[go: up one dir, main page]

CN114573586A - Polycyclic compound for inhibiting Bruton's tyrosine kinase activity, pharmaceutical composition and application thereof - Google Patents

Polycyclic compound for inhibiting Bruton's tyrosine kinase activity, pharmaceutical composition and application thereof Download PDF

Info

Publication number
CN114573586A
CN114573586A CN202011365603.3A CN202011365603A CN114573586A CN 114573586 A CN114573586 A CN 114573586A CN 202011365603 A CN202011365603 A CN 202011365603A CN 114573586 A CN114573586 A CN 114573586A
Authority
CN
China
Prior art keywords
substituted
unsubstituted
alkyl
amino
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202011365603.3A
Other languages
Chinese (zh)
Other versions
CN114573586B (en
Inventor
周星露
刘兴国
胡苗
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Hertz Pharmaceutical Co ltd
Original Assignee
Hangzhou Hertz Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Hertz Pharmaceutical Co ltd filed Critical Hangzhou Hertz Pharmaceutical Co ltd
Priority to CN202011365603.3A priority Critical patent/CN114573586B/en
Publication of CN114573586A publication Critical patent/CN114573586A/en
Application granted granted Critical
Publication of CN114573586B publication Critical patent/CN114573586B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a series of novel small molecule inhibitors for overcoming BTK C481S mutation resistance, in particular discloses a compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition of the compound, and application of the compound and the pharmaceutical composition containing the compound in treating BTK dysfunction related diseases such as B cell proliferative diseases and autoimmune diseases. The inventor of the invention proves that the compound can inhibit wild type and 481-th cysteine-mutated BTK kinase at the same time through experiments. The inventor of the invention proves that the compound has the anti-proliferation inhibition effect on tumor cell strains such as MINO, OCI-LY10 and the like through experiments.

Description

Polycyclic compound for inhibiting Bruton's tyrosine kinase activity, pharmaceutical composition and application thereof
Technical Field
The present invention relates to a novel class of polycyclic compounds, pharmaceutical compositions, which inhibit both wild-type BTK and mutant BTK, and their use in the preparation of a medicament for the treatment of diseases, disorders, or conditions that benefit from inhibition of bruton's tyrosine kinase activity, such as B-cell proliferative diseases and autoimmune diseases, alone or in combination with other medicaments.
Background
Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays a crucial role in B cell signaling pathways that link cell surface B Cell Receptor (BCR) stimulation to downstream intracellular responses. Btk is a key regulator of B cell development, activation, signaling, and survival. In addition, Bkt plays a role in numerous other hematopoietic cell signaling pathways, such as Toll-like receptor (TLR) and cytokine receptor mediated TNF- α production in macrophages, immunoglobulin E receptor (fcepsilonr 1) signaling in mast cells, signaling in B-lineage lymphoid cells to inhibit Fas/APO-1 apoptosis, and collagen-stimulated platelet aggregation. See, e.g., C.A. Jeffries et al, J.Bio.chem. (2003)278:26258-26264, N.J.Horwood et al, J.exp.Med. (2003)197: 1603-1611. Recent studies have shown that Btk signaling pathway is a new focus in the current clinical treatment of non-hodgkin's lymphoma (NHL), especially Chronic Lymphocytic Leukemia (CLL), B-cell lymphoma, and autoimmune diseases. The small molecule Btk inhibitor acts on a BCR signal channel, is combined with Btk to inhibit the autophosphorylation of Btk and prevent the activation of Btk, thereby blocking cell conduction and inducing apoptosis.
The Btk inhibitor ibrutinib is listed on the market and is determined as a novel breakthrough drug by FDA, and the research and development prospect is wide. In use, patients have developed drug resistant mutations, such as the 481 cysteine mutation (C481S), with first generation covalent BTK inhibitors represented by ibrutinib. There is therefore an urgent need to develop novel BTK inhibitors that can overcome resistance mutations.
In addition, BTK plays an important role in the regulation of the function of various immune cells including B cells. The activity of BTK kinase can be inhibited to effectively inhibit the activation of B cells and reduce the generation of autoantibodies. Thus, in addition to B-cell malignancies, BTK inhibitors have also been applied in the treatment of autoimmune diseases. At present, a plurality of BTK inhibitors are used in the second-stage and third-stage clinical research stages of pemphigus, Immune Thrombocytopenic Purpura (ITP), chronic graft-versus-host disease (cGvHD), rheumatoid arthritis and systemic lupus erythematosus. Therefore, novel BTK inhibitors with low toxic and side effects can be developed and used for treating autoimmune diseases.
Disclosure of Invention
The invention aims to provide a novel BTK inhibiting compound which is not reported in the literature and has high-efficiency wild type and mutant BTK inhibiting activity, high specificity (good kinase selectivity) and excellent PK property, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition comprising the compound and a stereoisomer or a stereoisomer mixture or a pharmaceutically acceptable salt or a solvate thereof.
The invention also provides the use of a compound as described above, and stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts or solvates thereof, for the manufacture of a medicament for the treatment of a disease, disorder or condition which would benefit from inhibition of bruton's old amsuan kinase activity.
The invention adopts the following technical scheme:
in a first aspect of the invention, there is provided a compound of formula I, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002805342420000021
ring A is:
Figure BDA0002805342420000022
X1selected from: n, CR11；
X2Selected from: n, CO, CR12；
X3Selected from: n, CR13；
X4Selected from: o, N, NR15，CR15；
X5Selected from: absence, N, CO, NR16，CR16；
X6Selected from: n, NR17，NHR17，CO，CR17；
X7Selected from: absence or CHR18；R18Selected from: c1-C5An alkyl group; when X is present6Selected from NR17，NHR17，CO，CR17When R is17Can be reacted with R18Linking to form a ring;
in ring A, the dotted line indicates that the bond may or may not be present; further, the single-dashed line indicates that the chemical bond may be present (as a single bond) or absent; the double dashed line indicates that the chemical bond is a double bond, a single bond, or absent;
Y1、Y2、Y3is independently selected from CR7、N；
m is selected from 0, 1, 2,3 and 4;
n is selected from 0, 1 and 2;
L1selected from the group consisting of chemical bonds, O, NR8、(CH2)p、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH；
L2Selected from the group consisting of chemical bonds, O, NR8、(CH2)p、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH；
And L is1And L2At least one is O, NR8、NHC(O)、NHS(O)2C (O) NH or S (O)2NH；
p is selected from 1, 2 and 3;
R1selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted halogeno C1-C6Alkyl, substituted or unsubstituted halogeno C1-C6Alkoxy, substituted or unsubstituted C3-C5A cycloalkyl group;
R2selected from: substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C3-C7Cycloalkyl (not containing norbornyl), substituted or unsubstituted four-to seven-membered heterocyclic group, substituted or unsubstituted C3-C7Cycloalkenyl, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl;
r is as defined above2Can be further substituted by 1-5RXSubstituted, RXIndependently selected from: d, C1-C3Alkyl, halogen, amino, nitro, hydroxy, oxo, C1-C3Alkoxy, halo C1-C3Alkyl radical, C1-C3Hydroxyalkyl, -amino C1-C3Alkyl, -C (O) C1-C3Alkyl radical, -C: (O)O-C1-C3Alkyl radical, -C1-C3Alkylamino, halogeno C1-C3Hydroxyalkyl, halo C1-C3Alkylamino radical, C3-C5Cycloalkyl, four-to six-membered heterocycloalkyl;
R3selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted halogeno C1-C6Alkyl, substituted or unsubstituted halogeno C1-C6Alkoxy, substituted or unsubstituted C3-C5A cycloalkyl group;
R11，R12，R13，R14，R15，R16，R17each independently selected from: is absent, H, D, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3～C5Cycloalkyl, C3-C7 cycloalkenyl, four-to seven-membered heterocyclyl, C6-C10 aryl, five-to ten-membered heteroaryl, halogen, nitro, cyano, ORa, SRa, NH (CH)2)Ra，C(O)Ra，S(O)Ra，SO2Ra, C (O) ORa, OC (O) Ra, NRbRc, C (O) N (Rb) Rc, N (Rb) C (O) Rc, -P (O) RbRc; said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl may be further substituted with 1 or more Rd;
ra, Rb, Rc are selected from: h, D, alkyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl
Rd is selected from: h, D, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, C1-C3 acyl, alkoxycarbonyl, alkylamino, halohydroxyalkyl, haloalkylamino, cycloalkyl, heterocyclyl;
R7selected from the group consisting of: h, D, halogen, cyano, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted halogeno C1-C3Alkyl, substituted or unsubstituted C3-C5A cycloalkyl group;
R8selected from: h, D, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted halogeno C1-C3Alkyl, substituted or unsubstituted C3-C5A cycloalkyl group.
Further, as a limiting condition:
X1is C, X2Is N or CH, X4Is N, X5Is CH, X6Is N or CR16，-L1-L2when-is-CONH-, R2C not being substituted or unsubstituted1-C10Alkyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted four-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7Cycloalkenyl radicals
X2Is N, X3Is N, X5In the absence of, -L1-L2-is not-CH2NHCO；
X2Is N, X4Is N, X5Is CH, X6When N is present; -L1-L2-is not-CH2NHCO-；
X1Is C, X2Is N, X3Is N, -L1-L2-the combination of-C (O) NH-or-NHC (O) -;
R2is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C3-C7Cycloalkenyl, one of the following conditions is satisfied: -L1-L2Not being a chemical bond, O, NR8C (O) NH, -CONH-or X5Is absent; further:
X1selected from: n, C;
X2selected from: n, CO, CR12；
X3Selected from: n is added to the reaction solution to form a reaction solution,C；
X4selected from: o, N, CR15；
X5Selected from the group consisting of: absence, N, NR16，CR16；
X6Selected from: n, CO, NHR17，CR17；
When X is present2Selected from the group consisting of CO, X1，X3And is N at the same time;
when X is present4Selected from O, X5Is absent, X6Is NHR17At this time R17And R2Can be connected to form a ring;
when X is present6Selected from the group consisting of CO, X5Is NR16X4 is N;
further, the method comprises the following steps:
ring a is selected from the following heterocyclic structures:
Figure BDA0002805342420000051
when ring A is selected from one of (A) (B) (C) (D) (E) (F) (G) (H) (K) (M), and-L1-L2A combination of-is not-CH2NHC (O) -, R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three to seven membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group;
when ring A is selected from (I), -L1-L2The combination of-is-CO (NH) -, and R2Selected from substituted or unsubstituted
Substituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl;
when ring A is selected from (Q), -L1-L2A combination of-is not- (CH)2)p-NHC(O)-；
When ring A is selected from (J), and-L1-L2When the combination of (A) is-C (O) NH-, R2Selected from substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl;
when ring A is selected from (J), and-L1-L2The combination of (A) is not-C (O) NH-and- (CH)2)pwhen-NHC (O), R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group.
Still further preferred compounds of the invention have the structure shown in formula IIa or IIb or IIc:
Figure BDA0002805342420000061
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
Still further preferred compounds of the invention have the structure of formula IIIa or IIIb or IIIc:
Figure BDA0002805342420000062
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; wherein:
ring A of IIIa is selected from one of rings (A) (C) (D) (E) (F) (G) (I) (J) (M) (P) (Q);
ring A of IIIb is selected from one of rings (A) (C) (D) (E) (F) (G) (J) (M) (P);
ring A of IIIc is selected from one of rings (A) (C) (D) (E) (F) (G) (J) (M) (P) (Q);
when the general structural formula is selected from IIIa and ring A is selected from one of (A), (C), (D), (E), (F), (G), (M), R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group;
when the general structural formula is selected from IIIa and ring A is selected from one of (I) (J), R2Selected from substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl;
when the general structural formula is selected from IIIc and ring A is selected from one of (A), (C), (D), (E), (F), (G), (J), (M), R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group.
Still further preferred compounds of the invention have a structure according to formula IVa or IVb:
Figure BDA0002805342420000071
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; wherein:
ring A of IVa is selected from one of rings (A) (Q) (I) (J);
ring A of IVb is selected from one of rings (A) (F) (G) (J).
When the general structural formula is selected from IVa and ring A is selected from (A), R2C not substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three to seven membered heterocyclyl, substituted or unsubstituted C3-C7(iii) a cycloalkenyl group. When the general structural formula is selected from IVa and ring A is selected from (I) (J), R2 is selected from substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl.
Still further preferred compounds of the invention have the structures shown in formulas Va to Vh:
Figure BDA0002805342420000072
Figure BDA0002805342420000081
or a stereoisomer thereof, or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof; wherein: r1Selected from: h, D, halogen (fluorine, chlorine), hydroxyl, amino,cyano, carboxyl, -OMe, -OEt, -OiPr, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted halogeno C1-C3Alkyl radical, OCF3Substituted or unsubstituted 3-to 5-membered cycloalkyl, substituted or unsubstituted 3-to 5-membered cycloalkoxy.
R2Selected from: h, D, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted five to seven membered heteroaryl, wherein alkyl, phenyl, heteroaryl may be further substituted by one or more substituents selected from: d, C1-C3Alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, C1-C3Alkoxy, halo C1-C3Alkyl radical, C1-C3Hydroxyalkyl, V-amino C1-C3Alkyl, -C (O) C1-C3Alkyl, -C (O) O-C1-C3Alkyl radical, -C1-C3Alkylamino, halogeno C1-C3Hydroxyalkyl, halo C1-C3Alkylamino radical, C3-C5Cycloalkyl, four-to six-membered heterocycloalkyl;
when the structure is selected from Vb or Vc, R2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted five-to seven-membered heteroaryl;
still further preferred compounds of the invention have the structure shown in formulae VIa to VIe:
Figure BDA0002805342420000082
Figure BDA0002805342420000091
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;
wherein R is1Selected from: h, D, halogen (fluorine, chlorine), hydroxy, amino, cyano, carboxy, -OMe, -OEt, -OiPr, substituted or unsubstitutedC1-C3Alkyl, substituted or unsubstituted halogeno C1-C3Alkyl radical, OCF3Substituted or unsubstituted 3-to 5-membered cycloalkyl, 3-to 5-membered cycloalkoxy
R2Selected from:
Figure BDA0002805342420000092
wherein R is2May be further substituted with 0 to 5 substituents selected from: D. f, Cl, CN, OMe, OEt, OiPr, NH2、NHMe，NHAc、CH2OH、CH2CH2OH、CO2H、CH2CO2H、Me、Et、iPr、CF3、CH2CF3、COOMe、COOiPr、CONH2、CH2CONH2。
Preferably, the compound is selected from the following compounds:
Figure BDA0002805342420000101
Figure BDA0002805342420000111
Figure BDA0002805342420000121
Figure BDA0002805342420000131
Figure BDA0002805342420000141
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof,
n- (4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide 001
N- (4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 002
5-amino-1-isopropyl-3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-4-carboxamide 003
5-amino-1-isopropyl-3- (4- (pyridin-2-ylcarbamoyl) phenyl) -1H-pyrazole-4-carboxamide 004
3-amino-4-cyclopentyl-1- (4- ((2-methoxybenzamido) methyl) phenyl) -1H-pyrrole-2-carboxamide 005
5-fluoro-N- (4- (9-isopropyl-6- (methylamino) -8-oxo-8, 9-dihydro-7H-purin-7-yl) phenyl) -2-methoxybenzamide 006
N- (4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) -3-fluorobenzyl) -2-methoxybenzamide 007
N- (4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) -2, 3-difluorobenzyl) -2-methoxybenzamide 008
N- (4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -5-fluoro-2-methoxybenzamide 009
N- (4- (6-amino-9- (1-hydroxypropan-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -5-fluoro-2-methoxybenzamide 010
N- (4- (6-amino-9- (4-hydroxycyclohexyl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -5-fluoro-2-methoxybenzamide 011
4- (6-amino-7- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -8-oxo-7H-purin-9 (8H) -yl) cyclohexenecarboxylic acid 012
N- (4- (6-amino-9- (3-hydroxycyclohexyl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -5-fluoro-2-methoxybenzamide 013
N- (4- (6-amino-9- (1- (2-hydroxyacetyl) piperidin-3-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -5-fluoro-2-methoxybenzamide 014
N- (4- (6-amino-9- (1- (2-morpholinoacetyl) piperidin-3-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -5-fluoro-2-methoxybenzamide 015
N- (4- (6-amino-8-oxo-9- (1,1, 1-trifluoropropan-2-yl) -8, 9-dihydro-7H-purin-7-yl) benzyl) -5-fluoro-2-methoxybenzamide 016
N- (4- (6-amino-8-oxo-9-phenyl-8, 9-dihydro-7H-purin-7-yl) benzyl) -5-fluoro-2-methoxybenzamide 017
N- (4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -2-methoxybenzamide 018
N- (4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -2-ethoxybenzamide 019
N- (4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -2-fluorobenzamide 020
N- (4- (4-amino-7- (1-hydroxypropyl-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 021
N- (4- (4-amino-7- (1,1, 1-trifluoropropan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 022
N- (4- (4-amino-7-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 023
024 of N- (4- (4-amino-7- (1-hydroxypropyl-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -3-fluorobenzyl) -5-fluoro-2-methoxybenzamide
N- ((5- (4-amino-7- (1-hydroxypropyl-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) pyridin-2-yl) methyl) -5-fluoro-2-methoxybenzamide 025
N- (4- (4-amino-7- (4-hydroxycyclohexyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 026
N- (4- (4-amino-7- (3-hydroxycyclohexyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 027
N- (4- (4-amino-7- (1- (2-hydroxyacetyl) piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 028
N- (4- (4-amino-7-isopropyl-6-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 029
N- (4- (4-amino-7- (1- (2-hydroxyacetyl) piperidin-3-yl) -6-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 030
N- (4- (4-amino-1-isopropyl-7-oxo-6, 7-dihydro-1H-pyrazolo [3,4-d ] pyridazin-3-yl) benzyl) -5-fluoro-2-methoxybenzamide 031
N- (4- (4-amino-7-oxo-1-phenyl-6, 7-dihydro-1H-pyrazoline [3,4-d ] pyridazin-3-yl) benzyl) -5-fluoro-2-methoxybenzamide 032
N- (4- (4-amino-1- (1- (2-hydroxyacetyl) piperidin-3-yl) -7-oxo-6, 7-dihydro-1H-pyrazolo [3,4-d ] pyridazin-3-yl) benzyl) -5-fluoro-2-methoxybenzamide 033
N- (4- (4-amino-1-isopropyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-3-yl) benzyl) -5-fluoro-2-methoxybenzamide 034
N- (4- (4-amino-1- (1- (2-hydroxyacetyl) piperidin-3-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-3-yl) benzyl) -5-fluoro-2-methoxybenzamide 035
4- (4-amino-1-phenyl-1H-pyrazoline [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 036
4- (4-amino-1- (3-hydroxyphenyl) -1H-pyrazolin [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 037
4- (4-amino-1- (pyridin-3-yl) -1H-pyrazolin [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 038
N- (4- (4-amino-1-isopropyl-1H-pyrazoline [3,4-d ] pyrimidin-3-yl) phenyl) picolinamide 039
4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 040
4- (6-amino-8-oxo-9- (1,1, 1-trifluoropropan-2-yl) -8, 9-dihydro-7H-purin-7-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 041
4- (6-amino-9- (1-hydroxypropan-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 042
4- (4-amino-1-isopropyl-7-oxo-6, 7-dihydro-1H-pyrazolo [3,4-d ] pyridazin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 043
4- (4-amino-1- (1-hydroxypropan-2-yl) -7-oxo-6, 7-dihydro-1H-pyrazoline [3,4-d ] pyridazin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 044
4- (4-amino-1- (1-morpholinopropan-2-yl) -7-oxo-6, 7-dihydro-1H-pyrazolo [3,4-d ] pyridazin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 045
4- (4-amino-1- (1-hydroxypropan-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide 046
5-amino-3- (2-fluoro-4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1-isopropyl-1H-pyrazole-4-carboxamide 047
5-amino-3- (2, 3-difluoro-4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1-isopropyl-1H-pyrazole-4-carboxamide 048
5-amino-3- (2, 6-difluoro-4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1-isopropyl-1H-pyrazole-4-carboxamide 049
5- (5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) picolinamide 050
5-amino-1- (1-hydroxypropan-2-yl) -3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-4-carboxamide 051
5-amino-1- (tetrahydro-2H-pyran-4-yl) -3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-4-carboxamide 052
5-amino-1- (3, 3-difluorocyclobutyl) -3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-4-carboxamide 053
5-amino-1- (1- (2-hydroxyacetyl) piperidin-3-yl) -3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-4-carboxamide 054
N- (4- (5-amino-4-carbamoyl-1-isopropyl-1H-pyrazol-3-yl) phenyl) picolinamide 055
5-amino-1-isopropyl-3- (4-phenoxyphenyl) -1H-pyrazole-4-carboxamide 056
5-amino-3- (2, 3-difluoro-4-phenoxyphenyl) -1-isopropyl-1H-pyrazole-4-carboxamide 057
5-amino-3- (4- (2-fluoro-3-methoxyphenoxy) phenyl) -1-isopropyl-1H-pyrazole-4-carboxamide 058
5-amino-3- (4- (benzyloxy) phenyl) -1-isopropyl-1H-pyrazole-4-carboxamide 059
5-amino-1-isopropyl-3- (4- (phenoxymethyl) phenyl) -1H-pyrazole-4-carboxamide 060
5-amino-1-isopropyl-3- (4- (phenylamino) phenyl) -1H-pyrazole-4-carboxamide 061
5-amino-1-isopropyl-3- (4- (N- (3- (trifluoromethyl) phenyl) sulfamoyl) phenyl) -1H-pyrazole-4-carboxamide 062
5-amino-1-isopropyl-3- (4- (N- (4- (trifluoromethyl) pyridin-2-yl) sulfamoyl) phenyl) -1H-pyrazole-4-carboxamide 063
5-amino-1-isopropyl-3- (4- (phenylsulfanylmethyl) phenyl) -1H-pyrazole-4-carboxamide 064
3-amino-4-cyclopentyl-1- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -1H-pyrrole-2-carboxamide 065
3-amino-4- (1- (2-hydroxyacetyl) piperidin-3-yl) -1- (4- ((2-methoxybenzamido) methyl) phenyl) -1H-pyrrole-2-carboxamide 066
4-amino-3-cyclopentyl-1- (4- ((2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carboxamide 067
4-amino-3-isopropyl-1- (4- ((2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carboxamide 068
4-amino-3- (1- (2-hydroxyacetyl) piperidin-3-yl) -1- (4- ((2-methoxybenzamido) methyl) phenyl) -1H-pyrazole-5-carboxamide 069
3-amino-4-isopropyl-1- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrrole-2-carboxamide 070
4-amino-3-isopropyl-1- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-5-carboxamide 071
5-amino-3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carboxamido) phenyl) -1- (1,1, 1-trifluoropropan-2-yl) -1H-pyrazole-4-carboxamide 072
5-amino-3- (2-fluoro-4- ((4- (trifluoromethyl) pyridin-2-yl) carboxamido) phenyl) -1- (1,1, 1-trifluoropropan-2-yl) -1H-pyrazole-4-carboxamide 073
5-amino-3- (2-fluoro-4- ((4- (trifluoromethyl) pyridin-2-yl) carboxamido) phenyl) -1- (1,1, 1-trifluorobutan-2-yl) -1H-pyrazole-4-carboxamide 074
Description of the terms
The term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms in which one fused ring may be partially saturated. Non-limiting examples of aromatic rings are: benzene ring, naphthalene ring, anthracene ring, indene ring, indanyl (indanyl). The aromatic ring may be unsubstituted or substituted. The substituent of the aromatic ring is selected from D, halogen (preferably fluorine, chlorine, bromine and iodine), cyano, nitro, amino, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide and C1-C6Alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C1-C6Hydroxyalkyl (preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C1-C6Alkoxy (preferably methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halogeno C1-C6Alkyl (preferably halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloisobutyl, halosec-butyl, halotert-butyl, etc.), halogeno-C1-C6Hydroxyalkyl (preferably halogenated hydroxymethyl, halogenated hydroxyethyl, halogenated hydroxypropyl, halogenated hydroxyisopropyl, etc.), halogenated C1-C6Alkoxy (preferably halogenomethoxy, halogenoethoxy, halogenopropoxy, halogenoisopropoxy, halogenobutoxy, halogenoisobutoxy, halogenosec-butyloxy, halogenotert-butyloxy, etc.), C3-C6Cycloalkyl (preferably cyclopropyl, cyclopentyl, cyclohexyl, etc.), halogeno C3-C6Cycloalkyl (preferably halo-cyclopropyl, halo-cyclopentyl, halo-halo)Cyclohexyl, etc.), 3-to 10-membered heterocyclic group (preferably tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.), C6-C12Aryl radical, C5-C14A heteroaryl group; the substitution of the aromatic ring can be mono-substitution (such as ortho-substitution, meta-substitution and para-substitution), and can also be di-substitution or tri-substitution, and the like.
The term "heteroaryl" as used herein refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (wherein one fused ring may be partially saturated), corresponding to the replacement of one or more carbons in the above-mentioned "aryl" by heteroatoms such as oxygen, nitrogen, sulfur, and the like. The heteroaromatic ring may be monocyclic or bicyclic, i.e., formed by the fusion of two rings. Specific heteroaryl (heterocycloaryl) groups may be: D. pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, indoline, benzimidazole and the like. The heterocyclic aryl group may be unsubstituted or substituted. The substituent of the heterocyclic aryl is selected from halogen, cyano, nitro, amino, hydroxyl and C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halo C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "alkyl" as used herein refers to a straight-chain saturated monovalent hydrocarbon group having one to six carbon atoms or a branched-chain saturated monovalent hydrocarbon group having three to six carbon atoms, and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, or the like. The alkyl can be unsubstituted, mono-substituted or multi-substituted, and the substituents can be the same or different when the alkyl is multi-substituted; the substituent of the alkyl is selected from D, halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, isopropyl ester, carbamoyl and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "hydroxyalkyl" as used herein means-alkyl-OH wherein alkyl is as defined above. Examples of "hydroxyalkyl" as used herein include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like. "hydroxyalkyl" also includes substituted hydroxyalkyl groups, which may be D, halogen, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "aminoalkyl" as used herein means-alkyl-NH2Wherein alkyl is as defined above. Examples of "aminoalkyl" as used herein include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, and the like. "aminoalkyl" also includes substituted aminoalkyl groups, which may have substituents of D, halo, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14Heteroaryl, wherein the substituents may be substituted on alkyl or NH2The above.
The term "alkylamino" as used herein refers to alkyl-NH-, wherein alkyl is as defined above. Examples of "alkylamino" groups used in the present invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like. "alkylamino" also includes substituted alkylamino groups, substituents thereofCan be D, halogen, amino, hydroxyl, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14And heteroaryl, wherein the substituent may be substituted on the alkyl or on the NH.
The term "alkoxy" as used herein refers to an-O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. "alkoxy" also includes substituted alkoxy groups, the substituents of which can be D, halo, amino, hydroxy, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "cycloalkyl" as used herein refers to a non-aromatic monovalent hydrocarbon group having three to ten carbon atoms of a monocyclic or polycyclic ring (two monocyclic rings are chemically linked or bridged or spiro or fused) ring, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., wherein one or two carbon atoms may be replaced by an oxo group. The cycloalkyl group may be unsubstituted or substituted, and the substituents are selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halogeno C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6Alkyl radical、C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "cycloalkenyl" as used herein refers to a non-aromatic hydrocarbon radical having three to ten carbon atoms, either monocyclic or polycyclic (chemically bonded or bridged or spiro or fused between two monocyclic rings), and at least one further double bond, preferably cyclobutenyl, cyclopentenyl, cyclohexenyl and the like, wherein one or two carbon atoms may be replaced by an oxo group. The cycloalkenyl can be unsubstituted or substituted, with the substituents being selected from D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halogeno C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino groups, which may be identical or different, are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "heterocyclyl" as used herein refers to a non-aromatic cyclic group having three to ten ring atoms, either monocyclic or polycyclic (two monocyclic rings are chemically linked or bridged or spirocyclic or fused), wherein some of the chemical bonds may be unsaturated double or triple bonds, having one or more heteroatoms selected from N, O, S. The heterocyclic group may be unsubstituted or substituted, and the substituent is selected from the group consisting of D, halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, oxo, thioxo, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Hydroxyalkyl, halo C1-C6Alkoxy radical, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl, C6-C12Aryl radical, C5-C14A heteroaryl group.
The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing at least one double bond and having from 2 to 10 carbon atoms (i.e., C)2-C10Alkenyl) including, but not limited to, vinyl, allyl, but-1-enyl, pent-1, 4-di-enyl, and the like. The alkenyl group may be substituted with one or more substituents independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing at least one triple bond and having from 2 to 10 carbon atoms (i.e., C)2-C10Alkynyl) including but not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted with one or more substituents independently being D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
The term "halogen" as used herein means fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine or bromine.
The term "halo" as used herein means substituted by halogen, either by the same atom or by a different atom, either once or multiple times, e.g., di-or tri-substituted.
The term "haloalkyl" as used herein refers to an alkyl group substituted with halo, preferably fluoro, chloro, bromo, iodo, wherein alkyl is as defined above. "haloalkyl" may be substituted one or more times with halo.
The term "halohydroxyalkyl" as used herein refers to a hydroxyalkyl group substituted with halogen, preferably fluorine, chlorine, bromine, iodine, wherein hydroxyalkyl is as defined above. "haloalkyl" may be substituted one or more times with halo.
The salts of the compounds of the present invention may be prepared by methods well known to those skilled in the art. The salt can be organic acid salt, inorganic acid salt, etc., and the organic acid salt comprises citrate, fumarate, oxalate, malate, lactate, camphorsulfonate, p-toluenesulfonate, methanesulfonate, etc.; the inorganic acid salt comprises hydrohalic acid salt, sulfate, phosphate, nitrate and the like. For example, with lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and the like, methanesulfonate, trifluoromethanesulfonate, etc. may be formed; with arylsulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid, etc. to form p-toluenesulfonic acid salts, benzenesulfonic acid salts; corresponding salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; with amino acids, such as glutamic acid or aspartic acid, glutamate or aspartate can be formed. Corresponding salts can also be formed with inorganic acids, such as hydrohalic acids (e.g., hydrofluoric, hydrobromic, hydroiodic, hydrochloric), nitric, carbonic, sulfuric or phosphoric acids, and the like.
A second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds according to any of the above-mentioned embodiments. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above embodiments with other compounds, or one or more of the compounds described in any of the above embodiments.
The present invention provides a pharmaceutical formulation comprising at least one active ingredient which is one or more of the compounds according to any of the preceding claims. The pharmaceutical formulation comprises at least one active ingredient, which may be any one or any plurality of the BTK inhibitor compounds of the present invention, optical isomers of the compounds, pharmaceutically acceptable salts of the compounds or the optical isomers thereof, solvates of the compounds or the optical isomers thereof, and one or more pharmaceutically acceptable carriers or excipients.
The carrier includes conventional diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc., and flavoring agent, sweetener, etc. may be added if necessary.
The medicine can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection and the like, and the medicines of the various forms can be prepared according to the conventional method in the pharmaceutical field.
In another aspect, the invention provides the use of compounds of formulae I to V disclosed herein and optical isomers thereof or pharmaceutically acceptable salts or solvates thereof for inhibiting bruton's tyrosine kinase (Btk) activity or for treating diseases, disorders or conditions that benefit from inhibition of bruton's tyrosine kinase (Btk) activity.
In a further preferred embodiment, the present invention provides a method of inhibiting bruton's tyrosine kinase activity in a subject by administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound or a composition comprising the compound, wherein the compound has a structure represented by formula I to formula V. In some embodiments, the subject in need thereof is suffering from an autoimmune disease, such as inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, hashimoto's disease, diabetes mellitus, or diabetes mellitus, diabetes mellitus, or diabetes mellitus, or diabetes, diabetes mellitus, or diabetes mellitus, or the likeThyroiditis (Hashimoto's thyroiditis), Ord's thyroiditis (Ord's thyroiditis), Graves' disease, and rheumatoid arthritis syndrome (A)
Figure BDA0002805342420000231
syndrome), multiple sclerosis, infectious neuronitis (Guillain-Barr é syndrome), acute disseminated encephalomyelitis, Addison's disease, ocular clonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid-antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, Immune Thrombocytopenic Purpura (ITP), optic neuritis, scleroderma, primary biliary cirrhosis, Retle's syndrome, Takaya's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, systemic alopecia, Behcet's disease (Behcet's disease)
Figure BDA0002805342420000232
disease), chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular stiffness, scleroderma or vulvodynia, and chronic graft-versus-host disease (cGvHD).
In further embodiments, the subject in need thereof is suffering from cancer. In one embodiment, the cancer is a B-cell proliferative disease, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia: (a)
Figure BDA0002805342420000233
macroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, lymph node marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymus) large B cell lymphoma, intravascular large B cell lymphomaB cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma (Burkitt lymphoma)/leukemia, or lymphomatoid granulomatosis.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing a BTK inhibitor, in particular application in preparing medicines for treating cell proliferative diseases. The cell proliferative disease includes cancer. In other words, the invention also provides the application of the compounds shown in the general formulas I to V, and the optical isomers or the pharmaceutically acceptable salts or solvates thereof in treating proliferative diseases (such as cancer) singly or in combination with other medicines. Antineoplastic agents that can be used in combination with the compounds provided herein or pharmaceutically acceptable salts thereof include, but are not limited to, at least one of the following: mitotic inhibitors (e.g., vinblastine, vindesine, and vinorelbine); tubulysin decomposition inhibitors (e.g., taxol); alkylating agents (such as cisplatin, carboplatin, and cyclophosphamide); antimetabolites (e.g., 5-fluorouracil, tegafur, methotrexate, cytarabine, and hydroxyurea); antibiotics (such as adriamycin, mitomycin and bleomycin) can be inserted; enzymes (e.g., asparaginase); topoisomerase inhibitors (e.g., etoposide and camptothecin); biological response modifiers (such as interferon); immune checkpoint inhibitors (e.g., PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors); CD20 monoclonal antibody; BCL2 inhibitors.
The inventor of the invention proves that the compound can inhibit wild type and 481-th cysteine-mutated BTK kinase at the same time through experiments.
The inventor of the invention proves that the compound has the anti-proliferation inhibition effect on tumor cell strains such as MINO, OCI-LY10 and the like through experiments.
Detailed Description
The implementation of the present invention is illustrated by the following examples, and those skilled in the art should understand that the corresponding technical features can be modified or replaced according to the teaching of the prior art, and still fall into the protection scope of the present invention.
Example 1: preparation of N- (4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide (001)
Figure BDA0002805342420000241
Step 1, dissolving 4, 6-dichloro-5-aminopyrimidine (2.5g) in 25mL of N-butanol, adding isopropylamine (3.91mL), heating to reflux reaction for about 24 hours, cooling to room temperature after TLC detection reaction is finished, decompressing and concentrating to remove the solvent, and purifying the obtained residue by silica gel column chromatography to obtain a light yellow solid product 6-chloro-N4Isopropylpyrimidine-4, 5-diamine (2.3g) in 82% yield.
Step 2, adding 6-chloro-N4Dissolving (1.9g) isopropylpyrimidine-4, 5-diamine in 50mL tetrahydrofuran solution, adding CDI (5.1g), heating to reflux reaction for 20 hours, detecting by TLC after the reaction is finished, removing tetrahydrofuran by rotary evaporation under reduced pressure, then adding ethyl acetate and water for extraction, washing the obtained organic phase saturated saline solution by separation, drying anhydrous sodium sulfate, filtering, and purifying the obtained residue by silica gel column chromatography under reduced pressure to obtain a solid product 6-chloro-9-isopropyl-7H-purin-8 (9H) -ketone (1.1g) with the yield of 51%.
Step 3, dissolving 6-chloro-9-isopropyl-7H-purin-8 (9H) -one (0.85g) in 10mL of n-butanol, adding 4-methoxybenzylamine (1.37g), heating to reflux for about 18 hours, detecting by TLC after the reaction is finished, cooling to room temperature, concentrating under reduced pressure to remove the solvent, and purifying the obtained residue by silica gel column chromatography to obtain a solid product, namely 9-isopropyl-6- ((4-methoxybenzyl) amino) -7H-purin-8 (9H) -one (1.11g), with the yield of 89%.
Step 4, 9-isopropyl-6- ((4-methoxybenzyl) amino) -7H-purin-8 (9H) -one (0.23g) and (4- ((2-methoxybenzamido) methyl) phenyl) boronic acid (0.64g) were dissolved in 5mL of anhydrous DMF solution, and 0.2g was added
Figure BDA0002805342420000242
Molecular sieve and anhydrous copper acetate (0.15g), finally adding 0.4mL triethylamine, stirring at room temperature for about 36 hours, and monitoring by TLC that the reaction is finished; filtering the reaction solution with diatomaceous earth, extracting the filtrate with ethyl acetate and water to obtain insoluble substance, and passing through diatomaceous earthThe mixture was filtered, the filtrate was allowed to stand for separation, the obtained organic phase was washed with water and saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to give N- (4- (9-isopropyl-6- ((4-methoxybenzyl) amino) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide (0.23g) as a solid product in a yield of 56%.
Step 5, dissolving N- (4- (9-isopropyl-6- ((4-methoxybenzyl) amino) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide (0.21g) in 1.5mL of dichloromethane, adding 3mL of trifluoroacetic acid, heating to reflux for about 20 hours, detecting by TLC after the reaction is finished, and concentrating under reduced pressure to remove the solvent; adding dichloromethane for redissolution, washing with saturated sodium bicarbonate aqueous solution, separating organic phase, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain white solid product N- (4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide (0.11g) with yield of 71%, LC-MS (ESI-MS):433[ M + H-purine-7-yl)]+。
Example 2: preparation of N- (4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide (002)
Figure BDA0002805342420000251
Step 1, 4-amino-5-iodopyrrolo [2,3-D ] pyrimidine (2.6g) and isopropanol (1.6mL) were dissolved in 20mL of anhydrous tetrahydrofuran, and after addition of triphenylphosphine (5.24g), DIAD (4.1mL) was added slowly dropwise, and after completion of the addition, the reaction was stirred at room temperature for about 2 hours; after TLC detection reaction is finished, the solvent is removed by concentration under reduced pressure, 10mL of acetonitrile is added and stirred and pulped for about 1 hour, the mixture is filtered, 10mL of acetonitrile is added again to a filter cake and stirred and pulped for 1 hour, the filtration is carried out, and the filter cake is dried by air blast to obtain a solid product 5-iodine-7-isopropyl-7H-pyrrole [2,3-d ] pyrimidine-4-amine (1.45g) with the yield of 48 percent.
Step 2, adding 5-iodo-7-isopropyl-7H-pyrrole [2,3-d]Pyrimidin-4-amine (0.3g) and (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) boronic acid (0.48g) were dissolved in 10mL of tetrahydrofuran,then water (2mL), sodium carbonate (0.21g) and palladium tetrakistriphenylphosphine (106mg) were added and heated to reflux for about 12 hours, TLC monitored for completion of the reaction and allowed to cool to room temperature; extracting with ethyl acetate and water, washing with water and saturated sodium chloride solution, separating organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue with silica gel column chromatography to obtain solid product N- (4- (4-amino-7-isopropyl-7H-pyrrole [2, 3-d)]Pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide (0.28g), yield 66%,1H NMR(500 MHz,CD3OD)δ8.13(s,1H),7.63(dd,J＝9.2,3.3 Hz,1H),7.48(s,4H),7.30(s,1H),7.27–7.23(m,1H),7.17(dd,J＝9.1,4.2 Hz,1H),5.03(dd,J＝13.6,6.9 Hz,1H),4.67(s,2H),3.96(s,3H),1.53(d,J＝6.8 Hz,6H).LC-MS(ESI-MS):434[M+H]+。
example 3: preparation of 5-amino-1-isopropyl-3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-4-carboxamide (003)
Figure BDA0002805342420000261
Step 1, dissolving 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1.1g) in 20mL anhydrous DMF, adding isopropyl iodide (2.1g) and cesium carbonate (1.5g), stirring at room temperature for reaction overnight, and monitoring by TLC for completion of the reaction; water and ethyl acetate were added for extraction, the ethyl acetate layer was separated, washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to give a solid product of 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carbonitrile (0.85g) in 62% yield.
Step 2, weighing 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carbonitrile (0.69g), adding trifluoroacetic acid (5mL), dropwise adding concentrated sulfuric acid (0.3mL) while stirring, heating to 60 ℃, stirring for reacting overnight, after TLC detection reaction, cooling, placing in an ice bath, adding water, carefully adding sodium carbonate solid, stirring for neutralizing until the solution is weakly alkaline, extracting with ethyl acetate, separating an ethyl acetate layer, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained residue by silica gel column chromatography to obtain a solid product 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carboxamide (0.64g) with the yield of 86%.
Step 3, 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carboxamide (0.25g) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (0.78g) were dissolved in 10mL of 1, 4-epoxyhexacyclic ring, and water (2mL), potassium carbonate (0.28g) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (109mg), heating to reflux reaction overnight under the protection of nitrogen, after TLC detection reaction, cooling to room temperature, adding ethyl acetate and water for extraction, separating an ethyl acetate layer, washing with water and saturated saline respectively, then drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a residue, purifying by silica gel column chromatography to obtain a solid product of 5-amino-1-isopropyl-3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-4-formamide (186mg), wherein the yield is 43%,1H NMR(500 MHz,CDCl3)δ9.15(s,1H),8.72(s,1H),8.48(d,J＝5.1 Hz,1H),8.05(d,J＝8.3 Hz,2H),7.76(d,J＝8.2 Hz,2H),6.61(d,J＝8.4 Hz,1H),5.51(s,2H),5.40–5.20(brs,2H),4.30(dd,J＝13.3,6.6 Hz,1H),1.52(d,J＝6.6 Hz,6H).LC-MS(ESI-MS):433[M+H]+。
example 4: preparation of 5-amino-1-isopropyl-3- (4- (pyridin-2-ylcarbamoyl) phenyl) -1H-pyrazole-4-carboxamide (004)
Figure BDA0002805342420000262
Referring to the synthetic route and method of example 3,4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide was replaced with N- (pyridin-2-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide to synthesize the objective compound 5-amino-1-isopropyl-3- (4- (pyridin-2-ylcarbamoyl) phenyl) -1H-pyrazole-4-carboxamide (110mg),1H NMR(500MHz,CDCl3)δ8.70(s,1H),8.40(d,J＝8.5 Hz,1H),8.32(d,J＝4.1 Hz,1H),8.03(d,J＝8.4 Hz,2H),7.82–7.76(m,1H),7.74(d,J＝8.2 Hz,2H),7.13–7.08(m,1H),5.43(s,2H),5.30(brs,2H),4.29(dd,J＝13.2,6.6 Hz,1H),1.52(d,J＝6.6 Hz,6H).LC-MS(ESI-MS):365[M+H]+。
example 5: preparation of 3-amino-4-cyclopentyl-1- (4- ((2-methoxybenzamido) methyl) phenyl) -1H-pyrrole-2-carboxamide (005)
Figure BDA0002805342420000271
Step 1, dissolving 2-cyclopentyl acetonitrile (1.1g) in 50mL of anhydrous tetrahydrofuran, cooling to-78 ℃ under the protection of nitrogen, dropwise adding an LDA solution (5mL,2M in THF), continuing to react for 15 minutes after dropwise adding, and then slowly dropwise adding a tetrahydrofuran (5mL) solution of ethyl formate (0.81 g); after the dropwise addition, the reaction was allowed to proceed for 1 hour, and then the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction was quenched with water, and then the solution was adjusted to pH 3 with 2N aqueous hydrochloric acid, extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to give 2-cyclopentyl-3-oxopropanenitrile (0.8g) as an oily product in 58% yield.
Step 2, 2- (4-aminobenzyl) isoindoline-1, 3-dione (1.26g) was dissolved in 20mL of anhydrous tetrahydrofuran, and bromoethylcyanide (0.78g) and triethylamine (1.5mL) were added to the solution, and the mixture was heated to reflux for about 12 hours. After TLC detection reaction is finished, cooling to room temperature, adding ethyl acetate and water for extraction, separating an organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and carrying out silica gel column chromatography and purification on residues obtained by decompression concentration to obtain a solid product, namely 2- ((4- ((1, 3-dioxoisoindol-2-yl) methyl) phenyl) amino) acetonitrile (1.18g) with the yield of 81%.
Step 3, dissolving 2-cyclopentyl-3-oxopropanenitrile (0.5g) and 2- ((4- ((1, 3-dioxoisoindol-2-yl) methyl) phenyl) amino) acetonitrile (0.87g) in 15mL toluene, adding p-toluenesulfonic acid (100mg), heating to reflux overnight, TLC monitoring the reaction to completion and cooling to room temperature, concentrating under reduced pressure to remove most of the solvent, adding ethyl acetate and water for extraction, separating the organic layer, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure the residue obtained, purifying by silica gel column chromatography to obtain a solid product (Z) -3- ((cyanomethyl) (4- ((1, 3-dioxoisoindol-2-yl) methyl) phenyl) amino) -2-cyclopentylacrylonitrile (0.77g), the yield thereof was found to be 63%.
Step 4, (Z) -3- ((cyanomethyl) (4- ((1, 3-dioxoisoindol-2-yl) methyl) phenyl) amino) -2-cyclopentyl acrylonitrile (0.62g) was dissolved in 10mL of t-butanol, potassium t-butoxide (0.35g) was added, the mixture was heated to reflux for about 2 hours, the TLC detection reaction was completed, the temperature was decreased to room temperature, 10mL of 2N hydrochloric acid was then added and stirred for 10 minutes, followed by extraction with ethyl acetate, the separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography to give a solid product, 3-amino-4-cyclopentyl-1- (4- (((1, 3-dioxoisoindol-2-yl) methyl) phenyl) -1H-pyrrole-2-carbonitrile (0.37g), the yield thereof was found to be 60%.
Step 5, weighing 3-amino-4-cyclopentyl-1- (4- (((1, 3-dioxoisoindol-2-yl) methyl) phenyl) -1H-pyrrole-2-carbon nitrile (0.35g), adding trifluoroacetic acid (3mL), dropwise adding concentrated sulfuric acid (0.2mL) under stirring, heating to 60 ℃, stirring for overnight reaction, detecting reaction by TLC, cooling and placing in an ice bath, adding water, carefully adding a sodium carbonate solid, stirring for neutralization until the solution is weakly alkaline, extracting with ethyl acetate, separating an ethyl acetate layer, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained residue by silica gel column chromatography to obtain a solid product 3-amino-4-cyclopentyl-1- (4- (((1, 3-dioxoisoindol-2-yl) methyl) phenyl) -1H-pyrrole-2-carboxamide (0.28g) in 78% yield.
Step 6, 3-amino-4-cyclopentyl-1- (4- (((1, 3-dioxoisoindol-2-yl) methyl) phenyl) -1H-pyrrole-2-carboxamide (0.27g) was dissolved in 5mL of ethanol, hydrazine hydrate (0.15mL) was added, the mixture was heated to reflux for 2 hours, TLC monitored for completion of the reaction, cooled to room temperature, extracted with ethyl acetate and water, the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography to give 3-amino-1- (4- (aminomethyl) phenyl) -4-cyclopentyl-1H-pyrrole-2-carboxamide (0.16g) as a solid product in 85% yield.
Step 7, reacting 3-amino-1- (4- (aminomethyl) phenyl) -4-cyclopentyl-1H-pyrrole-2-carboxamide (0.12g) and 2-methoxybenzoic acid (80mg) were dissolved in 3mL of anhydrous DMF, HATU (0.3g) and DMAP (5mg) were added, the reaction was stirred at room temperature for about 6 hours, the completion of the reaction was monitored by TLC, extraction was performed with ethyl acetate and water, the separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography to give 3-amino-4-cyclopentyl-1- (4- ((2-methoxybenzamido) methyl) phenyl) -1H-pyrrole-2-carboxamide (0.13g) as a solid product in 75% yield (LC-MS (ESI-MS):433[ M + H-carboxamide)]+。
With reference to the synthetic methods of the above examples, the following compounds can be synthesized using similar synthetic routes and methods:
Figure BDA0002805342420000281
Figure BDA0002805342420000291
Figure BDA0002805342420000301
Figure BDA0002805342420000311
Figure BDA0002805342420000321
Figure BDA0002805342420000331
Figure BDA0002805342420000341
Figure BDA0002805342420000351
Figure BDA0002805342420000361
Figure BDA0002805342420000371
Figure BDA0002805342420000381
example 75: BTK WT & BTK C481S kinase activity assay
1. Compound preparation
Test compounds shown in Table 1 were dissolved in 100% DMSO to prepare 10mM stock solutions, which were stored under nitrogen in a dark place.
2. Kinase reaction process
(1) Prepare 1 XKinase buffer.
(2) Preparation of compound concentration gradient: test compounds were tested at an initial concentration of 1000nM, diluted to 100-fold final concentration in 100% DMSO solution in 384source plates, 5-fold diluted, 7 concentrations, single well assay. 250nl of 100-fold final concentration of the compound were transferred to the destination plate 384-well-plate using a dispenser Echo 550. Positive and negative control wells were loaded with 250nl of DMSO.
(3) A2.5 fold final concentration of Kinase solution was prepared using a 1 XKinase buffer.
(4) Add 10. mu.l of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; mu.l of 1 XKinase buffer was added to the negative control wells.
(5) Centrifuge at 1000rpm for 30 seconds, shake the plate and incubate at room temperature for 10 minutes.
(6) A mixture of ATP and Kinase substrate 2 was made up to a final concentration of 5/3 times using a 1 XKinase buffer.
(7) The reaction was initiated by adding 15. mu.l of a mixed solution of ATP and substrate at 5/3 fold final concentration.
(8) The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken and mixed and incubated at room temperature for 30 min.
(9) Add 30. mu.l of termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, and mix by shaking.
(10) The conversion was read using a Caliper EZ Reader.
(11) Fitting curve calculation IC50. The results are shown in Table 1.
Example 76: tumor cell proliferation inhibitory Activity test
The antitumor drug effect of the compound is tested by measuring the inhibition effect of the compound on the proliferation of OCI-LY10 and Mino cells. OCI-LY10 and Mino cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Digesting cells, inoculating the cells into 96-well plate according to the cell concentration of OCI-LY10 and Mino 10000/well, 37 ℃, 5% CO2Incubate overnight. Different concentrations (1000nM, 4 fold dilution, 8 concentrations) of compound were added to 96-well plates at 37 deg.C, 5% CO2After 72 hours incubation, 20uL MTS was added per well. After 2h incubation, the reaction was stopped by adding 25. mu.l of 10% SDS to each well. The absorbance at 490nm and 650nm was measured with a microplate reader. IC calculation Using GraphPad Prism 5.050. The results are shown in Table 1.
TABLE 1 data on kinase and tumor cell proliferation inhibitory Activity of Compounds
Figure BDA0002805342420000391
Figure BDA0002805342420000401
Figure BDA0002805342420000411
+:IC50<3nM；++:3nM<IC50<30nM；+++:30nM<IC50<300nM；++++:300nM<IC50
The results in table 1 show that the compounds of the present invention have strong inhibitory effect on both BTK WT (wild type) and BTK C481S (mutant type); meanwhile, the compound can also inhibit the proliferation of OCI-LY10 and Mino tumor cells and has antitumor activity.
Example 77: compounds 12, 14, 21, 25 inhibit B cell activation
The experimental steps are as follows:
1. collecting human whole blood by adopting a heparin sodium vacuum blood collection tube;
2. add 90. mu.l/well to 96-well plates at 37 ℃ with 5% CO2Incubating for 30min in the incubator;
3. the compound was added to each well at a concentration of 5% CO at 37 deg.C2Incubating in incubator for 60 min;
4. in each well outside the control group, 10uL anti-IgM was added at 37 ℃ with 5% CO2Incubating for 16h in an incubator;
5. adding anti-CD19 and anti-CD69 flow antibodies into each well by 5 microliters respectively, and dyeing for 30min at normal temperature;
6. adding erythrocyte lysate into each hole to break the erythrocyte;
7. flow type on-machine detection CD19&Proportion of CD69 double positive cells and calculating IC50。
TABLE 2 Compound B cell activating Activity
Figure BDA0002805342420000412
Figure BDA0002805342420000421
+:IC50<3nM；++:3nM<IC50<30nM；+++:30nM<IC50<300nM；++++:300nM<IC50
The results in table 2 indicate that the compounds of the present invention are effective in inhibiting B cell activation and are useful in the treatment of autoimmune diseases associated with B cell abnormalities and B cell proliferative disorders.
Example 78: treatment of rheumatoid arthritis using compounds
Arthritis was induced in Balb/c mice by administration of anti-collagen antibodies and lipopolysaccharides (Nandakumar et al, am.J. Pathol.2003,163: 1827-one 1837).
The specific method comprises the following steps: female Balb/c mice were injected intravenously with 100mg/kg of Chemico mAb cocktail against type II collagen on day 0 and intraperitoneally with 1.25mg/kg of lipopolysaccharide on day 1. On days 2 to 12, 10mg/kg of the compound was administered orally 1 time per day. After 13 days of abdominal anesthesia, the femoral artery was bled at about 4ml, centrifuged at 3000r/min for 20min, serum was taken and IL-1. beta. was detected using the kit, and the relevant tissue samples were observed at the same time.

Claims (15)

1. A compound having the structure shown in formula I:
Figure FDA0002805342410000011
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;
wherein: ring A is:
Figure FDA0002805342410000012
X1selected from: n, CR11；
X2Selected from: n, CO, CR12；
X3Selected from: n, CR13；
X4Selected from: o, N, NR15，CR15；
X5Selected from: absence, N, CO, NR16，CR16；
X6Selected from: n, NR17，NHR17，CO，CR17；
X7Selected from: absence or CHR18；R18Selected from: c1-C5An alkyl group; when X is present6Selected from NR17，NHR17，CO，CR17When R is17Can be reacted with R18Linking to form a ring;
in ring a, the dotted line indicates that the chemical bond may or may not be present;
Y1、Y2、Y3is independently selected from CR7、N；
m is selected from 0, 1, 2,3 and 4;
n is selected from 0, 1 and 2;
L1selected from the group consisting of chemical bonds, O, NR8、(CH2)p、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH；
L2Selected from the group consisting of chemical bonds, O, NR8、(CH2)p、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH；
And L is1And L2At least one is O, NR8、NHC(O)、NHS(O)2C (O) NH or S (O)2NH；
p is selected from 1, 2 and 3;
R1selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted halogeno C1-C6Alkyl, substituted or unsubstituted halogeno C1-C6Alkoxy, substituted or unsubstituted C3-C5A cycloalkyl group;
R2selected from: substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted four-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7Cycloalkenyl, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl;
r is as defined above2Can be further substituted by 1-5RXSubstituted, each RXIndependently selected from: d, C1-C3Alkyl, halogen, amino, nitro, hydroxy, oxo, C1-C3Alkoxy, halo C1-C3Alkyl radical, C1-C3Hydroxyalkyl, -amino C1-C3Alkyl, -C (O) C1-C3Alkyl, -C (O) O-C1-C3Alkyl radical, -C1-C3Alkylamino, halogeno C1-C3Hydroxyalkyl, halo C1-C3Alkylamino radical, C3-C5Cycloalkyl, four-to six-membered heterocycloalkyl;
R3selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted halogeno C1-C6Alkyl, substituted or unsubstituted halogeno C1-C6Alkoxy, substituted or unsubstituted C3-C5A cycloalkyl group;
R11，R12，R13，R14，R15，R16，R17each independently selected from: is absent, H, D, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3～C5Cycloalkyl, C3-C7 cycloalkenyl, four-to seven-membered heterocyclyl, C6-C10Aryl, five-to ten-membered heteroaryl, halogen, nitro, cyano, ORa, SRa, NH (CH)2)Ra，C(O)Ra，S(O)Ra，SO2Ra, C (O) ORa, OC (O) Ra, NRbRc, C (O) N (Rb) Rc, N (Rb) C (O) Rc, -P (O) RbRc; said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl may be further substituted with 1 or more Rd;
ra, Rb, Rc are each independently selected from: h, D, alkyl, alkenyl, alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, alkoxy, haloalkyl, hydroxyalkyl, amino-substituted alkyl, alkylcarbonyl, alkoxycarbonyl, alkyl-substituted amino, halohydroxyalkyl, haloalkylamino, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl;
rd is selected from: h, D, alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, alkoxy, haloalkyl, hydroxyalkyl, amino-substituted alkyl, C1-C3Acyl, alkoxycarbonyl, alkyl-substituted amino, halohydroxyalkyl, haloalkylamino, cycloalkyl, heterocyclyl;
R7selected from: h, D, halogen, cyano, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted halogeno C1-C3Alkyl, substituted or unsubstituted C3-C5A cycloalkyl group;
R8selected from: h, D, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted halogeno C1-C3Alkyl, substituted or unsubstituted C3-C5A cycloalkyl group;
X1is C, X2Is N or CH, X4Is N, X5Is CH, X6Is N or CR16，-L1-L2when-is-CONH-, R2C not being substituted or unsubstituted1-C10Alkyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted four-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group;
X2is N, X3Is N, X5In the absence of, -L1-L2-is not-CH2NHCO-；
X2Is N, X4Is N, X5Is CH, X6When N is present; -L1-L2-is not-CH2NHCO-；
X1Is C, X2Is N, X3When is N, -L1-L2-the combination of-C (O) NH-or-NHC (O) -;
R2is substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7Cycloalkenyl, one of the following conditions is satisfied: -L1-L2Not being a chemical bond, O, NR8-CONH-or X5Is absent.
2. The compound of claim 1,
X1selected from: n, C;
X2selected from: n, CO, CR12；
X3Selected from: n, C;
X4selected from: o, N, CR15；
X5Selected from: absence, N, NR16，CR16；
X6Selected from: n, CO, NHR17，CR17；
When X is present2Selected from the group consisting of CO, X1，X3And is N at the same time;
when X is present4Selected from O, X5Is absent, X6Is NHR17At this time R17And R2Can be connected to form a ring;
when X is present6Selected from the group consisting of CO, X5Is NR16，X4Is N.
3. The compound of claim 1,
ring a is selected from the following heterocyclic structures:
Figure FDA0002805342410000031
when ring A is selected from one of (A) (B) (C) (D) (E) (F) (G) (H) (K) (M), and-L1-L2A combination of-is not-CH2NHC (O) -, R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group;
when ring A is selected from (I), -L1-L2The combination of-is-CO (NH) -, and R2Selected from substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl;
when ring A is selected from (Q), -L1-L2A combination of-is not- (CH)2)p-NHC(O)-；
When ring A is selected from (J), and-L1-L2When the combination of (A) is-C (O) NH-, R2Selected from substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl;
when ring A is selected from (J), and-L1-L2The combination of (A) is not-C (O) NH-and- (CH)2)pwhen-NHC (O), R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group.
4. The compound of claim 1, having a structure according to formula IIa or IIb or IIc:
Figure FDA0002805342410000041
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1, having a structure according to formula IIIa or IIIb or IIIc:
Figure FDA0002805342410000051
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; wherein:
ring A of IIIa is selected from one of rings (A) (C) (D) (E) (F) (G) (I) (J) (M) (P) (Q);
ring A of IIIb is selected from one of rings (A) (C) (D) (E) (F) (G) (J) (M) (P);
ring A of IIIc is selected from one of rings (A) (C) (D) (E) (F) (G) (J) (M) (P) (Q);
when the general structural formula is selected from IIIa and ring A is selected from one of (A), (C), (D), (E), (F), (G), (M), R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group;
when the general structural formula is selected from IIIa and ring A is selected from one of (I) (J), R2Selected from substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl;
when the general structural formula is selected from IIIc and ring A is selected from one of (A), (C), (D), (E), (F), (G), (J), (M), R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group.
6. The compound of claim 1, having a structure according to formula IVa or IVb:
Figure FDA0002805342410000061
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof; wherein:
ring A of IVa is selected from one of rings (A) (Q) (I) (J);
ring A of IVb is selected from one of rings (A) (F) (G) (J);
when the general structural formula is selected from IVa and ring A is selected from (A), R2C not being substituted or unsubstituted3-C7Cycloalkyl, substituted or unsubstituted three-to seven-membered heterocyclyl, substituted or unsubstituted C3-C7A cycloalkenyl group;
when the general structural formula is selected from IVa and ring A is selected from (I) (J), R2Selected from substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted five to ten membered heteroaryl.
7. The compound of claim 1, having a structure represented by formulas Va to Vh:
Figure FDA0002805342410000062
Figure FDA0002805342410000071
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;
wherein:
R1selected from: h, D, halogen (fluorine, chlorine), hydroxy, amino, cyano, carboxy, -OMe, -OEt, -OiPr, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted halogeno C1-C3Alkyl radical, OCF3Substituted or unsubstituted 3-to 5-membered cycloalkyl, substituted or unsubstituted 3-to 5-membered cycloalkoxy.
R2Selected from: h, D, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted five to seven membered heteroaryl, wherein alkyl, phenyl, heteroaryl may be further substituted by one or more substituents selected from: d, C1-C3Alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, C1-C3Alkoxy, halo C1-C3Alkyl radical, C1-C3Hydroxyalkyl, V-amino C1-C3Alkyl, -C (O) C1-C3Alkyl, -C (O) O-C1-C3Alkyl radical, -C1-C3Alkylamino, halogeno C1-C3Hydroxyalkyl, halo C1-C3Alkylamino radical, C3-C5Cycloalkyl, four-to six-membered heterocycloalkyl;
when the structure is selected from Vb or Vc, R2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted five-to seven-membered heteroaryl.
8. The compound of claim 1, having a structure represented by formulas VIa to VIe:
Figure FDA0002805342410000072
Figure FDA0002805342410000081
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;
wherein,
R1selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, -OMe, -OEt, -OiPr, substituted or unsubstituted C1-C3Alkyl, substituted or unsubstituted halogeno C1-C3Alkyl radical, OCF3Substituted or unsubstituted 3-to 5-membered cycloalkyl, 3-to 5-membered cycloalkyloxy;
R2selected from the group consisting of:
Figure FDA0002805342410000082
Figure FDA0002805342410000083
wherein R is2May be further substituted with 0 to 5 substituents selected from: D. f, Cl, CN, OMe, OEt, OiPr, NH2、NHMe，NHAc、CH2OH、CH2CH2OH、CO2H、CH2CO2H、Me、Et、iPr、CF3、CH2CF3、COOMe、COOiPr、CONH2、CH2CONH2。
9. The compound of claim 1, selected from the group consisting of:
Figure FDA0002805342410000091
Figure FDA0002805342410000101
Figure FDA0002805342410000111
Figure FDA0002805342410000121
Figure FDA0002805342410000131
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising one or more of the compounds of any one of claims 1 to 9.
11. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of a disease, disorder or condition which benefits from inhibition of bruton's tyrosine kinase activity, alone or in combination with other medicaments.
12. The use of claim 11, wherein the disease, disorder or condition is one that would benefit from inhibition of bruton's tyrosine kinase mutation.
13. The use of claim 11, wherein the disease is selected from the group consisting of a B cell proliferative disease and an autoimmune disease.
14. The use of claim 11, wherein the B cell proliferative disorder comprises diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, lymph node marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphoma-like granulomatosis.
15. The use of claim 11, wherein the autoimmune disease comprises inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, diabetes, myasthenia gravis, hashimoto's thyroiditis, graves ' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acute disseminated encephalomyelitis, addison's disease, ocular clonus-myoclonus syndrome, mandatory spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, goodpasture's syndrome, immune thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporal arteritis, arterial disease, Warm autoimmune hemolytic anemia, wegener's granulomatosis, psoriasis, general alopecia, behcet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular stiffness, scleroderma or vulvodynia, and chronic graft-versus-host disease.
CN202011365603.3A 2020-11-28 2020-11-28 Polycyclic compound for inhibiting Bruton tyrosine kinase activity, pharmaceutical composition and application thereof Active CN114573586B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011365603.3A CN114573586B (en) 2020-11-28 2020-11-28 Polycyclic compound for inhibiting Bruton tyrosine kinase activity, pharmaceutical composition and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011365603.3A CN114573586B (en) 2020-11-28 2020-11-28 Polycyclic compound for inhibiting Bruton tyrosine kinase activity, pharmaceutical composition and application thereof

Publications (2)

Publication Number Publication Date
CN114573586A true CN114573586A (en) 2022-06-03
CN114573586B CN114573586B (en) 2023-11-03

Family

ID=81767932

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011365603.3A Active CN114573586B (en) 2020-11-28 2020-11-28 Polycyclic compound for inhibiting Bruton tyrosine kinase activity, pharmaceutical composition and application thereof

Country Status (1)

Country Link
CN (1) CN114573586B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115443277A (en) * 2020-03-12 2022-12-06 重庆复尚源创医药技术有限公司 Compounds as kinase inhibitors
WO2023143355A1 (en) * 2022-01-28 2023-08-03 Hansoh Bio Llc Azacycle amide derivative, preparation methods and medicinal uses thereof
WO2023165570A1 (en) * 2022-03-03 2023-09-07 深圳市塔吉瑞生物医药有限公司 Cycloalkyl or heterocyclyl substituted heteroaryl compound, and composition and use thereof
WO2024235166A1 (en) * 2023-05-12 2024-11-21 武汉人福创新药物研发中心有限公司 Composition containing btk inhibitor, and use thereof
WO2025067568A1 (en) * 2023-09-28 2025-04-03 杭州市第一人民医院 Pyrrole degrader and pharmaceutical use thereof

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014173289A1 (en) * 2013-04-25 2014-10-30 Beigene, Ltd. Fused heterocyclic compounds as protein kinase inhibitors
CN104603124A (en) * 2012-08-10 2015-05-06 勃林格殷格翰国际有限公司 Heteroaromatic compounds as bruton's tyrosine kinase (btk) inhibitors
WO2016019237A2 (en) * 2014-07-31 2016-02-04 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
CN105451741A (en) * 2013-08-06 2016-03-30 福建海西新药创制有限公司 Inhibitors of bruton's tyrosine kinase
US20160168149A1 (en) * 2013-07-02 2016-06-16 Pharmacyclics Llc Purinone compounds as kinase inhibitors
CN108431007A (en) * 2015-09-16 2018-08-21 洛克索肿瘤学股份有限公司 Pyrazolopyrimidine derivatives as BTK inhibitors for the treatment of cancer
US20180243311A1 (en) * 2017-02-24 2018-08-30 Gilead Sciences, Inc. Inhibitors of bruton's tyrosine kinase
CN110483521A (en) * 2018-05-14 2019-11-22 杭州和正医药有限公司 A kind of reversible covalent bruton's tyrosine kinase inhibitor, pharmaceutical composition and its application
CN111018865A (en) * 2019-10-17 2020-04-17 山东大学 1-substituted benzyl pyrazolopyrimidine derivative and preparation method and application thereof
WO2020150681A1 (en) * 2019-01-18 2020-07-23 Xibin Liao Bruton's tyrosine kinase inhibitors
CN111454268A (en) * 2019-01-18 2020-07-28 明慧医药（上海）有限公司 Cyclic molecules as Bruton's tyrosine kinase inhibitors
CN114075190A (en) * 2020-08-20 2022-02-22 北京诺诚健华医药科技有限公司 Heterocyclic BTK inhibitors
CN115443277A (en) * 2020-03-12 2022-12-06 重庆复尚源创医药技术有限公司 Compounds as kinase inhibitors

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104603124A (en) * 2012-08-10 2015-05-06 勃林格殷格翰国际有限公司 Heteroaromatic compounds as bruton's tyrosine kinase (btk) inhibitors
WO2014173289A1 (en) * 2013-04-25 2014-10-30 Beigene, Ltd. Fused heterocyclic compounds as protein kinase inhibitors
US20160168149A1 (en) * 2013-07-02 2016-06-16 Pharmacyclics Llc Purinone compounds as kinase inhibitors
CN105451741A (en) * 2013-08-06 2016-03-30 福建海西新药创制有限公司 Inhibitors of bruton's tyrosine kinase
WO2016019237A2 (en) * 2014-07-31 2016-02-04 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
US20180298008A1 (en) * 2015-09-16 2018-10-18 Redx Pharma Plc Pyrazolopyrimidine derivatives as btk inhibitors for the treatment of cancer
CN108431007A (en) * 2015-09-16 2018-08-21 洛克索肿瘤学股份有限公司 Pyrazolopyrimidine derivatives as BTK inhibitors for the treatment of cancer
US20180243311A1 (en) * 2017-02-24 2018-08-30 Gilead Sciences, Inc. Inhibitors of bruton's tyrosine kinase
CN110483521A (en) * 2018-05-14 2019-11-22 杭州和正医药有限公司 A kind of reversible covalent bruton's tyrosine kinase inhibitor, pharmaceutical composition and its application
WO2020150681A1 (en) * 2019-01-18 2020-07-23 Xibin Liao Bruton's tyrosine kinase inhibitors
CN111454268A (en) * 2019-01-18 2020-07-28 明慧医药（上海）有限公司 Cyclic molecules as Bruton's tyrosine kinase inhibitors
CN111018865A (en) * 2019-10-17 2020-04-17 山东大学 1-substituted benzyl pyrazolopyrimidine derivative and preparation method and application thereof
CN115443277A (en) * 2020-03-12 2022-12-06 重庆复尚源创医药技术有限公司 Compounds as kinase inhibitors
CN114075190A (en) * 2020-08-20 2022-02-22 北京诺诚健华医药科技有限公司 Heterocyclic BTK inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
张鹏应等: "布鲁顿酪氨酸激酶及其抑制剂研究进展", 《上海医药》 *
张鹏应等: "布鲁顿酪氨酸激酶及其抑制剂研究进展", 《上海医药》, vol. 41, no. 15, 31 August 2020 (2020-08-31), pages 8 - 12 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115443277A (en) * 2020-03-12 2022-12-06 重庆复尚源创医药技术有限公司 Compounds as kinase inhibitors
WO2023143355A1 (en) * 2022-01-28 2023-08-03 Hansoh Bio Llc Azacycle amide derivative, preparation methods and medicinal uses thereof
WO2023165570A1 (en) * 2022-03-03 2023-09-07 深圳市塔吉瑞生物医药有限公司 Cycloalkyl or heterocyclyl substituted heteroaryl compound, and composition and use thereof
WO2024235166A1 (en) * 2023-05-12 2024-11-21 武汉人福创新药物研发中心有限公司 Composition containing btk inhibitor, and use thereof
WO2025067568A1 (en) * 2023-09-28 2025-04-03 杭州市第一人民医院 Pyrrole degrader and pharmaceutical use thereof

Also Published As

Publication number Publication date
CN114573586B (en) 2023-11-03

Similar Documents

Publication Publication Date Title
CN114573586B (en) Polycyclic compound for inhibiting Bruton tyrosine kinase activity, pharmaceutical composition and application thereof
JP7321194B2 (en) Ligands for cereblon (CRBN)
TWI743401B (en) Indole carboxamide compounds
JP7485609B2 (en) Pyridine-Containing Heterocyclic Compounds Useful as Modulators of IL-12, IL-23 and/or IFNα Responses - Patent application
JP7490107B2 (en) Sulfonepyridine alkylamide substituted heteroaryl compounds
TW202200562A (en) Quinoxaline dione derivative as irreversible inhibitor of KRAS G12C mutant protein
TWI734240B (en) Quinoline derivatives
CN112778276A (en) Compound as SHP2 inhibitor and application thereof
CA2718618A1 (en) Chemokine receptor modulators
KR102760553B1 (en) Aminoborane derivatives and their preparation methods and applications
WO2021057882A1 (en) Egfr inhibitor, composition and preparation method therefor
KR20160022890A (en) Carbazole carboxamide compounds useful as kinase inhibitors
CN110950876A (en) Furanolactam compounds, preparation method and application
AU2022324472A1 (en) Methods of treating migraine with mnk inhibitors
CN101312974A (en) Pyrazoloisoquinoline derivatives
CN107936024B (en) Anaplastic lymphoma kinase inhibitor and preparation method and application thereof
ES2987809T3 (en) Imidazopyridazine compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
CN113993871B (en) BTK inhibitors containing 5-azacycloheptane
WO2023155900A1 (en) Five-membered and six-membered heterocyclic compound, and use thereof as protein kinase inhibitor
WO2023279986A1 (en) Six-membered aryl or heteroaryl amides, and composition and use thereof
CN119490507A (en) A new type of kinase inhibitor
EA041710B1 (en) SULPHONE-, PYRIDINE-, ALKYL-, AMIDE-SUBSTITUTED HETEROARYL COMPOUNDS
NZ754113B2 (en) Indole carboxamide compounds useful as kinase inhibitors
NZ731946B2 (en) Indole carboxamide compounds useful as kinase inhibitors

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant