CN114920746A - BTK (BTK inhibitory or degrading agent) and application thereof in medicine - Google Patents

BTK (BTK inhibitory or degrading agent) and application thereof in medicine Download PDF

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CN114920746A
CN114920746A CN202210485930.5A CN202210485930A CN114920746A CN 114920746 A CN114920746 A CN 114920746A CN 202210485930 A CN202210485930 A CN 202210485930A CN 114920746 A CN114920746 A CN 114920746A
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alkyl
independently selected
substituted
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alkoxy
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张晨
廖雨亭
李瑶
严庞科
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Tibet Haisike Pharmaceutical Co ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in BTK related diseases such as tumors or autoimmune system diseases. B-L-K (I).

Description

BTK (BTK inhibitory or degrading agent) and application thereof in medicine
Technical Field
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in BTK related diseases such as tumors or autoimmune system diseases.
Background
Bruton's Tyrosine Kinase (BTK) is a member of the non-receptor protein tyrosine kinase Tec family, is a key regulator in the B cell antigen receptor (BCR) signaling pathway, and is distributed in the lymphatic, hematopoietic, and blood systems. BTK mutations cause activation of signal pathways such as proliferation, differentiation and angiogenesis of downstream tumor cells, leading to X-linked agammaglobulinemia, non-hodgkin's lymphoma (NHL) and many B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL), mantle cell lymphoma and diffuse large B-cell lymphoma. Because the BTK is mainly expressed in B cells and marrow cells, the BTK is a target with better targeting and safety.
PROTAC (protease targeting chimera) molecules are bifunctional compounds capable of simultaneously combining targeting proteins and E3 ubiquitin ligase, and the compounds can induce the recognition of the targeting proteins by proteasomes of cells, cause the degradation of the targeting proteins and effectively reduce the content of the targeting proteins in the cells. By introducing ligands capable of binding different target proteins into the ProTAC molecule, the application of the PROTAC technology to the treatment of various diseases becomes possible, and the technology has attracted much attention in recent years.
Disclosure of Invention
The invention develops a BTK inhibitor which has novel structure, good drug effect, high bioavailability and higher safety and is used for treating BTK related diseases such as tumors or autoimmune system diseases.
The invention develops a PROTAC compound of a BTK inhibitor and E3 ubiquitin ligase, which has novel structure, good drug effect, high bioavailability and higher safety and can inhibit or degrade BTK, and is used for treating BTK related diseases such as tumors or autoimmune system diseases.
As a first embodiment of the present invention, a compound represented by the following general formula (I) or a stereoisomer, tautomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
B-L-K (I)；
l is selected from-Ak 1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak 5-;
ak1, Ak2, Ak3, Ak4 and Ak5 are independently selected from CH 2 O or a bond;
cy1, Cy2, Cy3 and Cy4 are each independentlyA ring selected from 3 to 12 membered heterocycle, 3 to 12 membered cycloalkyl, 6 to 10 membered aryl or a bond, said heterocycle, cycloalkyl or aryl being optionally substituted with 1 to 4 groups selected from D, F, Cl, Br, I, OH, NH 2 、oxo、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
b is selected from
Figure BDA0003644199070000021
R b1 、R b2 Or R b3 Each independently selected from H, D, F, Cl, Br, I, OH, NH 2 、CN、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl and alkoxy being optionally substituted by 1 to 4 substituents selected from the group consisting of D, F, Cl, Br, I, OH, NH 2 、CN、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted with a substituent of alkoxy;
n1 is selected from 0, 1,2, 3,4 or 5;
n2 is selected from 0, 1,2, 3 or 4;
n3 is selected from 0, 1 or 2;
k is selected from
Figure BDA0003644199070000022
Q is each independently selected from the group consisting of a bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or 3-12 membered heterocycle, said heterocycle optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R q is selected from H or C 1-6 An alkyl group;
each F is independently selected from C 3-20 Carbocyclic ring, C 6-20 An aromatic ring, a 3-20 membered heterocyclic ring, or a 5-20 membered heteroaromatic ring, the heterocyclic or heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
R k2 each is independentIs selected from the group consisting of a bond, -C (═ O) -, -C (═ Se) -, -C (═ S) -, -P (═ O) H-, -P (═ O) (CH) 3 )-、-S(＝O) 2 -, -S (═ O) -, or-C (R) k3 ) 2 -；
R k5 Is selected from C (R) k3 ) Or N;
R k1 or R k3 Each independently selected from H, D, F, Cl, Br, I, OH, O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
or two R k3 And together with the atom or ring skeleton to which they are directly attached form C 3-8 Carbocyclic or 3-8 membered heterocyclic ring, two R k1 And together with the atom or ring skeleton to which they are directly attached form C 3-8 A carbocycle or 3-8 membered heterocycle optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 each independently selected from H, D, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl radical, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally substituted by 1 to 4 substituents selected from D, F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
p1 or p2 are each independently selected from 0, 1,2, 3,4 or 5.
As a second embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof,
l is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak 3-or-Cy 1-Cy2-Ak3-Cy 3-;
ak2 and Ak3 are respectively and independently selected from CH 2 Or O;
cy1, Cy2 or Cy3 are each independently selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azacyclohexenyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazepinyl, phenyl, cyclopropylaminocyclopropyl, cyclopropylbenzocyclobutyl, cyclopropylpentacyclopentyl, cyclopropylaminocyclohexyl, cyclobutylbenzocyclobutyl, cyclobutylpentacyclopentyl, cyclobutylocyclocyclohexyl, cyclopentocyclocyclopentyl, cyclopentocyclocyclohexyl, cyclohexylocyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl spirobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutyl spirocyclobutyl spirobutyl, cyclobutylspirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyloazetidinyl, cyclopropylpyrrolopyrrolidinyl, cyclopropylnopiperidinyl, cyclobutyloazetidinyl, cyclobutylobutylkinyl, cyclopentylpiperidyl, cyclohexylspirocyclohexyl, cyclopropyloxazetidiyl, cyclopropyloxazetidinyl, cyclobutyloxazetidinyl, cyclopentapyridyl, cyclopropyloxazetidinyl, cyclobutyloxazetidinyl, piperidinyl, and cyclopentadienylyl, Cyclobutyl-pyrrolopyrrolidinyl, cyclobutyl-oxopiperidinyl, cyclopentoazetidinyl, cyclopenteazolyl, cyclopenteaiperidyl, cyclohexyloazetidiyl, cyclohexyloxopyrrolidinyl, cyclohexyloxopiperidyl, azetidinoazetidinyl, azetidinobutylpyrrolidinyl, azetidinobiperidyl, pyrrolidinyloazetidiyl, pyrrolidinylopyrrolidinyl, pyrrolidinyloxopiperidyl, piperidinoazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutyl spiroazacyclobutyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiroazetidinyl, azacyclyl.Butyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinyl spiroazetidinyl, piperidinyl spiropyrrolidinyl, piperidinyl spiropiperidinyl,
Figure BDA0003644199070000041
Figure BDA0003644199070000042
Figure BDA0003644199070000043
When substituted, is optionally substituted with 1 to 2 substituents selected from D, F, Cl, Br, I, OH, NH 2 、COOH、CN、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted by a substituent of alkoxy;
b is selected from
Figure BDA0003644199070000044
R b1 、R b2 Or R b3 Each independently selected from H, D, F, Cl, Br, I, OH, NH 2 、CN、CONH 2 Methyl, ethyl, methoxy and ethoxy, wherein the methyl, ethyl, methoxy and ethoxy are optionally substituted by 1 to 4 groups selected from D, F, Cl, Br, I, OH and NH 2 、CN、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted by a substituent of alkoxy;
n1 or n2 are each independently selected from 0, 1,2 or 3;
the remaining definitions are the same as in the first embodiment of the present invention.
As a third embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof,
each Q is independently selected from the group consisting of a bond, -O-, -S-, -CH 2 -、-NH-、-CO-、-NHCO-、-CONH-；
Each F is independently selected from
Figure BDA0003644199070000045
Figure BDA0003644199070000051
C 3-7 Monocyclic alkyl, C 5-10 And cycloalkyl group, C 5-12 Spiro cycloalkyl, C 5-10 Bridged cycloalkyl radical, C 4-7 Mono-heterocycloalkyl, C 5-10 And heterocyclic alkyl, C 5-12 Spiroheterocycloalkyl, C 5-10 Bridged heterocycloalkyl, C 6-14 Aryl, 5-10 membered heteroaryl, said heteroaryl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S or N;
Figure BDA0003644199070000052
selected from single bonds or double bonds;
R k8 each independently selected from the group consisting of a bond,
Figure BDA0003644199070000053
C(CH 3 ) 2 、CH 2 、
Figure BDA0003644199070000054
-C(＝O)-、-C(＝Se)-、-C(＝S)-、-P(＝O)H-、-P(＝O)(CH 3 )-、-S(＝O) 2 -、-S(＝O)-；
R k6 Each independently selected from S, O, CH 2 Or NH;
R k7 each independently selected from CH or N;
R k9 each independently selected from O, S, CH 2 CH, NH, or N;
p3 is selected from 1,2 or 3;
R k2 each independently selected from-C (═ O) -, -C (═ Se) -, -C (═ S) -, -P (═ O) H-, -P (═ O) (CH) 3 )-、-S(＝O) 2 -, -S (═ O) -, or-CH 2 -；
R k5 Selected from CH or N;
R k1 、R k3 each independently selected from H, D, F, Cl, Br, I, OH, O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy being optionally substituted by 1 to 4 substituents selected from D, F, Cl, Br, I, OH or NH 2 Substituted with a substituent of (a);
or two R k3 And together with the atom or ring skeleton to which they are directly attached form C 3-6 Carbocyclic or 3-7 membered heterocyclic ring, two R k1 And together with the atom or ring skeleton to which they are directly attached form C 3-6 A carbocycle or 3-7 membered heterocycle, optionally substituted with 1 to 4 groups selected from D, F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 each independently selected from H, D, OH, NH 2 、CF 3 CN or C 1-4 An alkyl group;
the remaining definitions are the same as in the first or second embodiment of the present invention.
As a fourth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof,
each F is independently selected from
Figure BDA0003644199070000061
Figure BDA0003644199070000062
Figure BDA0003644199070000063
Cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1]Pentyl alkyl, bicyclo [2.2.2]Octyl, adamantyl, phenyl, naphthyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl,Imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzpyrazolyl, benzothiazolyl, benzothienyl, benzofuryl, benzopyrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyrazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazinyl, imidazopyridyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrimidopyridinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyrimidopyridazinyl, pyridopyrimidinyl, pyridinopyridyl, pyridopyridazinyl, pyridazinopyridazinyl, Pyridazinopyrazinyl, pyrazinopyrazinyl;
each Q is independently selected from a bond or-CH 2 -；
R k2 Each independently selected from-C (═ O) -, -C (═ Se) -, -C (═ S) -, -P (═ O) H-, -P (═ O) (CH) 3 )-；
R k1 、R k3 Each independently selected from H, D, F, Cl, Br, I, OH, O, NH 2 、CF 3 、CN、COOH、CONH 2 Methyl, ethyl, methoxy, ethoxy, said methyl, ethyl, methoxy, ethoxy optionally being substituted by 1 to 4 groups selected from D, F, Cl, Br, I, OH or NH 2 Substituted with the substituent(s);
or two R k1 And the atoms or the ring skeleton to which they are directly attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl group, optionally substituted by 1 to 4 groups selected from D, F, Cl, Br, I, OH or NH 2 Substituted with the substituent(s);
R k4 each independently selected from H or methyl;
the remaining definitions are the same as in the first, second or third embodiment of the present invention.
As a fifth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal thereof,
l is selected from-Cy 1-Cy2-Cy 3-or-Cy 1-Cy2-Ak3-Cy 3-;
ak3 is selected from CH 2 ；
Cy1, Cy2 or Cy3 are each independently selected from one of the following substituted or unsubstituted groups:
Figure BDA0003644199070000071
Figure BDA0003644199070000072
Figure BDA0003644199070000081
Figure BDA0003644199070000082
when substituted, by 1 to 4 substituents selected from D, F, CF 3 OH, methyl, ═ O, hydroxymethyl, COOH, CN or NH 2 Substituted with the substituent(s);
the remaining definitions are the same as in the first, second, third or fourth embodiment of the present invention.
As a sixth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal thereof,
b is selected from
Figure BDA0003644199070000083
L is selected from one of the structural fragments shown in Table L-1;
TABLE L-1
Figure BDA0003644199070000084
Figure BDA0003644199070000091
Figure BDA0003644199070000101
K is selected from one of the structural fragments shown in Table K-1;
TABLE K-1
Figure BDA0003644199070000102
Figure BDA0003644199070000111
The invention relates to a compound or a stereoisomer, a tautomer, a deuteron, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein the compound is selected from one of structures shown in a table S-1:
TABLE S-1
Figure BDA0003644199070000121
Figure BDA0003644199070000131
Figure BDA0003644199070000141
Figure BDA0003644199070000151
Figure BDA0003644199070000161
Figure BDA0003644199070000171
Figure BDA0003644199070000181
Figure BDA0003644199070000191
Figure BDA0003644199070000201
Figure BDA0003644199070000211
Figure BDA0003644199070000221
Figure BDA0003644199070000231
Figure BDA0003644199070000241
Figure BDA0003644199070000251
Figure BDA0003644199070000261
Figure BDA0003644199070000271
Figure BDA0003644199070000281
The invention also provides a pharmaceutical composition, which comprises the compound or the stereoisomer, the tautomer, the deuteron, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal thereof, and a pharmaceutically acceptable carrier.
The invention also provides the use of a compound of any one of the above or a stereoisomer, a tautomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof for the manufacture of a medicament for the treatment of a disease associated with the inhibition or degradation of BTK kinase, selected from cancer.
The first synthesis method comprises the following steps:
Figure BDA0003644199070000291
the general formula (Z-1) and the general formula (Z-2) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain a corresponding general formula (Z-3), if an amino protecting group is arranged at the reaction position of the general formula (Z-3), the amino protecting group is removed firstly, then the amino protecting group and the general formula (Z-4) are subjected to nucleophilic substitution reaction to obtain a corresponding general formula (II), namely a general formula (I), and the preparation of a longer chain can be repeatedly carried out according to the above first step method and the preparation of the deaminating protecting group;
R 4 -Cy1-R 5 (Z-2-1)+R 6- Cy2-R 7 (Z-2-2)→R 4 -Cy1-Ak2-Cy2-R 7 (Z-2-3)，
the reaction of the general formula (Z-2-1) with the general formula (Z-2-2) can be carried out by nucleophilic substitution reaction, coupling reaction or reductive amination to obtain the general formula (Z-2-3), and the preparation of longer chains can be repeatedly carried out according to the above method;
if the reaction position of (Z-2-1) has an amino protecting group, the reaction with the general formula (Z-2-2) after the protecting group is removed can obtain a general formula (Z-2-3) through nucleophilic substitution reaction or coupling reaction or reductive amination, and the preparation of a longer chain can be repeatedly prepared according to the method;
or the general formula (Z-1) and the general formula (Z-2-1) are subjected to nucleophilic substitution reaction, coupling reaction or reductive amination reaction (which can be obtained by increasing the length of the chain by the preparation method of the general formula (Z-2-3)) to obtain the corresponding general formula (II), namely the general formula (I), wherein the length of the L chain can be prepared by the preparation method of the general formula (Z-2-3).
And a second synthesis method comprises the following steps:
Figure BDA0003644199070000292
if the reaction site of the general formula (Z-2) has an amino protecting group, removing the amino protecting group, and then carrying out nucleophilic substitution reaction or coupling reaction with the general formula (Z-4) to obtain a corresponding general formula (Z-5), and carrying out nucleophilic substitution reaction or coupling reaction on the general formula (Z-5) and the general formula (Z-1) to obtain a corresponding general formula (II), namely a general formula (I);
the third synthesis method comprises the following steps:
part of the chain L can firstly carry out nucleophilic substitution reaction or coupling reaction on the general formula (Z-1), then carries out nucleophilic substitution reaction or coupling reaction on the chain L and other parts of the chain L (the synthetic method is shown in the general formula (Z-2-3) for preparation), and so on until the general formula (Z-3) is obtained, and the general formula (Z-3) and the general formula (Z-4) obtain the corresponding general formula (II), namely the general formula (I) through the nucleophilic substitution reaction or coupling reaction;
the synthesis method comprises the following steps:
or part of the chain L can be subjected to nucleophilic substitution reaction or coupling reaction before the general formula (Z-4), and then subjected to nucleophilic substitution reaction or coupling reaction with other parts of the chain L (the synthetic method is shown in the general formula (Z-2-3) for preparation), and so on until the general formula (Z-5) is obtained, and the general formula (Z-5) and the general formula (Z-1) are subjected to nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (II), namely the general formula (I).
Unless stated to the contrary, the terms used in the specification and claims of this application have the following meanings.
The carbon, hydrogen, oxygen, sulfur and nitrogen or F, Cl, Br and I related in the groups and compounds of the invention all comprise the same positionOptionally, the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are further replaced by one or more isotopes of their corresponding carbon, wherein isotopes of carbon include 12 C、 13 C and 14 c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including 16 O、 17 O and 18 isotopes of O, S including 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, F include 17 F and 19 isotopes of F, chlorine including 35 Cl and 37 cl, isotopes of bromine including 79 Br and 81 Br。
"halogen" means F, Cl, Br or I.
"halo-substituted" means F, Cl, Br or I-substituted, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 substituents selected from F, Cl, Br or I, 1 to 4 substituents selected from F, Cl, Br or I. "halogen-substituted" is simply referred to as "halo".
"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including, but not limited to, alkyl of 1 to 20 carbon atoms, alkyl of 1 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups, as found herein, are defined consistent with this definition. The alkyl group may be monovalent, divalent, trivalent or tetravalent.
"heteroalkyl" means that 1 or more (including but not limited to 2,3, 4, 5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH) 2 )v-X(CH 2 )v-X(CH 2 ) v-H (v is an integer from 1 to 5, X is each independently selected from a bond or a heteroatom including but not limited to N, O or S, and has at least 1X is selected from a heteroatom, and N or S in the heteroatom may be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, trivalent, or tetravalent.
"alkylene" refers to a substituted or unsubstituted, straight and branched chain, divalent saturated hydrocarbon radical, including- (CH) 2 ) v - (v is an integer of 1 to 10), examples of the alkylene group include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.
"Heteroalkylidene" means a substituted or unsubstituted alkylene group in which 1 or more (including but not limited to 2,3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH) 2 )v-X(CH 2 )v-X(CH 2 ) v-, v is an integer from 1 to 5, each X is independently selected from the group consisting of a bond, N, O or S, and at least 1X is selected from the group consisting of N, O or S.
"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having from 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. Cycloalkyl groups, as found herein, are defined as above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl may be attached to a heteroatom or carbon atom, heterocycloalkyl may be attached to an aromatic ring or to a non-aromatic ring, heterocycloalkyl may be attached to a bridged or spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl radical may be monovalent, divalent, trivalent or tetravalent
"alkenyl" means a substituted or unsubstituted straight and branched chain unsaturated hydrocarbon group having at least 1, and typically 1,2 or 3 carbon double bonds, the backbone including, but not limited to, 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; alkenyl groups are present herein, the definition of which is consistent with the present definition. The alkenyl group may be monovalent, divalent, trivalent or tetravalent.
"alkynyl" means a substituted or unsubstituted, straight and branched, monovalent, unsaturated hydrocarbon radical having at least 1, and typically 1,2 or 3 carbon-carbon triple bonds, the backbone containing from 2 to 10 carbon atoms, including but not limited to from 2 to 6 carbon atoms in the backbone and from 2 to 4 carbon atoms in the backbone, examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; alkynyl groups can be monovalent, divalent, trivalent or tetravalent.
"alkoxy" means a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.
"carbocyclyl" or "carbocycle" means substituted or unsubstitutedSubstituted saturated or unsaturated aromatic or non-aromatic rings which may be 3 to 8 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring systems, the carbocyclic group may be attached to an aromatic or non-aromatic ring, which is optionally monocyclic, bridged or spiro. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, and mixtures thereof,
Figure BDA0003644199070000321
"carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and contain 1 or more (including but not limited to 2,3, 4, or 5) heteroatoms selected from N, O or S, optionally substituted N, S of the heterocyclyl ring being oxidizable to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiayl, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, dihydropyranyl, spirocyclo-pyridyl, spiro-pyridyl, spirocyclo-pyridyl, oxacycloheptyl, azanyl, pyridyl, oxathianyl, thianyl, thienyl, pyridyl, etc, Benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrolyl, benzimidazolyl, benzothienylAzolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1]Octyl, azabicyclo [5.2.0 ] s]Nonoalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptalkyl group,
Figure BDA0003644199070000322
Figure BDA0003644199070000323
Figure BDA0003644199070000324
"Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.
"spiro" or "spirocyclic" refers to a polycyclic group that shares a single atom (referred to as a spiro atom) between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spiro system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including but not limited to 1,2, 3 or 4) double bonds, and optionally may contain 0 to 5 rings selected from N, O or S (═ O) n A heteroatom of (a).
Figure BDA0003644199070000331
The "spiro" or "spirocyclic" group may be monovalent, divalent, trivalent, or tetravalent.
"fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1,2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (═ O) n Or O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:
Figure BDA0003644199070000332
Figure BDA0003644199070000333
the "fused ring" or "fused ring group" may be monovalent, divalent, trivalent or tetravalent.
"bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 heteroatoms selected or heteroatom containing groups (including but not limited to N, S (═ O) n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include
Figure BDA0003644199070000341
Figure BDA0003644199070000342
Cubane and adamantane. The "bridge ring" or "bridge ring group" may be monovalent, divalent, trivalent, or tetravalent.
"carbocyclyl", "spirocarbocyclyl" or "carbospirocyclic" refers to a "spiro" ring whose ring system consists of only carbon atoms. The "carbospiro", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospiro" group, as referred to herein, is defined in accordance with the definition of spiro.
"carbocyclic", "fused carbocyclic group" or "fused carbocyclic group" means that the ring system is "fused" consisting of only carbon atoms. "carbocyclic ring", "fused carbocyclic ring group", "fused carbocyclic group", or "fused carbocyclic group" as used herein, is defined in accordance with fused rings.
"Carbobridged ring", "bridged carbocyclyl" or "carbocyclyl" refer to a "bridged ring" in which the ring system consists of only carbon atoms. "Carbobridged ring", "bridged carbocyclyl", or "carbobridyclyl" as used herein, is defined in accordance with the definition of bridged ring.
"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, and heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclic" as found herein, is defined consistent with the definition of heterocycle.
"Heterocyclo", "heterocyclocyclyl" or "heterocyclocyclyl" means a "fused ring" containing heteroatoms. The term "fused ring" as used herein refers to a "fused ring," fused ring group, "fused heterocyclic group," or "fused ring group," which is defined as being fused.
"Heterospirocyclic", "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" refers to "spirocyclic" containing heteroatoms. The definition of heterospiro, "heterospiro ring", "spiro heterocyclic" or "heterospiro ring" as used herein is consistent with spiro rings.
"heterobridged ring," "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The term "heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group", as used herein, is defined in accordance with the bridged ring.
"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single or fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include a phenyl ring, a naphthyl ring,
Figure BDA0003644199070000343
The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is located on the aryl ring.
"heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains from 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (═ O) n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridinePhenyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include
Figure BDA0003644199070000351
Heteroaryl groups, as found herein, are defined in accordance with the present definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the attachment site is on the heteroaryl ring.
The "5-membered and 5-membered heteroaromatic ring" means a 5-and 5-membered fused heteroaromatic ring in which at least 1 ring of 2 fused rings contains 1 or more heteroatoms (including but not limited to O, S or N), and the whole group has aromaticity, and non-limiting examples include pyrrolopyrrole rings, pyrazolopyrrole rings, pyrazolopyrazole rings, pyrrolofuran rings, pyrazolofuran rings, pyrrolothiophene rings, pyrazolothiophene rings.
"5 and 6 membered heteroaromatic ring" means a 5 and 6 membered fused heteroaromatic ring wherein at least 1 ring of the 2 fused rings contains more than 1 heteroatom (including but not limited to O, S or N) and the entire group is aromatic, non-limiting examples include benzo 5 membered heteroaryl, 6 membered heteroaromatic ring and 5 membered heteroaromatic ring.
"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2,3, 4, or 5) substituents including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(＝O)-R a 、-O-(CH 2 ) m -C(＝O)-R a 、-(CH 2 ) m -C(＝O)-NR b R c 、-(CH 2 ) m S(＝O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR b R c Etc. wherein R is b And R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b And R c Five or six membered cycloalkyl or heterocyclyl groups may be formed. R a And R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring.
By "containing 1 to 5 heteroatoms selected from O, S, N" is meant containing 1,2, 3,4 or 5 heteroatoms selected from O, S, N.
"substituted with 0 to X substituents" means substituted with 0, 1,2, 3.. X substituents, X is selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1,2, 3, or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1,2, 3,4, or 5 substituents. If "the heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted with 0, 1,2, 3 or 4 substituents selected from H or F.
X-Y membered rings (X is selected from integers less than Y and greater than 3, and Y is selected from any integer between 4 and 12) include X +1, X +2, X +3, X +4. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heteroatomic, heterocyclic spiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.
"pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, tautomers, deuterons, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.
"tautomer" refers to functional group isomers resulting from rapid movement of an atom in two positions in a molecule, such as keto-enol isomers and amide-imino-enol isomers, and the like.
“IC 50 "is the concentration of drug or inhibitor required to inhibit half of a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.).
Detailed Description
The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) at 10 -6 The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
MS was measured using Agilent 6120B (ESI) and Agilent 6120B (APCI);
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);
the thin layer chromatography silica gel plate is prepared from cigarette bench yellow sea HSGF 254 Or Qingdao GF 254 Silica gel plate with specification of 0.15-0.20 mm for Thin Layer Chromatography (TLC), and specification of 0.4-0.5 mm for thin layer chromatography separation and purification product;
the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier;
the known starting materials of the present invention can be synthesized by methods known in the art or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical industry, Shaoshanghi chemical technology, and Bailingwei technology;
P13I：
Figure BDA0003644199070000371
(synthetic references: Y.Sun, X.ZHao, N.Ding, H.Gao, Y.Wu, Y.Yang, M.ZHao, J.Hwang, Y.Song, W.Liu, Y.Rao, Cell Res.2018,28,779-
Tf: a trifluoromethanesulfonyl group;
boc: a tert-butoxycarbonyl group;
ts: a p-toluenesulfonyl group;
cbz: a benzyloxycarbonyl group;
TMS: trimethylsilyl group.
Example 1
3- (4- ((3- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) - [1,3 '-diazetidine ] -1' -yl) methyl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) piperidine-2, 6-dione (Compound 1)
3-(4-((3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
Figure BDA0003644199070000381
1- [1- [1- (azetidin-3-yl) azetidin-3-yl ] -4-piperidinyl ] -3- (4-phenoxyphenyl) pyrazolo [3,4-d ] pyrimidin-4-amine (1a) (synthesis see WO2020239103) (173mg,0.35mmol) was dissolved in 10mL of THF and 3mL of DMSO, 1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-4-carbaldehyde (1b) (synthesis see WO2020113233) (50mg, 0.17mmol) was added, the reaction was adjusted to pH 6 with acetic acid, stirred at room temperature for 3H, sodium triacetoxyborohydride (92mg, 0.43mmol), stirred at room temperature for 16 h. Slowly adding 10mL of saturated aqueous sodium bicarbonate solution into the reaction system, extracting with 100mL of dichloromethane, washing the organic phase with 50mL of water, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20:1) to obtain 3- (4- ((3- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) - [1,3 '-diazacyclobutan ] -1' -yl) methyl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) piperidin-2, 6-dione (Compound 1) (30mg, yield from Compound 1 b: 23%).
1 H NMR(400MHz,CDCl 3 )δ10.30–10.04(m,1H),8.42–8.30(m,1H),7.70–7.60(m,2H),7.45–7.35(m,2H),7.23–7.02(m,5H),7.00–6.90(m,2H),6.83–6.72(m,1H),5.81(br.s,2H),5.25–5.16(m,1H),4.86–4.71(m,1H),3.91–3.71(m,5H),3.70–3.54(m,2H),3.53–3.30(m,3H),3.28–3.04(m,5H),2.97–2.88(m,2H),2.88–2.79(m,2H),2.78–2.65(m,1H),2.45–2.35(m,2H),2.22–1.97(m,5H).
LCMS m/z＝768.4[M+1] +
Example 2:
5- (3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazetidin-1-yl) -N- (2, 6-dioxopiperidin-3-yl) pyridinecarboxamide (Compound 2)
5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide
Figure BDA0003644199070000391
The first step is as follows: 3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazaazetidine-1-carboxylic acid tert-butyl ester (2b)
tert-butyl 3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidine-1-carboxylate
Figure BDA0003644199070000401
1- ((3R,4S) -1- (azetidin-3-yl) -3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (2a) (synthesis method is disclosed in WO2020239103) (510mg,1.11mmol) is added to 50mL of 1, 2-dichloroethane, tert-butyl 3-fluoro-3-formylazetidine-1-carboxylate (synthesis method is disclosed in WO2018089355) (304mg, 1.5mmol) is added, after 1H reaction at room temperature, sodium triacetoxyborohydride (318mg,1.5mmol) is added, and the reaction is continued at room temperature for 12H. 50mL of methylene chloride was added to the reaction system, the pH was adjusted to 9.0 with a saturated sodium bicarbonate solution, the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methylene chloride/methanol (v/v) ═ 10:1) to give 3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazacyclobutan-1-carboxylic acid tert-butyl ester (2b) (600mg, yield: 84%).
LCMS m/z＝647.5[M+1] + 。
The second step is that: 1- ((3R,4S) -3-fluoro-1- (1- ((3-fluoroazetidin-3-yl) methyl) azetidin-3-yl) -piperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (2c)
1-((3R,4S)-3-fluoro-1-(1-((3-fluoroazetidin-3-yl)methyl)azetidin-3-yl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
Figure BDA0003644199070000402
Tert-butyl 3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazazetidin-1-carboxylate (2b) (600mg, 0.93mmol) was dissolved in 20mL of methanol, and 20mL of 4 mol/L1, 4-dioxane hydrochloride solution was added and reacted at room temperature for 1H. The reaction solution was concentrated under reduced pressure, dissolved in 100mL of dichloromethane, adjusted to pH 12.0 with 3mol/L sodium hydroxide solution, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 1- ((3R,4S) -3-fluoro-1- (1- ((3-fluoroazetidin-3-yl) methyl) azetidin-3-yl) -piperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (2c) (450 mg).
LCMS m/z＝547.3[M+1] + 。
The third step: methyl 5- (3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazetidin-1-yl) picolinate (2d)
methyl 5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)picolinate
Figure BDA0003644199070000411
The crude 1- ((3R,4S) -3-fluoro-1- (1- ((3-fluoroazetidin-3-yl) methyl) azetidin-3-yl) -piperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (2c) (500mg) described above was dissolved in 10mL of DMSO, 1.0mL of DIPEA and methyl 5-fluoropicolinate (200mg, 1.29mmol) were added, and the mixture was warmed to 95 ℃ for 7H. The reaction mixture was cooled to room temperature, 100mL of purified water was added to precipitate a solid, which was filtered, the filter cake was dissolved in a mixed solvent of dichloromethane/methanol (v/v) ═ 10:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give methyl 5- (3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazetidin-1-yl) picolinate (2d) (480mg, two-step yield from compound 2 b: 68%).
LCMS m/z＝682.3[M+1] +
The fourth step: 5- (3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazetidin-1-yl) picolinic acid (2e)
5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)picolinic acid
Figure BDA0003644199070000412
Methyl 5- (3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazetidin-1-yl) picolinate (2d) (480mg, 0.7mmol) was added to a mixed solvent of 10mL tetrahydrofuran, 10mL methanol and 10mL purified water, and sodium hydroxide solid (800mg,20mmol) was added and reacted at room temperature for 2H. The reaction solution was concentrated under reduced pressure, the pH of the system was adjusted to 6.0 with 1mol/L aqueous hydrochloric acid, 60mL of dichloromethane was added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 5- (3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazaazetidin-1-yl) picolinic acid (2e) (350 mg).
The fifth step: 5- (3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazetidin-1-yl) -N- (2, 6-dioxopiperidin-3-yl) picolinamide (Compound 2)
5-(3-((3-((3R,4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-fluoropiperidin-1-yl)azetidin-1-yl)methyl)-3-fluoroazetidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide
Figure BDA0003644199070000421
To the crude 5- (3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazetidin-1-yl) picolinic acid (2e) (350mg) above was added 10mL of DMF, followed by 3-aminopiperidine-2, 6-dione hydrochloride (250mg, 1.5mmol) and 1.0mL of triethylamine, followed by HATU (300mg, 0.8mmol) and reacted at room temperature for 16H. To the reaction solution was added 100mL of purified water to precipitate a solid, which was filtered, the filter cake was dissolved in a mixed solvent of dichloromethane/methanol (v/v) ═ 10:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 10:1) to give 5- (3- ((3- ((3R,4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) azetidin-1-yl) methyl) -3-fluoroazetidin-1-yl) -N- (2, 6-dioxopiperidin-3-yl) pyridinecarboxamide (compound 2) (180mg, the two-step overall yield was calculated from compound 2 d: 33%).
1 H NMR(400MHz,CDCl 3 )δ8.69(br.s,1H),8.41(d,1H),8.37(s,1H),8.01(d,1H),7.77(d,1H),7.65(d,2H),7.39(t,2H),7.22–7.04(m,5H),6.78(dd,1H),5.65(br.s,2H),5.20–5.00(m,1H),4.99–4.70(m,2H),4.19–3.99(m,4H),3.80–3.64(m,2H),3.31–3.10(m,4H),3.10–2.93(m,4H),2.89–2.71(m,2H),2.66–2.55(m,1H),2.37(dd,1H),2.27–2.06(m,2H),2.04–1.93(m,1H).
LCMS m/z＝778.3[M+1] +
Example 3:
5- (3- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -piperidin-1-yl) - [1,3 '-diazacyclobutane ] -1' -yl) -N- (2, 6-dioxopiperidin-3-yl) pyridinecarboxamide (Compound 3)
5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide
Figure BDA0003644199070000431
The first step is as follows: 5- (3-4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -piperidin-1-yl) - [1,3 '-diazetidine ] -1' -yl) -picolinic acid methyl ester (3b)
methyl 5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)picolinate
Figure BDA0003644199070000432
1- (1- ([1,3' -diazacyclobut ] -3-yl) piperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] -pyrimidin-4-amine (3a) (synthesis method WO2020239103) (600mg,1.2mmol) was dissolved in 10mL of DMSO, 1.0mL of DIPEA and methyl 5-fluoropicolinate (200mg, 1.29mmol) were added, and the mixture was heated to 95 ℃ for 7H. The reaction mixture was cooled to room temperature, 100mL of purified water was added to precipitate a solid, which was filtered off, the filter cake was dissolved in a mixed solvent of dichloromethane/methanol (v/v) ═ 10:1, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 15:1) to give methyl 5- (3-4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -piperidin-1-yl) - [1,3 '-diazacyclobutane ] -1' -yl) -picolinate (3b) (500mg, yield: 66%).
LCMS m/z＝632.3[M+1] +
The second step: 5- (3-4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) - [1,3 '-diazacyclobutane ] -1' -yl) -picolinic acid (3c)
5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)picolinic acid
Figure BDA0003644199070000441
To methyl 5- (3-4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -piperidin-1-yl) - [1,3 '-diazetidine ] -1' -yl) -picolinate (3b) (500mg, 0.79mmol) was added a mixed solvent of 10mL of tetrahydrofuran, 10mL of methanol and 10mL of purified water, and sodium hydroxide solid (800mg,20mmol) was added and reacted at room temperature for 2H. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6.0 with 1mol/L aqueous hydrochloric acid to precipitate a solid, which was then filtered to give a crude product of 5- (3-4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) - [1,3 '-diazacyclobutane ] -1' -yl) -picolinic acid (3c) (400 mg).
The third step: 5- (3- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -piperidin-1-yl) - [1,3 '-diazacyclobut ] -1' -yl) -N- (2, 6-dioxopiperidin-3-yl) pyridinecarboxamide (Compound 3)
5-(3-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-[1,3'-biazetidin]-1'-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide
Figure BDA0003644199070000442
To the crude 5- (3-4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) - [1,3 '-diazacyclobutyl ] -1' -yl) -picolinic acid (3c) (400mg) above was added 10mL of DMF followed by 3-aminopiperidine-2, 6-dione hydrochloride (250mg, 1.5mmol) and 1.0mL of triethylamine, followed by HATU (240mg, 0.63mmol), and reacted at room temperature for 16H. The reaction mixture was directly filtered by suction, and the filter cake was collected and washed with 20mL of ethyl acetate to give 5- (3- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -piperidin-1-yl) - [1,3 '-diazacyclobut ] -1' -yl) -N- (2, 6-dioxopiperidin-3-yl) pyridinecarboxamide (compound 3) (300mg, two-step total yield: 52% from compound 3 b).
1 H NMR(400MHz,DMSO-d 6 )δ10.81(br.s,1H),8.66(d,1H),8.23(s,1H),7.88–7.76(m,2H),7.70–7.62(m,2H),7.48–7.39(m,2H),7.23–7.08(m,5H),6.90(dd,1H),4.79–4.60(m,2H),4.05–3.94(m,2H),3.84–3.72(m,2H),3.71–3.60(m,1H),3.49–3.37(m,2H),3.09–2.94(m,3H),2.91–2.72(m,3H),2.58–2.51(m,1H),2.30–2.10(m,3H),2.10–1.95(m,3H),1.95–1.80(m,2H).
LCMS m/z＝728.3[M+1] +
Biological test example
1. Cell proliferation inhibition assay
The Mino and SU-DHL-6 culture medium is RPMI1640+ 10% FBS, and is cultured at 37 deg.C and 5% CO 2 In an incubator. Cells were plated in 96-well plates. Wherein Mino and SUDHL-6 cells 5000 cells/well, 90. mu.L per well. Each well was dosed with 10 μ L of compound at different concentrations. Each concentration is provided with 3 multiple wells, the last column is DMSO solvent control group, at 37 deg.C and 5% CO 2 The culture was continued under the conditions for 72 hours. After 72 hours, 50. mu.L of detection reagent (Cell Viability Assay, Promega, G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the fluorescence signal value was measured using a microplate reader (PHERAstar FSX). The inhibition rate was calculated using formula (1), wherein V sample Reading for drug treatment group, V vehicle control Is the average of the solvent control group. Using origin9.2 software, the IC of a compound to inhibit cell proliferation was calculated 50 The value is obtained.
inhi.％＝(1-V sample /V vehicle control ) X 100% of formula (1).
IC for inhibiting Mino cell proliferation by the compounds of the invention 50 The results are shown in Table 1-1.
TABLE 1-1 inhibition of Mino cell proliferation IC 50 Value of
Serial number Compound number IC 50 (nM)
1 Compound 1 136
2 Compound 2 368
Compounds of the invention inhibit SU-DHL-6 IC of cell proliferation 50 The results are shown in tables 1-2.
TABLE 1-2 IC inhibition of SU-DHL-6 cells 50 Value of
Serial number Compound numbering IC 50 (nM)
1 Compound 2 219
2 Compound 3 100
And (4) conclusion: the compound synthesized by the technology has certain inhibition effect on the proliferation of Mino cells (mantle cell lymphoma cells) and SU-DHL-6 cells (human B lymphoma cells).

Claims (10)

1. A compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
B-L-K (I)；
L is selected from-Ak 1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak 5-;
ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH 2 O or a bond;
cy1, Cy2, Cy3 and Cy4 are each independently selected from 3 to 12 membered heterocyclic ring, 3 to 12 membered cycloalkyl, 6 to 10 membered aryl or bond, said heterocyclic, cycloalkyl or aryl being optionally substituted with 1 to 4Selected from D, F, Cl, Br, I, OH, NH 2 、oxo、C 1 - 4 Alkyl or C 1-4 Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
b is selected from
Figure FDA0003644199060000011
R b1 、R b2 Or R b3 Each independently selected from H, D, F, Cl, Br, I, OH, NH 2 、CN、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl and alkoxy being optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, NH 2 、CN、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted by a substituent of alkoxy;
n1 is selected from 0, 1,2, 3,4 or 5;
n2 is selected from 0, 1,2, 3 or 4;
n3 is selected from 0, 1 or 2;
k is selected from
Figure FDA0003644199060000012
Q is each independently selected from the group consisting of a bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or 3-12 membered heterocycle, said heterocycle optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1 - 4 Alkyl or C 1-4 Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R q is selected from H or C 1-6 An alkyl group;
each F is independently selected from C 3-20 Carbocyclic ring, C 6-20 An aromatic ring, a 3-20 membered heterocyclic ring, or a 5-20 membered heteroaromatic ring, said heterocyclic or heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
R k2 each independently selected from the group consisting of a bond, -C (═ O) -, -C (═ Se) -, -C (═ S) -, -P (═ O) H-, -P (═ O) (CH) 3 )-、-S(＝O) 2 -, -S (═ O) -, or-C (R) k3 ) 2 -；
R k5 Is selected from C (R) k3 ) Or N;
R k1 or R k3 Each independently selected from H, D, F, Cl, Br, I, OH, O, NH 2 、CN、COOH、CONH 2 、C 1 - 6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
or two R k3 And together with the atom or ring skeleton to which they are directly attached form C 3-8 Carbocyclic or 3-8 membered heterocyclic ring, two R k1 And together with the atom or ring skeleton to which they are directly attached form C 3-8 A carbocycle or 3-8 membered heterocycle optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 each independently selected from H, D, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl radical, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally substituted by 1 to 4 substituents selected from D, F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
p1 or p2 are each independently selected from 0, 1,2, 3,4 or 5.
2. A compound according to claim 1 or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
L is selected from-Cy 1-, -Cy1-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak 3-or-Cy 1-Cy2-Ak3-Cy 3-;
ak2 and Ak3 are respectively and independently selected from CH 2 Or O;
cy1, Cy2 or Cy3 are each independently selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azacyclohexenyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazepinyl, phenyl, cyclopropylaminocyclopropyl, cyclopropylbenzocyclobutyl, cyclopropylpentacyclopentyl, cyclopropylaminocyclohexyl, cyclobutylbenzocyclobutyl, cyclobutylpentacyclopentyl, cyclobutylocyclocyclohexyl, cyclopentocyclocyclopentyl, cyclopentocyclocyclohexyl, cyclohexylocyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl spirobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutyl spirocyclobutyl spirobutyl, cyclobutylspirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyloazetidinyl, cyclopropylpyrrolopyrrolidinyl, cyclopropylnopiperidinyl, cyclobutyloazetidinyl, cyclobutylobutylkinyl, cyclopentylpiperidyl, cyclohexylspirocyclohexyl, cyclopropyloxazetidiyl, cyclopropyloxazetidinyl, cyclobutyloxazetidinyl, cyclopentapyridyl, cyclopropyloxazetidinyl, cyclobutyloxazetidinyl, piperidinyl, and cyclopentadienylyl, Cyclobutyl-pyrrolopyrrolidinyl, cyclobutyl-piperidyl, cyclopentoazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazacyclobutyl, cyclohexylpyrrolopyrrolidinyl, cyclohexylaminopiperidinyl, azetidinyl-azetidinyl, azetidinylbopyrrolidinyl, azetidinylpiperidyl, pyrrolidinyloazetidiyl, pyrrolidinylpyrrolopyrrolidinyl, pyrrolidinylpiperidylpiperidyl, piperidinoazetidiyl, piperidinylpyrrolidinyl, piperidinopiperidinyl, cyclobutyl-spiroazetidinyl, cyclobutyl-spiropyrrolidinyl, cyclopentyl-spiroazetidinyl, cyclopentyl-spiropyrrolyl, cyclopentyl-spiropiperidinyl, cyclohexyl-spiroazetidinyl, cyclohexyl-spiropiperidinyl, azetidinyl-spiropyrrolyl, Azetidinyl spiropiperidinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidineA group, pyrrolidinylspiropiperidinyl, piperidinyl spiroazetidinyl, piperidinyl spiropyrrolidinyl, piperidinyl spiropiperidinyl,
Figure FDA0003644199060000031
Figure FDA0003644199060000032
Figure FDA0003644199060000033
When substituted, is optionally substituted with 1 to 2 substituents selected from D, F, Cl, Br, I, OH, NH 2 、COOH、CN、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted by a substituent of alkoxy;
b is selected from
Figure FDA0003644199060000034
R b1 、R b2 Or R b3 Each independently selected from H, D, F, Cl, Br, I, OH, NH 2 、CN、CONH 2 Methyl, ethyl, methoxy and ethoxy, wherein the methyl, ethyl, methoxy and ethoxy are optionally selected from 1 to 4 of D, F, Cl, Br, I, OH and NH 2 、CN、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted with a substituent of alkoxy;
n1 or n2 are each independently selected from 0, 1,2 or 3.
3. The compound of claim 2, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,
each Q is independently selected from the group consisting of a bond, -O-, -S-, -CH 2 -、-NH-、-CO-、-NHCO-、-CONH-；
Each F is independently selected from
Figure FDA0003644199060000041
Figure FDA0003644199060000042
C 3-7 Monocycloalkyl radical, C 5-10 And cycloalkyl group, C 5-12 Spiro cycloalkyl, C 5-10 Bridged cycloalkyl radical, C 4-7 Mono-heterocycloalkyl, C 5-10 And heterocyclic alkyl, C 5-12 Spiroheterocycloalkyl, C 5-10 Bridged heterocycloalkyl, C 6-14 Aryl, 5-10 membered heteroaryl, said heteroaryl or heterocycloalkyl containing 1 to 4 heteroatoms selected from O, S or N;
Figure FDA0003644199060000043
selected from single bonds or double bonds;
R k8 each independently selected from the group consisting of a bond,
Figure FDA0003644199060000044
C(CH 3 ) 2 、CH 2 、
Figure FDA0003644199060000045
-C(＝O)-、-C(＝Se)-、-C(＝S)-、-P(＝O)H-、-P(＝O)(CH 3 )-、-S(＝O) 2 -、-S(＝O)-；
R k6 Each independently selected from S, O, CH 2 Or NH;
R k7 each is independently selected from CH or N;
R k9 each independently selected from O, S, CH 2 CH, NH, or N;
p3 is selected from 1,2 or 3;
R k2 each independently selected from-C (═ O) -, -C (═ Se) -, -C (═ S) -, -P (═ O) H-, -P (═ O) (CH) 3 )-、-S(＝O) 2 -, -S (═ O) -, or-CH 2 -；
R k5 Selected from CH or N;
R k1 、R k3 each independently selected from H, D, F, Cl, Br, I, OH, O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1 - 4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy being optionally substituted by 1 to 4 substituents selected from D, F, Cl, Br, I, OH or NH 2 Substituted with the substituent(s);
or two R k3 And together with the atom or ring skeleton to which they are directly attached form C 3-6 Carbocyclic or 3-7 membered heterocyclic ring, two R k1 And together with the atom or ring skeleton to which they are directly attached form C 3-6 A carbocycle or 3-7 membered heterocycle, optionally substituted with 1 to 4 groups selected from D, F, Cl, Br, I, OH, ═ O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 each independently selected from H, D, OH, NH 2 、CF 3 CN or C 1-4 An alkyl group.
4. The compound of claim 3, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,
each F is independently selected from
Figure FDA0003644199060000051
Figure FDA0003644199060000052
Figure FDA0003644199060000053
Cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1]Pentyl alkyl, bicyclo [2.2.2 ] s]Octyl, adamantane, phenyl, naphthyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrrolidineOxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyrazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyridinyl, pyrimidopyridinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl;
each Q is independently selected from a bond or-CH 2 -；
R k2 Each independently selected from-C (═ O) -, -C (═ Se) -, -C (═ S) -, -P (═ O) H-, -P (═ O) (CH) 3 )-；
R k1 、R k3 Each independently selected from H, D, F, Cl, Br, I, OH, O, NH 2 、CF 3 、CN、COOH、CONH 2 Methyl, ethyl, methoxy, ethoxy, said methyl, ethyl, methoxy, ethoxy optionally being substituted by 1 to 4 groups selected from D, F, Cl, Br, I, OH or NH 2 Substituted with the substituent(s);
or two R k1 And the atom or ring skeleton to which they are directly attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl group, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl group being optionally substituted by 1 to 4 substituents selected from D, F, Cl, Br, I, OH or NH 2 Substituted with the substituent(s);
R k4 each independently selected from H or methyl.
5. The compound of claim 4, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,
l is selected from-Cy 1-Cy2-Cy 3-or-Cy 1-Cy2-Ak3-Cy 3-;
ak3 is selected from CH 2 ；
Cy1, Cy2 or Cy3 are each independently selected from one of the following substituted or unsubstituted groups:
Figure FDA0003644199060000061
Figure FDA0003644199060000062
Figure FDA0003644199060000071
Figure FDA0003644199060000072
when substituted, by 1 to 4 substituents selected from D, F, CF 3 OH, methyl, ═ O, hydroxymethyl, COOH, CN or NH 2 Substituted with the substituent(s).
6. The compound of claim 5, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein,
b is selected from
Figure FDA0003644199060000073
L is selected from one of the structural fragments shown in Table L-1;
k is selected from one of the structural fragments shown in Table K-1.
7. The compound of claim 1, or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, wherein the compound is selected from one of the structures shown in table S-1.
8. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a stereoisomer, tautomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1-8, or a stereoisomer, a tautomer, a deutero-solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, for the preparation of a medicament for the treatment of a disease associated with the inhibition or degradation of BTK kinase.
10. The use according to claim 9, wherein the disease is selected from cancer.
CN202210485930.5A 2021-07-15 2022-05-16 BTK (BTK inhibitory or degrading agent) and application thereof in medicine Pending CN114920746A (en)

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