hz，1H)，8.31(s，2H)，7.74(d，J＝2.4Hz，1H)，7.49-7.37(m，3H)，7.34-7.25(m，2H)，6.76(d，J＝2.4Hz，1H)，4.99(q，J＝9.1Hz，2H)，4.32(t，J＝8.2Hz，2H)，4.08(s，2H)，3.25(d，J＝8.3Hz，2H).
LCMS：m/z538.0(M+H)；RT＝5.72min(10min)
Example 237: synthesis of 5- (2- (1-deuteromethyl-1H-pyrazol-3-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A237)
Figure GPA0000243696240001111
1H-NMR(500MHz，DMSO-d6)9.76(s，1H)，8.47(d，J＝5.2Hz，1H)，8.30(s，2H)，7.56(d，J＝2.1Hz，1H)，7.49-7.36(m，3H)，7.35-7.28(m，2H)，6.57(d，J＝2.1Hz，1H)，4.32(t，J＝8.2Hz，2H)，4.08(s，2H)，3.26(t，J＝8.1Hz，2H).
LCMS：m/z473.1(M+H)；RT＝5.16min(10min)
Example 238: synthesis of 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2, 5-dimethyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -1, 3-dihydro-1H-indole-7-carbonitrile (A238)
Figure GPA0000243696240001112
In a dry 25mL single neck flask compound 77(60mg, 0.132mmol), compound 103(29mg, 0.264mmol), DMF (2mL), Pd2(dba)3(12mg, 0.0132mmol), Ruphosor xanthphos (0.0132mmol) were added in sequence at room temperature and stirred for 80min at 90 ℃. After LCMS detection reaction was complete, the crude product was purified by prep-HPLC to give the product 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2, 5-dimethyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -1, 3-dihydro-1H-indole-7-carbonitrile a238(4.2mg, yellow solid), yield: 6.56 percent.
1H-NMR(500MHz，DMSO-d6)δ9.47(s，1H)，8.49(d，J＝5.2Hz，1H)，8.39-8.17(m，3H)，7.85(d，J＝7.6Hz，1H)，7.54-7.39(m，2H)，6.06(s，1H)，4.35(t，J＝8.1Hz，2H)，4.12(s，2H)，3.59(s，3H)，3.27(t，J＝8.0Hz，2H)，2.10(s，3H).
LCMS：m/z485.1(M+H)；RT＝4.57min(10min)
Example 239: synthesis of 1- (2, 2, 2-trifluoroethyl) -5-nitro-1H-pyrazole (106)
Figure GPA0000243696240001113
In a dry 50mL single neck flask, compound 104(10g, 88.4mmol), compound 105(41g, 176.9mmol), potassium carbonate (31g, 221mmol) and DMF (100mL) were added sequentially at room temperature and stirred at room temperature for 4 hours. After LCMS detection of the reaction, water was added and extracted with EA, the organic phase was washed with saturated brine, and after spin-drying the crude product was purified with combiflash (EA/PE 0-50%) to give the product 1- (2, 2, 2-trifluoroethyl) -5-nitro-1H-pyrazole 4(900mg, yellow liquid) in yield: 5 percent.
LCMS：m/z196.0(M+H)；RT＝5.05min(10min)
Synthesis of 1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-5-amine (107)
Figure GPA0000243696240001114
In a dry 50mL single-neck flask, compound 106(900mg, 4.6mmol), Pd/C (90mg), MeOH (10mL) were added sequentially at room temperature, displaced with hydrogen 3 times, and stirred at room temperature for 16 hours. Upon completion of the LCMS check reaction, concentration by filtration afforded the crude product 1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-5-amine 107(650mg, yellow liquid), yield: 85 percent.
LCMS：m/z166.1(M+H)；RT＝1.06min(10min)
Synthesis of 5- (2- (1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A239)
Figure GPA0000243696240001121
In a dry 25mL single-necked flask at room temperature were added compound 74(80mg, 0.176mmol), compound 107(88mg, 0.529mmol), Pd in succession2(dba)3(16mg, 0.0176mmol), Ruphos (16mg, 0.0352mmol), TEA (18mg, 0.176mmol) and DMF (1mL) were replaced with nitrogen 3 times and stirred at 100 ℃ for 2 hours. After LCMS detection reaction was complete, the crude product was purified by prep-HPLC 5- (2- (1- (2, 2, 2-trifluoroethyl) -1H-pyrazol-5-ylamino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile a239(17mg, yellow solid) in yield: 18 percent.
1H-NMR(500MHz，DMSO-d6)δ9.77(s，1H)，8.54(d，J＝5.2Hz，1H)，8.30(d，J＝2.4Hz，2H)，7.60-7.37(m，4H)，7.35-7.27(m，2H)，6.49(d，J＝1.6Hz，1H)，5.12(dd，J＝18.1，8.9Hz，2H)，4.32(t，J＝8.2Hz，2H)，4.08(s，2H)，3.26(t，J＝8.1Hz，2H).
LCMS：m/z538.0(M+H)；RT＝5.84min(10min)
Example 240: synthesis of indolin-2-ylmethanol (109)
Figure GPA0000243696240001122
To a solution of compound 108(1.0g, 6.1mmol) in THF was slowly added BH dropwise with stirring at 0 deg.C3THF (12.2mol, 1M in THF), the reaction was left to react at 70 ℃ for 4 h. The reaction was cooled to room temperature and placed at 0 ℃ with the sequential addition of MeOH (5.0mL) and concentrated HCl (1.5mL) to the interior, the reaction was allowed to react at 70 ℃ for 1h, the reaction was concentrated, basified to pH 8 with NaOH (8M) solution, diluted with water, extracted with ethyl acetate, the organic phases combined and dried over anhydrous sodium sulfate, filtered, and spun dry. The crude product was isolated by column chromatography (PE: EA: 10: 1) to give the title compound 109(913mg, 6.1mmol, yellow liquid) in 99% yield.
LCMS：t＝0.61min，ESI：[M+H]+m/z150.
Synthesis of 2- (((tert-butyldimethylsilyl) oxy) methyl) indoline (110)
Figure GPA0000243696240001123
To a solution of compound 109(913mg, 6.1mmol) in DCM was added under stirring, Imid (625mg, 9.19mmol) and TBSCl (1.38g, 9.19mmol) in that order slowly, and the reaction was left to react at room temperature for 2 h. Filtration was carried out, the filtrate was spin-dried, and the resulting crude product was isolated by column chromatography (PE: EA: 10: 1) to give the title compound 110(648mg, 2.46mmol, colorless oily liquid) in 40% yield.
Synthesis of 5-bromo-2- (((tert-butyldimethylsilyl) oxy) methyl) indoline (111)
Figure GPA0000243696240001124
To a dry 25mL round bottom flask was added compound 110(277mg, 1.04mmol), CH in that order3CN (5.0mL), NBS (186mg, 1.04mmol) was added slowly to the inside at-40 ℃. After 5min of reaction, the reaction was quenched with saturated NaHCO3Quenching the solution, extracting with ethyl acetate, combining the organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating the resulting crude product by column chromatography (PE: EA ═ 10: 1) to give the title compound 111(320mg, 0.94mmol, colorless liquid)The yield was 90%.
LCMS：t＝2.70min，ESI：[M+H]+m/z342.
Synthesis of 1- (5-bromo-2- (((tert-butyldimethylsilyl) oxy) methyl) indolin-1-yl) -2- (2-chlorophenyl) ethan-1-one (113)
Figure GPA0000243696240001131
In a25 mL eggplant type bottle were added compound 111(320mg, 0.94mmol), 112(239mg, 1.4mmol), HATU (532mg, 1.5mmol), DMF (5.0mL), DIPEA (364mg, 2.8mmol) in that order, and the reaction was allowed to stand at room temperature overnight. The reaction solution was spin-dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and spin-dried. The obtained crude product was isolated by column chromatography (petroleum ether: ethyl acetate 10: 1) to give the objective compound 113(354mg, 0.72mmol, white solid) in a yield of 76%.
LCMS：t＝2.86min，ESI：[M+H]+m/z 494.
Synthesis of 1- (2- (((tert-butyldimethylsilyl) oxy) methyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indolin-1-yl) -2- (2-chlorophenyl) ethan-1-one (114)
Figure GPA0000243696240001132
To a dry 25mL round bottom flask was added compound 113(296mg, 0.6mmol), followed by B2Pin2(229mg，0.9mmol)，KOAc(176mg，1.8mmol)，Pd(dppf)2Cl2(44mg, 0.06mmol), DMSO (3.0mL), nitrogen substitution 3 times, the reaction was placed in a90 ℃ oil bath for 0.5 h. After completion of the reaction, extraction was performed with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was separated by column chromatography (PE: EA ═ 10: 1) to obtain the objective compound 114(319mg, 0.59mmol, white solid) with a yield of 98%.
LCMS：t＝2.96min，ESI：[M+H]+m/z542.
Synthesis of 1- (2- (((tert-butyldimethylsilyl) oxy) methyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -2- (2-chlorophenyl) ethan-1-one (115)
Figure GPA0000243696240001133
In a25 mL round bottom flask was added sequentially compound 114(46mg, 0.085mmol), 86(27mg, 0.13mmol), NaHCO3(29mg，0.34mmol)，Pd(dppf)Cl2(9mg，0.013mmol)，1，4-dioxane(0.8mL)，H2O (0.2mL), replaced with nitrogen 3 times, and the reaction was placed in an oil bath at 70 ℃ for 2 hours. After the reaction was completed, extraction was performed with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was isolated by column chromatography to give the objective compound 115(35mg, 0.059mmol, white solid) in 67% yield.
LCMS：t＝2.58min，ESI：[M+H]+m/z589.
Synthesis of (2-chlorophenyl) -1- (2- (hydroxymethyl) -5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indolin-1-yl) ethan-1-one (A240)
Figure GPA0000243696240001141
In a dry 25mL round bottom flask was added compound 9(30mg, 0.05mmol) and THF (1.0mL), and TBAF (0.1mL, 1.0M in THF) was added to the reaction with stirring at 0 deg.C and reacted at that temperature for 3 h. LCMS showed reaction completion, extraction with ethyl acetate, combined organic phases and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, filtrate concentrated under reduced pressure and crude product isolated by HPLC to afford the title compound (14mg, 0.029mmol, white solid) in 53% yield.
1H NMR(600MHz，CDCl3)δ8.42(d，J＝4.3Hz，1H)，8.21(s，1H)，7.92(s，1H)，7.86(s，1H)，7.50(d，J＝1.8Hz，1H)，7.46-7.38(m，1H)，7.34(s，1H)，7.27(s，1H)，7.16(d，J＝5.3Hz，1H)，6.83(s，1H)，6.35(d，J＝1.7Hz，1H)，5.10(s，2H)，4.77(s，2H)，4.16(d，J＝12.9Hz，2H)，3.78(d，J＝16.7Hz，2H)，3.76(s，1H)，3.42(dd，J＝16.0，9.1Hz，1H)，2.97(s，2H).
LCMS：t＝1.78min，ESI：[M+H]+m/z475.
Example 241: synthesis of 1- (2- (2-chlorophenyl) acetyl) -5- (2- ((1, 3-dimethyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A241)
Figure GPA0000243696240001142
Prepared in a similar manner to example 240.
1H NMR(500MHz，DMSO)δ9.46(s，1H)，8.52(d，J＝5.2Hz，1H)，8.32(d，J＝10.5Hz，2H)，7.50(dd，J＝12.5，4.4Hz，2H)，7.45-7.41(m，1H)，7.35(dd，J＝5.8，3.5Hz，2H)，6.07(s，1H)，4.35(t，J＝8.3Hz，2H)，4.11(s，2H)，3.61(s，3H)，3.28(t，J＝8.0Hz，2H)，2.12(s，3H).
LCMS：t＝1.92min，ESI：[M+H]+m/z 484.
Example 242: synthesis of 4-iodo-5-methyl-N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-amine
Figure GPA0000243696240001143
To a dry 5mL microwave tube were added compound 97(160mg, 1.7mmol), compound 116(200mg, 0.85mmol) in that order,tBuOK (14mg, 0.015mmol) and DMSO (0.3mL), and the reaction was left at 70 ℃ for 3 hours. LCMS to monitor reaction completion, quench the reaction with water, extract with dichloromethane, combine the organic phases and wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude by column chromatography (PE: EA ═ 2: 1)Compound 117(132mg, 0.42mmol, yellow solid) was obtained in 45% yield.
Synthesis of 1- (2- (2-chloropyridin-3-yl) acetyl) -5- (5-methyl-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyridin-4-yl) -7-carbonitrile (A242)
Figure GPA0000243696240001144
In a dry 25mL round bottom flask were added compound 116(75mg, 0.24mmol), compound 100(152mg, 0.36mmol), Pd (dppf) Cl in that order2(26mg，0.036mmol)，NaHCO3(84mg, 0.96mmol), 1, 4-dioxane (1.0mL) and H2O (0.2mL), replaced with nitrogen 3 times, and the reaction was placed in an oil bath at 70 ℃ for 1 hour. After completion of the reaction monitored by LCMS, extraction with dichloromethane was performed, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by HPLC to give the title compound a242(50mg, 0.10mmol, yellow solid) in 43% yield.
1H NMR(400MHz，DMSO)δ8.70(s，1H)，8.37(dd，J＝4.8，1.9Hz，1H)，8.04(s，1H)，7.89(dd，J＝7.6，1.8Hz，1H)，7.64(s，1H)，7.56(s，1H)，7.46(dd，J＝7.5，4.8Hz，1H)，7.31(d，J＝1.8Hz，1H)，6.64(s，1H)，6.22(d，J＝1.8Hz，1H)，4.35(t，J＝8.1Hz，2H)，4.14(s，2H)，3.66(s，3H)，3.26(t，J＝7.9Hz，2H)，2.11(s，3H).
LCMS：t＝1.84min，ESI：[M+H]+m/z 484.
The 243-compound was prepared using a method analogous to example 242:
example 243: synthesis of 5- (2- ((1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A243)
Figure GPA0000243696240001151
1H NMR(400MHz，DMSO)δ9.95(s，1H)，8.52(d，J＝5.1Hz，1H)，8.35(d，J＝3.1Hz，2H)，7.65(s，1H)，7.46(d，J＝5.2Hz，1H)，7.37(dd，J＝16.3，9.3Hz，2H)，7.28-7.13(m，2H)，6.56(s，1H)，4.34(t，J＝8.1Hz，2H)，4.05(s，2H)，3.28(t，J＝8.0Hz，2H).
Example 244: synthesis of 4- (1- (2- (2-chloropyridin-3-yl) ethyl) -1H-pyrrolo [2, 3-b ] pyridin-5-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyridin-2-yl) pyrimidin-2-amine (A244)
Figure GPA0000243696240001152
1H NMR(400MHz，CDCl3)δ9.02(s，1H)，8.57(s，1H)，8.33(s，1H)，8.26(d，J＝2.9Hz，1H)，7.59(s，1H)，7.41(d，J＝5.9Hz，1H)，7.23(dd，J＝7.5，1.8Hz，1H)，7.07(d，J＝3.5Hz，1H)，7.04(dd，J＝7.4，4.9Hz，1H)，6.53(d，J＝3.4Hz，1H)，5.34(m，1H)，4.64(t，J＝6.9Hz，2H)，3.92(s，3H)，3.33(t，J＝6.8Hz，2H).
Example 245: synthesis of 2- (3-chlorophenyl) -N- (5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) pyridin-2-yl) (A245)
Figure GPA0000243696240001153
1H NMR(400MHz，CDCl3)δ8.83(s，1H)，8.39(d，J＝5.6Hz，1H)，8.25(s，1H)，8.01(s，1H)，7.42(d，J＝2.0Hz，1H)，7.27(m，3H)，7.18(m，1H)，7.09(d，J＝5.2，1H)，6.83(s，1H)，6.27(d，J＝2.0Hz，1H)，3.74(s，3H)，3.69(s，2H).
Example 246: synthesis of 1-acetyl-5- (2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A246)
Figure GPA0000243696240001161
1H NMR(500MHz，DMSO)δ9.50(s，1H)，8.53(d，J＝5.2Hz，1H)，8.30(d，J＝17.3Hz，2H)，7.52(d，J＝5.2Hz，1H)，7.37(d，J＝1.8Hz，1H)，6.28(d，J＝1.6Hz，1H)，4.23(t，J＝8.2Hz，2H)，3.70(s，3H)，3.23(t，J＝8.2Hz，2H)，2.28(s，3H).
Example 247: 5- (2- ((1H-pyrazol-4-yl) amino) pyridin-4-yl) -1- (2- (2-chloropyridin-3-yl) acetyl) indoline-7-carbonitrile (A247)
Figure GPA0000243696240001162
1H-NMR(400MHz，DMSO-d6)δ12.42(s，1H)，8.74(s，1H)，8.34(dd，J＝4.8，1.9Hz，1H)，8.12(d，J＝5.4Hz，1H)，8.01-7.81(m，3H)，7.79(d，J＝1.7Hz，1H)，7.56-7.39(m，2H)，6.96-6.82(m，2H)，4.33(t，J＝8.2Hz，2H)，4.11(s，2H)，3.27-3.22(m，2H).
Example 248: synthesis of 1- (2- (2-chlorophenyl) acetyl) -5- (5-fluoro-2- ((1-methyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A248)
Figure GPA0000243696240001163
1H-NMR(400MHz，DMSO-d6)δ9.61(s，1H)，8.63(d，J＝3.5Hz，1H)，8.14(d，J＝3.5Hz，2H)，7.50-7.41(m，2H)，7.35(dd，J＝5.7，3.4Hz，3H)，6.25(d，J＝1.8Hz，1H)，4.35(t，J＝8.1Hz，2H)，4.12(s，2H)，3.69(s，3H)，3.29(t，J＝8.1Hz，2H).
Example 249: synthesis of 1- [2- (2-chloro-pyridin-3-yl) -acetyl ] -5- [2- (2-deuterated methyl-2H-pyrazol-3-ylamino) -pyrimidin-4-yl ] -2, 3-dihydro-1H-indole-7-carbonitrile (A249)
Figure GPA0000243696240001164
1H-NMR(400MHz，DMSO-d6)δ9.48(s，1H)，8.50(d，J＝5.3Hz，1H)，8.37-8.19(m，3H)，7.90-7.82(m，1H)，7.49(d，J＝5.2Hz，1H)，7.43(dd，J＝7.5，4.7Hz，1H)，7.34(s，1H)，6.24(s，1H)，4.35(t，J＝8.2Hz，2H)，4.12(s，2H)，3.26(t，J＝8.1Hz，2H).
LCMS：m/z474.2(M+H)；RT＝4.55min(10min)
Example 250: synthesis of 5- (2- ((1-acetyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -1- (2- (2-chlorophenyl) acetyl) indoline-7-carbonitrile (A250)
Figure GPA0000243696240001165
1H NMR(500MHz，DMSO)δ10.01(s，1H)，8.63(s，1H)，8.58(s，1H)，8.35(s，1H)，7.99(s，1H)，7.50(dd，J＝10.6，4.4Hz，1H)，7.48-7.40(m，1H)，7.35(dd，J＝5.8，3.5Hz，1H)，4.37(t，J＝8.2Hz，2H)，4.12(s，2H)，3.33-3.26(m，2H)，2.62(s，3H).
LCMS：t＝2.07min，ESI：[M+H]+m/z 498.
Example 251: synthesis of 1- (2- (2-chlorophenyl) acetyl) -5- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) indoline-7-carbonitrile (A251)
Figure GPA0000243696240001171
1H NMR(500MHz，DMSO)δ8.83(s，1H)，8.16(d，J＝5.4Hz，1H)，7.96(s，1H)，7.89(s，1H)，7.82(s，1H)，7.44(s，1H)，7.39-7.33(m，1H)，6.96(d，J＝5.8Hz，1H)，6.90(s，1H)，4.34(t，J＝8.2Hz，1H)，4.11(s，1H)，3.81(s，1H)，3.26(d，J＝8.2Hz，1H).
LCMS：t＝2.00min，ESI：[M+H]+m/z 469.
Example 252: synthesis of 5- (2- ((1, 3-dimethyl-1H-pyrazol-5-yl) amino) pyrimidin-4-yl) -1- (2- (2-fluorophenyl) acetyl) indoline-7-carbonitrile (A252)
Figure GPA0000243696240001172
1H NMR(400MHz，dmso)δ9.38(s，1H)，8.45(d，J＝5.1Hz，1H)，8.25(d，J＝8.3Hz，1H)，7.44(d，J＝5.1Hz，1H)，7.36-7.25(m，1H)，7.21-7.10(m，1H)，6.00(s，1H)，4.28(t，J＝8.2Hz，1H)，3.98(s，1H)，3.54(s，1H)，3.25-3.17(m，1H)，2.06(s，1H).
LCMS：t＝1.96min，ESI：[M+H]+m/z468.
Comparative example C1: synthesis of 4- (6-aminopyridin-3-yl) -N- (1-methyl-1H-pyrazol-5-yl) pyrimidin-2-amine
Figure GPA0000243696240001173
A round-bottomed flask 25mL was charged with A15(180mg, 0.58mmol), sodium hydroxide (116mg, 2.91mmol), methanol (5mL) and water (2mL) in that order. The reaction was stirred at 80 ℃ for 6h, TLC checked for completion, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol 5: 1) to give compound C1(124mg, yield: 80%) as a yellow solid.
1HNMR(400MHz，CDCl3-d)δ8.75(d，1H，J＝1.6Hz)，8.38(d，1H，J＝5.2Hz)，8.10(dd，1H，J＝2.4Hz，8.8Hz)，7.49(d，1H，J＝2.0Hz)，7.10(d，1H，J＝5.6Hz)，6.83(s，1H)，6.56(d，1H，J＝8.8Hz)，6.34(d，1H，J＝1.6Hz)，4.81(s，2H)，3.80(s，3H)。
LCMS：m/z 268.2(M+H)+；RT＝0.648min。
Comparative example C2: preparation of 4- (6-aminopyridin-3-yl) pyrimidin-2-amine:
Figure GPA0000243696240001181
in a dry 50mL three-necked flask were added in the order compound C2-1(200mg, 1.45mmol), C2-2(188mg, 1.45mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (110mg, 0.15mmol), potassium carbonate (300mg, 2.17mmol), 1, 4-dioxane (8mL) and water (2 mL). Heating to 100 ℃ under the protection of nitrogen, and reacting for 3 hours. After completion of the reaction, the reaction mixture was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was washed successively with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified with Flash (dichloromethane: methanol ═ 30: 1 to 10: 1) to give product C2(120mg, light yellow solid), yield: 30 percent.
1HNMR(400MHz，MeOD-d4)δ8.76(d，1H，J＝1.6Hz)，8.59(dd，1H，J＝2.0Hz，9.2Hz)，8.31(d，1H，J＝6.4Hz)，7.36(d，1H，J＝6.4Hz)，7.09(d，1H，J＝9.2Hz)。
LCMS：m/z188.1(M+H)；RT＝0.29min(2min).
Test example 1: determination of ERK kinase Activity by Compounds of the invention
Materials and instruments
ERK2 enzyme(PV3595，Invitrogen)
Figure GPA0000243696240001182
Kinase Assay Kit-Ser/Thr 3 Peptide(PV3176)
Synergy 2 Microplate Reader(BioTec)
ProxiPlate-384 Plus F，Black 384-shallow well Microplate(Cat.6008269，PerkinElmer)
The test method comprises the following steps:
Z′-LYTETMSer/Thr 3 Peptide Substrate, Phospho-Peptide, 5X Kinase Buffer, ATP, Development Reagent A, Development Buffer, Stop Reagent all reagents were equilibrated to room temperature in preparation for loading.
Screening concentrations to test compounds for their effect on ERK kinase activity were 3-fold gradient dilutions starting at 1 μ M (0.2 μ M), 8 concentrations, each concentration being taken in duplicate wells, using 4% DMSO as co-solvent. After the reaction was completed, 5. mu.l of Development Reagent A diluted with Development buffer was added to all reaction wells, and after 1 hour of reaction at room temperature, 5. mu.l of Stop Reagent was added to all reaction wells to terminate the reaction, and a fluorescent signal (excitation wavelength 400nm, emission wavelength 460nm, 528nm) was detected using a Synergy 2 Microplate Reader.
The inhibition rate of each well was calculated from the total active and background signal wells. The experiment was repeated in parallel twice. IC50 values can be calculated from the inhibition of the kinase by the test compound at a range of different concentrations.
TABLE 1 inhibition of various kinase activities by the compounds of the invention
Figure GPA0000243696240001183
Figure GPA0000243696240001191
Figure GPA0000243696240001201
Figure GPA0000243696240001211
Wherein A represents IC50 ≤ 10 nM; b represents 10nM < IC50 ≦ 100 nM; c represents 100nM < IC50 ≦ 1000 nM; d indicates IC50 > 1000 nM.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound of formula Ib, a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof,
Figure FDA0002821815880000011
wherein the content of the first and second substances,
X1、X2、X3、X5、X6each independently selected from CR5Or N;
R5selected from the group consisting of: H. d, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkoxy, -OH, cyano, -CON (C)1-C4Alkyl radical)2、-CONH2Halogen, -CF3Amino, substituted or unsubstituted C1-C8Alkylamino radical, substituted or unsubstituted C1-C8Alkylcarbonyl, substituted or unsubstituted C1-C8Alkoxycarbonyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur;
p is 1;
q is 1;
y and Z are both-CH2-；
R2Selected from the group consisting of: substituted or unsubstituted C1-C10An alkyl group, a substituted or unsubstituted 5-8 membered aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, and a substituted or unsubstituted 3-8 membered heterocyclic group; or R1And R2Taken together with the adjacent N atom to form a substituted or unsubstituted 5-8 membered heterocyclic group;
R4selected from H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C1-C8Alkoxy, -CO (CR)6R7)mR8、-SO2(CR6R7)mR8、-CONR9(CR6R7)mR8、-COO(CR6R7)mR8An amino group; wherein m is 0, 1, 2 or 3;
each R6And R7Each independently selected from the group consisting of: H. d, substituted or unsubstituted C1-C8Alkyl radical, C1-C8Alkylene hydroxy, substituted or unsubstituted C1-C8Alkoxy and halogen;
each R8Selected from the group consisting of: H. substituted or unsubstituted C1-C8An alkyl group, a substituted or unsubstituted 5-8 membered aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, and a substituted or unsubstituted 3-8 membered heterocyclic group;
each R9Selected from the group consisting of: H. substituted or unsubstituted C1-C8An alkyl group;
wherein, R is2、R4、R5、R6、R7、R8、R9Wherein said "substituted" refers to having one or more substituents selected from group B: D. halogen, -OH, -CN, -CD3、-COOH、-NH2、-NO2、C1-C4Alkyl radical, C1-C4Haloalkyl, -C1-C4alkyl-O-R11、C1-C8Alkoxy radical, C1-C8Alkylamino radical, (C)1-C6Alkyl) COO-, C1-C6Alkoxycarbonyl, substituted or unsubstituted 5-8 membered heteroarylcarbonyl, N (R)11R12) CO-, substituted or unsubstituted C3-C6Heterocyclylcarbonyl, substituted or unsubstituted C1-C4Alkylsulfonyl radical, C1-C4Hydroxyalkyl radical, C1-C4Alkylamino, aminosulfonyl, piperazinosulfonyl, substituted or unsubstituted 3-to 8-membered cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, benzyloxyacyl, benzyloxycarbonyl; wherein R is11、R12Each independently selected from: c1-C3Alkyl and H, wherein "substituted" refers to having one or more substituents selected from group C: c1-C6Alkoxycarbonyl, C1-C4Alkyl radical, C1-C4Alkoxy, -OH, -NH2、Boc。
2. The compound of claim 1, stereoisomers, racemates or pharmaceutically acceptable salts thereof, wherein the compound of formula Ib is:
Figure FDA0002821815880000021
wherein p is 1;
q is 1;
y and Z are both-CH2；
R2、R4、R5Is as defined in claim 1.
3. The compound, its stereoisomers, racemates or pharmaceutically acceptable salts thereof according to claim 1 wherein in said Ib compound R2Selected from the group consisting of:
Figure FDA0002821815880000022
wherein each Ra is independently selected from: H. halogen, C1-C4Alkoxycarbonyl group, C1-C3Alkyl, -OH, cyano, amino, -COOH, CF3-、CF3CH2-、CD3-、C1-C8Alkylamino radical, C1-C4Alkylsulfonyl radical, C1-C4Hydroxyalkyl, benzyloxycarbonyl, substituted or unsubstituted piperidinyl, C1-C4Alkoxy, NH2CO-, substituted or unsubstituted piperazinylcarbonyl, substituted or unsubstituted tetrahydropyrrolylcarbonyl, substituted or unsubstituted piperazinesulfonyl, (C)1-C6Alkyl) COO-; wherein the substituent is a substituent having one or more selected from the group consisting of: c1-C3Alkyl radical, C1-C4Alkoxycarbonyl, C1-C4Alkoxy, n is 0, 1, 2 or 3.
4. The compound, its stereoisomers, racemates or pharmaceutically acceptable salts thereof according to claim 1 wherein X2Is substituted or unsubstituted CR5；R4is-CO (CR)6R7)mR8(ii) a Wherein m is 1, 2 or 3.
5. A compound, a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof, as shown below, wherein the compound is selected from the group consisting of:
Figure FDA0002821815880000023
Figure FDA0002821815880000031
Figure FDA0002821815880000041
Figure FDA0002821815880000051
Figure FDA0002821815880000061
Figure FDA0002821815880000071
Figure FDA0002821815880000081
Figure FDA0002821815880000091
。
6. a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the compounds of any one of claims 1-5, stereoisomers, racemates or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
7. Use of a compound according to any one of claims 1 to 5, a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the preparation of a medicament for the prevention and treatment of diseases associated with ERK kinase and targeted inhibitors of ERK kinase.
8. A method of non-therapeutically inhibiting ERK kinase activity comprising the steps of: contacting a compound of any one of claims 1 to 5, stereoisomers, racemates or pharmaceutically acceptable salts thereof with ERK kinase, thereby inhibiting ERK kinase.
9. Use of a compound according to any one of claims 1 to 5, stereoisomers, racemates or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention and/or treatment of a disease associated with ERK kinase activity.
10. The use according to claim 9, wherein the disease associated with ERK kinase activity is selected from the group consisting of: skin cancer, carcinoma of large intestine, ovarian cancer, pancreatic cancer, lung cancer, renal cancer, hepatocarcinoma, melanoma, colorectal cancer, acute myelogenous leukemia, myelodysplastic syndrome, breast cancer, and glioma.
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