CN114573586B - Polycyclic compound for inhibiting Bruton tyrosine kinase activity, pharmaceutical composition and application thereof - Google Patents

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

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CN114573586B
CN114573586B CN202011365603.3A CN202011365603A CN114573586B CN 114573586 B CN114573586 B CN 114573586B CN 202011365603 A CN202011365603 A CN 202011365603A CN 114573586 B CN114573586 B CN 114573586B
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amino
cycloalkyl
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CN114573586A (en
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周星露
刘兴国
胡苗
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Hangzhou Hertz Pharmaceutical Co ltd
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Hangzhou Hertz Pharmaceutical Co ltd
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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Abstract

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

Description

Polycyclic compound for inhibiting Bruton 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 and mutant BTK, and to the use thereof in the manufacture of a medicament for the treatment of diseases, disorders or conditions benefiting from inhibition of bruton's tyrosine kinase activity, such as B-cell proliferative 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 critical role in connecting B-cell receptor (BCR) stimulated B-cell signaling pathways 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 (Toll like receptor, TLR) and cytokine receptor mediated TNF- α production in macrophages, immunoglobulin E receptor (fcer 1) signaling in mast cells, signaling that inhibits Fas/APO-1 apoptosis in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. See, e.g., C.A. Jeffries et al, J.Bio.chem. (2003) 278:26158-26264, N.J. Horwood et al, J.exp.Med. (2003) 197:1603-1611. Recent studies have shown that Btk signaling pathway is a new hotspot in current clinical therapeutic studies of non-hodgkin lymphomas (NHL), particularly Chronic Lymphocytic Leukemia (CLL), B-cell lymphomas, and autoimmune diseases. The small molecule Btk inhibitor inhibits the autophosphorylation of Btk by acting on BCR signaling pathway and binding to Btk, preventing activation of Btk, thereby blocking cell conduction and inducing apoptosis.
The Btk inhibitor ibutenib is marketed and is defined as a 'breakthrough' new drug by the FDA, and has wide research and development prospect. In use, the first generation of covalent BTK inhibitors, represented by ibutenib, patients have developed drug resistance mutations, such as the cysteine mutation at position 481 (C481S). There is therefore an urgent need to develop novel BTK inhibitors that can overcome drug resistance mutations.
In addition, BTK plays an important role in the functional regulation of a variety of immune cells including B cells. By inhibiting the activity of BTK kinase, the activation of B cells can be effectively inhibited, and the generation of autoantibodies can be reduced. Thus, in addition to B-cell malignancies, BTK inhibitors are also being used in the treatment of autoimmune diseases. Several BTK inhibitors are currently used in the secondary and tertiary clinical study stages of tenascus, immune Thrombocytopenic Purpura (ITP), chronic graft versus host disease (cGvHD), rheumatoid arthritis, systemic lupus erythematosus. Therefore, the development of novel BTK inhibitors with low toxic and side effects can be used for the treatment of autoimmune system diseases.
Disclosure of Invention
The object of the present invention is to provide novel BTK inhibiting compounds having highly potent wild-type and mutant BTK inhibiting activity, high specificity (excellent kinase selectivity) and excellent PK properties, and optical isomers thereof or pharmaceutically acceptable salts thereof, which are not reported in the literature.
The invention also provides a pharmaceutical composition comprising the above compound, and stereoisomers or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof.
The invention also provides application of the compound and stereoisomers or stereoisomer mixtures or pharmaceutically acceptable salts or solvates thereof in preparing medicaments for treating diseases, disorders or conditions which benefit from inhibition of the activity of the Bruton's old An Suan kinase.
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 its stereoisomers, or a pharmaceutically acceptable salt thereof:
ring a is:
X 1 selected from: n, CR 11 ；
X 2 Selected from: n, CO, CR 12 ；
X 3 Selected from: n, CR 13 ；
X 4 Selected from: o, N, NR 15 ，CR 15 ；
X 5 Selected from: absence of N, CO, NR 16 ，CR 16 ；
X 6 Selected from: n, NR 17 ，NHR 17 ，CO，CR 17 ；
X 7 Selected from: absence or CHR 18 ；R 18 Selected from: c (C) 1 -C 5 An alkyl group; when X is 6 Selected from NR 17 ，NHR 17 ，CO，CR 17 When R is 17 Can be combined with R 18 Linking into a ring;
in ring a, the dotted line indicates that the chemical bond may or may not be present; further, the single dotted line indicates that a chemical bond may or may not exist (represented by a single bond); double dashed lines indicate that the chemical bond is a double bond, a single bond, or is absent;
Y 1 、Y 2 、Y 3 Independently selected from CR 7 、N；
m is selected from 0, 1, 2, 3, 4;
n is selected from 0, 1, 2;
L 1 selected from chemical bonds, O, NR 8 、(CH 2 )p、NHC(O)、NHS(O) 2 、C(O)NH、S(O) 2 NH；
L 2 Selected from chemical bonds, O, NR 8 、(CH 2 )p、NHC(O)、NHS(O) 2 、C(O)NH、S(O) 2 NH；
And L is 1 And L 2 At least one is O, NR 8 、NHC(O)、NHS(O) 2 C (O) NH or S (O) 2 NH；
p is selected from 1, 2 and 3;
R 1 selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted halogenated C 1 -C 6 Alkyl, substituted or unsubstituted halogenated C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 5 Cycloalkyl;
R 2 selected from: substituted or unsubstituted C 1 -C 10 Alkyl, substituted or unsubstituted C 3 -C 7 Cycloalkyl (excluding norbornyl), substituted or unsubstituted quaternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 Cycloalkenyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted five-to ten-membered heteroaryl;
r is as described above 2 Can be further substituted with 1-5R X Substituted, R X Independently selected from: d, C 1 -C 3 Alkyl, halogen, amino, nitro, hydroxy, oxo, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, -amino C 1 -C 3 Alkyl, -C (O) C 1 -C 3 Alkyl, -C (O) O-C 1 -C 3 Alkyl, -C 1 -C 3 Alkylamino, halo C 1 -C 3 Hydroxyalkyl, halo C 1 -C 3 Alkylamino, C 3 -C 5 Cycloalkyl, quaternary to six membered heterocycloalkyl;
R 3 Selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted halogenated C 1 -C 6 Alkyl, substituted or unsubstitutedHalogenated C 1 -C 6 Alkoxy, substituted or unsubstituted C3-C 5 Cycloalkyl;
R 11 ，R 12 ，R 13 ，R 14 ，R 15 ，R 16 ，R 17 each independently selected from: absence of H, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 ～C 5 Cycloalkyl, C3-C7 cycloalkenyl, quaternary 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，SO 2 Ra, C (O) ORa, OC (O) Ra, NRbRc, C (O) N (Rb) Rc, N (Rb) C (O) Rc, -P (O) RbRc; the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl groups 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;
R 7 Selected from: h, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted halogenated C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 5 Cycloalkyl;
R 8 selected from: h, D, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted halogenated C 1 -C 3 Alkyl, substituted or unsubstituted C 3 -C 5 Cycloalkyl groups.
Further, as a limiting condition:
X 1 is C, X 2 Is N or CH, X 4 Is N, X 5 Is CH, X 6 Is N or CR 16 ，-L 1 -L 2 when-CONH-, R 2 Not substituted or unsubstituted C 1 -C 10 Alkyl, substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted quaternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 Cycloalkenyl group
X 2 Is N, X 3 Is N, X 5 When it is absent, -L 1 -L 2 -not being-CH 2 NHCO；
X 2 Is N, X 4 Is N, X 5 Is CH, X 6 When N is the same; -L 1 -L 2 -not being-CH 2 NHCO-；
X 1 Is C, X 2 Is N, X 3 When N is, -L 1 -L 2 -the combination is-C (O) NH-or-NHC (O) -;
R 2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C 3 -C 7 When cycloalkenyl, the following condition is satisfied: -L 1 -L 2 -not being a chemical bond, O, NR 8 C (O) NH, -CONH-, or X 5 Absence of; further:
X 1 selected from: n, C;
X 2 selected from: n, CO, CR 12 ；
X 3 Selected from: n, C;
X 4 selected from: o, N, CR 15 ；
X 5 Selected from: absence, N, NR 16 ，CR 16 ；
X 6 Selected from: n, CO, NHR 17 ，CR 17 ；
When X is 2 X is selected from CO 1 ，X 3 And simultaneously N;
when X is 4 X is selected from O 5 To be absent, X 6 Is NHR 17 At this time R 17 And R is R 2 Can be connected into a ring;
when X is 6 X is selected from CO 5 Is NR (NR) 16 X4 is N;
further:
ring a is selected from the following heterocyclic structures:
when ring A is selected from one of (A) (B) (C) (D) (E) (F) (G) (H) (K) (M), and-L 1 -L 2 The combination of-is not-CH 2 NHC (O) -at the same time, R 2 Not substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted ternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 A cycloalkenyl group;
when ring A is selected from (I), -L 1 -L 2 The combination of-is-CO (NH) -, and R 2 Selected from substituted or unsubstituted
Substituted C 6 -C 10 Aryl, substituted or unsubstituted five-to ten-membered heteroaryl;
when ring A is selected from (Q), -L 1 -L 2 The combination is not- (CH) 2 ) p -NHC(O)-；
When ring A is selected from (J), and-L 1 -L 2 When the combination of-and-is-C (O) NH-R 2 Selected from substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted five-to ten-membered heteroaryl;
when ring A is selected from (J), and-L 1 -L 2 The combination of-is not-C (O) NH-and- (CH) 2 ) p R in NHC (O) 2 Not substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted ternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 A cycloalkenyl group.
Still further preferred compounds of the invention have the structure of formula IIa or IIb or IIc:
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:
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 the ring A is selected from one of (A) (C) (D) (E) (F) (G) (M), R 2 Not substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted ternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 A cycloalkenyl group;
when the general structural formula is selected from IIIa and ring A is selected from one of (I) (J), R 2 Selected from substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted five-to ten-membered heteroaryl;
when the general structural formula is selected from IIIc and the ring A is selected from one of (A) (C) (D) (E) (F) (G) (J) (M), R 2 Not substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted ternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 A cycloalkenyl group.
Still further preferred compounds of the invention have the structure shown in formula IVa or IVb:
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 the ring A is selected from (A), R 2 Not substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted ternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 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 C 6 -C 10 Aryl, substituted or unsubstituted five-to ten-membered heteroaryl.
Still further preferred compounds of the present invention have the structure represented by formulas Va-Vh:
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; wherein: r is R 1 Selected from: h, D, halogen (fluorine, chlorine), hydroxy, amino, cyano, carboxy, -OMe, -OEt, -OiPr, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted halogenated C 1 -C 3 Alkyl, OCF 3 Substituted or unsubstituted 3-to 5-membered cycloalkyl, substituted or unsubstituted 3-to 5-membered cycloalkoxy.
R 2 Selected from: h, D, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted five-to seven-membered heteroaryl, wherein the alkyl, phenyl, heteroaryl may be further substituted with one or more substituents, takenThe substituents are selected from: d, C 1 -C 3 Alkyl, halogen, cyano, amino, nitro, hydroxy, oxo, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, V-amino C 1 -C 3 Alkyl, -C (O) C 1 -C 3 Alkyl, -C (O) O-C 1 -C 3 Alkyl, -C 1 -C 3 Alkylamino, halo C 1 -C 3 Hydroxyalkyl, halo C 1 -C 3 Alkylamino, C 3 -C 5 Cycloalkyl, quaternary to six membered heterocycloalkyl;
when the structure is selected from Vb or Vc, R2 is selected from substituted or unsubstituted phenyl, and substituted or unsubstituted five-membered to seven-membered heteroaryl;
still further preferred compounds of the present invention have the structure shown in formulas VIa-VIa:
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;
wherein R is 1 Selected from: h, D, halogen (fluorine, chlorine), hydroxy, amino, cyano, carboxy, -OMe, -OEt, -OiPr, substituted or unsubstituted C 1 -C 3 Alkyl, substituted or unsubstituted halogenated C 1 -C 3 Alkyl, OCF 3 Substituted or unsubstituted 3-to 5-membered cycloalkyl, 3-to 5-membered cycloalkoxy
R 2 Selected from:
wherein R is 2 May be further substituted with 0 to 5 substituents selected from the group consisting of:D、F、Cl、CN、OMe、OEt、OiPr、NH 2 、NHMe，NHAc、CH 2 OH、CH 2 CH 2 OH、CO 2 H、CH 2 CO 2 H、Me、Et、iPr、CF 3 、CH 2 CF 3 、COOMe、COOiPr、CONH 2 、CH 2 CONH 2 。
preferably, the compound is selected from the following compounds:
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or a stereoisomer thereof, or a mixture of its stereoisomers, 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-methoxybenzamide) 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) cyclohexene carboxylate 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-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-pyrrole [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide 021
N- (4- (4-amino-7- (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
N- (4- (4-amino-7- (1-hydroxypropyl-2-yl) -7H-pyrrole [2,3-d ] pyrimidin-5-yl) -3-fluorobenzyl) -5-fluoro-2-methoxybenzamide 024
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-pyrazolin [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-pyrazolin [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-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-pyrazolin [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- (phenylsulfanilamide methyl) 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-methoxybenzamide) methyl) phenyl) -1H-pyrrole-2-carboxamide 066
4-amino-3-cyclopentyl-1- (4- ((2-methoxybenzamide) methyl) phenyl) -1H-pyrazole-5-carboxamide 067
4-amino-3-isopropyl-1- (4- ((2-methoxybenzamide) 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-trifluoropropan-2-yl) -1H-pyrazole-4-carboxamide 072
5-amino-3- (2-fluoro-4- ((4- (trifluoromethyl) pyridin-2-yl) carboxamide) phenyl) -1- (1, 1-trifluoropropan-2-yl) -1H-pyrazole-4-carboxamide 073
5-amino-3- (2-fluoro-4- ((4- (trifluoromethyl) pyridin-2-yl) carboxamide) phenyl) -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 ring of 6 to 12 carbon atomsPolycyclic groups (wherein 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 substituents of the aromatic ring being selected from D, halogen (preferably fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxy, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 Alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C 1 -C 6 Hydroxyalkyl (preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C 1 -C 6 Alkoxy (preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halo C 1 -C 6 Alkyl (preferably halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloisobutyl, halosec-butyl, halotert-butyl, etc.), halo C 1 -C 6 Hydroxyalkyl (preferably halohydroxymethyl, halohydroxyethyl, halohydroxypropyl, halohydroxyisopropyl, etc.), haloC 1 -C 6 Alkoxy (preferably halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, halobutoxy, haloisobutyloxy, halosec-butyloxy, halotert-butyloxy, etc.) radicals, C 3 -C 6 Cycloalkyl (preferably cyclopropyl, cyclopentyl, cyclohexyl, etc.), halo C 3 -C 6 Cycloalkyl (preferably halocyclopropyl, halocyclopentyl, halocyclohexyl, etc.), 3-to 10-membered heterocyclyl (preferably tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.), C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl; the aromatic ring may be substituted by mono-substitution (e.g., ortho, meta, para), di-substitution, tri-substitution, etc.
As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (one of which may be partially saturated) corresponding to one or more carbons of the "aryl" group described above being replaced by a heteroatom such as oxygenNitrogen, sulfur, etc. The heteroaromatic ring may be a single ring or may be a double ring, i.e., fused together through two rings. Specific heteroaryl (heterocyclylaryl) groups may be: D. pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, indoline, benzimidazole, and the like. The heteroaryl group may be unsubstituted or substituted. The substituents of the heterocyclic aryl groups are selected from halogen, cyano, nitro, amino, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halogenated C 1 -C 6 Hydroxyalkyl, halogenated C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl groups.
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, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and the like. The alkyl group may be unsubstituted or mono-substituted or poly-substituted, and the substituents may be the same or different in the case of poly-substitution; the substituents of the alkyl groups are selected from D, halogen, nitro, hydroxy, carboxyl, methyl carboxylate, ethyl carboxylate, isopropyl carboxylate, carbamoyl and C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or mono-or polysubstituted amino, wherein the substituents for the amino groups may be the same or different and are selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl groups.
The term "hydroxyalkyl" as used herein refers to-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 substituents may be D, halogen, amino, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl groups.
The term "aminoalkyl" as used herein refers to-alkyl-NH 2 Wherein 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 be substituted with D, halogen, amino, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl, the substituents of which may be substituted on alkyl or NH 2 And (3) upper part.
The term "alkylamino" as used herein refers to an alkyl-NH-group, wherein alkyl is as defined above. Examples of "alkylamino" groups useful in the present invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like. "alkylamino" also includes substituted alkylamino groups, the substituents of which may be D, halogen, amino, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl, the substituents of which may be substituted on alkyl or NH.
The term "alkoxy" as used herein refers to an-O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxyRadical, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. "alkoxy" also includes substituted alkoxy groups, which substituents may be D, halogen, amino, hydroxy, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl groups.
The term "cycloalkyl" as used herein refers to a non-aromatic monovalent hydrocarbon group having a single or multiple rings of three to ten carbon atoms (two single rings being linked by a chemical bond or bridged or spiro or fused), 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, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halogenated C 1 -C 6 Hydroxyalkyl, halogenated C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or mono-or polysubstituted amino, wherein the substituents for the amino groups may be the same or different and are selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl groups.
The term "cycloalkenyl" as used herein refers to a non-aromatic hydrocarbon group having a single or multiple rings of three to ten carbon atoms (with chemical bonds between the two rings or bridged or spiro or fused) and having at least one double bond, preferably cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like, wherein one or two carbon atoms may be To be replaced by an oxo group. The cycloalkenyl group may be unsubstituted or substituted, and the substituents are selected from D, halogen, nitro, hydroxy, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halogenated C 1 -C 6 Hydroxyalkyl, halogenated C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or mono-or polysubstituted amino, wherein the substituents for the amino groups may be the same or different and are selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl groups.
The term "heterocyclyl" as used herein refers to a monocyclic or polycyclic (two monocyclic rings are linked by a bond or bridged or spiro or fused) non-aromatic cyclic group having three to ten ring atoms, wherein part of the 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 substituents are selected from D, halogen, nitro, hydroxy, carboxyl, methyl carboxylate, ethyl carboxylate, carboxamide, oxo, thio, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halogenated C 1 -C 6 Hydroxyalkyl, halogenated C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, 3 to 10 membered heterocyclic group, or amino or mono-or polysubstituted amino, wherein the substituents for the amino groups may be the same or different and are selected from hydrogen, and a pharmaceutically acceptable salt thereof,C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 Heteroaryl groups.
The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain radical (i.e., C) consisting of carbon and hydrogen atoms, containing at least one double bond and having 2 to 10 carbon atoms 2 -C 10 Alkenyl) including, but not limited to, vinyl, allyl, but-1-enyl, pent-1, 4-di-alkenyl, and the like. Alkenyl groups 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 (i.e., C) consisting of carbon and hydrogen atoms, containing at least one triple bond and having 2 to 10 carbon atoms 2 -C 10 Alkynyl) including, but not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups 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 "halogen" as used herein refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine or bromine.
The term "halo" as used herein refers to a substitution of the same atom or different atoms with halogen, either once or more than once, such as di-or tri-substitution.
The term "haloalkyl" as used herein refers to an alkyl group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein alkyl is as defined above. "haloalkyl" may be substituted one or more times with halogen.
The term "halogenated hydroxyalkyl" as used herein refers to a hydroxyalkyl group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein hydroxyalkyl is as defined above. "halo hydroxyalkyl" may be substituted one or more times with halogen.
Salts of the compounds of the present invention may be prepared by methods well known to those skilled in the art. The salt may be an organic acid salt, an inorganic acid salt, etc., and the organic acid salt includes citrate, fumarate, oxalate, malate, lactate, camphorsulfonate, p-toluenesulfonate, methanesulfonate, etc.; the inorganic acid salt comprises halogen acid salt, sulfate, phosphate, nitrate and the like. For example, methanesulfonic acid, trifluoromethanesulfonic acid salt may be formed with lower alkylsulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, etc.; para-toluene sulfonate, benzene sulfonate, etc. may be formed with aryl sulfonic acids such as benzene sulfonic acid or para-toluene sulfonic acid; with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid, etc., to form corresponding salts; glutamate or aspartate may be formed with amino acids such as glutamate or aspartate. Corresponding salts may 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 aspects. The pharmaceutical composition of the present invention may be composed of one or more of the compounds according to any one of the above-mentioned technical schemes and other compounds, or one or more of the compounds according to any one of the above-mentioned technical schemes.
The present invention provides a pharmaceutical formulation comprising at least one active ingredient which is one or more of the compounds according to any one of the above-mentioned aspects. The pharmaceutical formulation comprises at least one active ingredient, which may be any one or more of the BTK inhibitor compounds of the invention, optical isomers of the compounds, pharmaceutically acceptable salts of the compounds or optical isomers thereof, solvates of the compounds or optical isomers thereof, and one or more pharmaceutically acceptable carriers or excipients.
The carrier includes a conventional diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. in the pharmaceutical field, and if necessary, a flavoring agent, sweetener, etc. may be added.
The medicine of the invention 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 methods in the pharmaceutical field.
In another aspect, provided herein are methods of using the compounds of formulas I-V, and optical isomers thereof, or pharmaceutically acceptable salts or solvates thereof, disclosed herein to inhibit or treat a disease, disorder, or condition that would benefit from inhibition of bruton's tyrosine kinase (Btk) activity.
In a further preferred embodiment, the present invention provides a method of inhibiting the activity of bruton's tyrosine kinase in a subject by administering to the subject in need thereof a composition comprising a therapeutically effective amount of at least one compound having the formula I-V. In some embodiments, a subject in need thereof suffers 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 thyroiditis, oldhamitis (Ord's thyroiditis), graves' disease, rheumatoid arthritis syndrome synrome), multiple sclerosis, infectious neuronal inflammation (Guillain-Barre syndoms), acute disseminated encephalomyelitis, addison's disease, ocular clonus-myoclonus syndrome, compulsive spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmuneEpidemic hepatitis, celiac disease (celiac disease), goodpasture's syndrome (Goodpasture's syndrome), immune Thrombocytopenic Purpura (ITP), optic neuritis, scleroderma, primary biliary cirrhosis, reiter's syndrome, high-safety arteritis (Takayasu's artertitis), temporal arteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis (Wegener's granulosis), psoriasis, systemic dehairing, behcet's disease (Wegener's disease)>disease), chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular rigidity, scleroderma or vulvodynia, and chronic graft versus host disease (cGvHD).
In further embodiments, a subject in need thereof suffers from cancer. In one embodiment, the cancer is a B cell proliferative disorder, such as diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, B cell pre-lymphocytic leukemia, lymphoplasmacytoid lymphoma/Waldenstein macroglobulinemia macrolobulinema), 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 lymphoma, primary exudative 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 a medicine for treating cell proliferation diseases. The cell proliferation diseases include cancers. In other words, the invention also provides the application of the compounds shown in the general formulas I-V, optical isomers or pharmaceutically acceptable salts or solvates thereof in treating proliferative diseases (such as cancers) singly or in combination with other medicaments. Antitumor agents which may 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 classes: mitotic inhibitors (e.g., vinblastine, vindesine, and vinorelbine); tubulin degradation 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 alexin, mitomycin, and bleomycin) may be inserted; enzymes (e.g., asparaginase); topoisomerase inhibitors (e.g. etoposide and camptothecins); biological response modifiers (e.g., interferons); immune checkpoint inhibitors (e.g., PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors); CD20 mab; BCL2 inhibitors.
The inventor of the present invention has proved through experiments that the compound of the present invention can inhibit both wild type and 481 cysteine mutated BTK kinase.
Experiments prove that the compound has an anti-proliferation inhibition effect on tumor cell lines such as MINO, OCI-LY10 and the like.
Detailed Description
The following examples illustrate the feasibility of the invention, and it will be understood by those skilled in the art that modifications and substitutions of corresponding technical features are possible, according to the teachings of the prior art, while still falling within the scope of the invention as claimed.
Example 1: preparation of N- (4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide (001)
Step 1, dissolving 4, 6-dichloro-5-aminopyrimidine (2.5 g) in 25mL of N-butanol, adding isopropylamine (3.91 mL), heating to reflux for about 24 hours, cooling to room temperature after TLC detection, concentrating under reduced pressure to remove solvent, and purifying the obtained residue by silica gel column chromatography to obtain a pale yellow solid product 6-chloro-N 4 Isopropyl pyrimidine-4, 5-diamine (2.3 g), yield 82％。
Step 2, 6-chloro-N 4 Isopropyl pyrimidine-4, 5-diamine (1.9 g) was dissolved in 50mL of tetrahydrofuran solution, CDI (5.1 g) was added, heated to reflux for 20 hours, tetrahydrofuran was removed by rotary evaporation under reduced pressure after completion of TLC detection, ethyl acetate and water were then added for extraction, the separated organic phase was 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 6-chloro-9-isopropyl-7H-purin-8 (9H) -one (1.1 g) as a solid product in a yield of 51%.
Step 3, 6-chloro-9-isopropyl-7H-purin-8 (9H) -one (0.85 g) was dissolved in 10mL of n-butanol, 4-methoxybenzylamine (1.37 g) was added, heated to reflux for about 18 hours, TLC was checked for completion of the reaction, cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography to give 9-isopropyl-6- ((4-methoxybenzyl) amino) -7H-purin-8 (9H) -one (1.11 g) as a solid product in 89% yield.
Step 4, 9-isopropyl-6- ((4-methoxybenzyl) amino) -7H-purin-8 (9H) -one (0.23 g) and (4- ((2-methoxybenzamido) methyl) phenyl) boronic acid (0.64 g) were dissolved in 5mL of anhydrous DMF solution and 0.2g was addedMolecular sieve and anhydrous copper acetate (0.15 g), finally adding 0.4mL triethylamine, stirring at room temperature for reaction for about 36 hours, and monitoring the completion of the reaction by TLC; the reaction solution was filtered through celite, ethyl acetate and water were added to the obtained filtrate to extract, insoluble matters were precipitated, the filtrate was filtered through celite, the filtrate was allowed to stand still 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 a solid product N- (4- (9-isopropyl-6- ((4-methoxybenzyl) amino) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide (0.23 g), yield 56%.
Step 5N- (4- (9-isopropyl-6- ((4-methoxybenzyl) amino) -8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide (0.21 g) was dissolved in 1.5mL of dichloromethane,3mL of trifluoroacetic acid is added, the mixture is heated to reflux for reaction for about 20 hours, TLC detection is finished, and the solvent is removed by decompression concentration; dichloromethane was added for redissolving, the saturated aqueous sodium bicarbonate solution was used for washing, the separated organic phase was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the white solid product N- (4- (6-amino-9-isopropyl-8-oxo-8, 9-dihydro-7H-purin-7-yl) benzyl) -2-methoxybenzamide (0.11 g), yield 71%, LC-MS (ESI-MS): 433[ M+H ]] + 。
Example 2: preparation of N- (4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide (002)
Step 1, 4-amino-5-iodopyrrolo [2,3-D ] pyrimidine (2.6 g) and isopropyl alcohol (1.6 mL) were dissolved in 20mL of anhydrous tetrahydrofuran, triphenylphosphine (5.24 g) was added thereto, DIAD (4.1 mL) was slowly added dropwise thereto, and the mixture was stirred at room temperature after the completion of the dropwise addition to react for about 2 hours; after the TLC detection, the reaction is finished, the solvent is removed by decompression concentration, 10mL of acetonitrile is added, stirred and beaten for about 1 hour, the filtration is carried out, 10mL of acetonitrile is added again to the filter cake, stirred and beaten for 1 hour, the filtration is carried out, and the filter cake is dried by blowing to obtain a solid product of 5-iodo-7-isopropyl-7H-pyrrole [2,3-d ] pyrimidine-4-amine (1.45 g), and the yield is 48%.
Step 2, 5-iodo-7-isopropyl-7H-pyrrole [2,3-d ]]Pyrimidine-4-amine (0.3 g) and (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) boronic acid (0.48 g) were dissolved in 10mL of tetrahydrofuran, then water (2 mL), sodium carbonate (0.21 g) and palladium tetraphenylphosphine (106 mg) were added, heated to reflux for about 12 hours, and the reaction was monitored by TLC and cooled to room temperature; adding ethyl acetate and water for extraction, washing with water and saturated saline water in turn, drying the separated organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying the obtained residue by silica gel column chromatography to obtain a solid product N- (4- (4-amino-7-isopropyl-7H-pyrrole [2, 3-d))]Pyrimidin-5-yl) benzyl) -5-fluoro-2-methoxybenzamide (0.28 g), 66% yield, 1 H NMR(500 MHz,CD 3 OD)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)
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Step 1, 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1.1 g) was dissolved in 20mL anhydrous DMF, isopropyl iodide (2.1 g) and cesium carbonate (1.5 g) were added, and the reaction was stirred at room temperature overnight, and TLC monitoring the reaction was complete; water and ethyl acetate were added for extraction, and the ethyl acetate layer was separated and washed with saturated brine, then 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 of 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carbonitrile (0.85 g), yield 62%.
Step 2, weighing 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carbonitrile (0.69 g), adding trifluoroacetic acid (5 mL), dropwise adding concentrated sulfuric acid (0.3 mL) under stirring, heating to 60 ℃ and stirring for reaction overnight, after TLC detection, cooling and placing in an ice bath, adding water and carefully adding sodium carbonate solid, stirring for neutralizing until the solution is alkalescent, extracting with ethyl acetate, separating an ethyl acetate layer, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a residue, and purifying the residue by silica gel column chromatography to obtain a solid product, namely 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carboxamide (0.64 g), wherein the yield is 86%.
Step 3 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carboxamide (0.25 g) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (0.78 g) were dissolved in 10mL of 1, 4-epoxyhexacyclic ring, water (2 mL), potassium carbonate (0.28 g) and [1,1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride (109 mg) was heated to reflux under nitrogen for overnight, TLC was checked for completion of the reaction, cooled to room temperature, extracted with ethyl acetate and water, and the ethyl acetate layer was separatedWashing with water and saturated brine, respectively, then drying over anhydrous sodium sulfate, filtering, concentrating the resulting residue under reduced pressure, purifying the residue by silica gel column chromatography to give the solid product 5-amino-1-isopropyl-3- (4- ((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) -1H-pyrazole-4-carboxamide (186 mg), yield 43%, 1 H NMR(500 MHz,CDCl 3 )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)
The synthesis of the title compound 5-amino-1-isopropyl-3- (4- (pyridin-2-ylcarbamoyl) phenyl) -1H-pyrazole-4-carboxamide (110 mg) was carried out by substituting 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide with N- (pyridin-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide according to the synthetic route and method of example 3, 1 H NMR(500MHz,CDCl 3 )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-methoxybenzamide) methyl) phenyl) -1H-pyrrole-2-carboxamide (005)
Step 1, 2-cyclopentylacetonitrile (1.1 g) is dissolved in 50mL of anhydrous tetrahydrofuran, cooled to-78 ℃ under the protection of nitrogen, LDA solution (5 mL,2M in THF) is dropwise added, the reaction is continued for 15 minutes after the dropwise addition, and then tetrahydrofuran (5 mL) solution of ethyl formate (0.81 g) is slowly dropwise added; after the completion of the dropwise addition, the reaction was allowed to stand for 1 hour, and then naturally warmed to room temperature and reacted overnight. The reaction was quenched with water, then the pH of the solution was adjusted to about 3 with a 2N aqueous hydrochloric acid solution, extracted with ethyl acetate, the separated organic phase 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 2-cyclopentyl-3-oxopropanenitrile (0.8 g) as an oily product in 58% yield.
Step 2, 2- (4-aminobenzyl) isoindoline-1, 3-dione (1.26 g) was dissolved in 20mL of anhydrous tetrahydrofuran, and bromoethyl cyanide (0.78 g) and triethylamine (1.5 mL) were added thereto and heated to reflux for about 12 hours. After completion of TLC detection, the reaction was cooled to room temperature, ethyl acetate and water were added to extract, the separated organic phase 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 2- ((4- ((1, 3-dioxoisoindol-2-yl) methyl) phenyl) amino) acetonitrile (1.18 g), yield 81%.
Step 3, 2-cyclopentyl-3-oxopropanenitrile (0.5 g) and 2- ((4- ((1, 3-dioxoisoindol-2-yl) methyl) phenyl) amino) acetonitrile (0.87 g) were dissolved in 15mL toluene, p-toluenesulfonic acid (100 mg) was added, heated to reflux overnight, TLC monitored after completion of the reaction, cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, ethyl acetate and water were added, the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography to give (Z) -3- ((cyanomethyl) (4- ((1, 3-dioxoisoindol-2-yl) methyl) phenyl) amino) -2-cyclopentylacrylonitrile (0.77 g) as a solid product in 63% yield.
Step 4, (Z) -3- ((cyanomethyl) (4- ((1, 3-dioxoisoindol-2-yl) methyl) phenyl) amino) -2-cyclopentylacrylonitrile (0.62 g) was dissolved in 10mL of t-butanol, potassium t-butoxide (0.35 g) was added, the reaction was heated to reflux for about 2 hours, the TLC detection was completed, cooled to room temperature, then 10mL of 2N hydrochloric acid was added and stirred for 10 minutes, then extracted with ethyl acetate, 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-4-cyclopentyl-1- (4- (((1, 3-dioxoisoindol-2-yl) methyl) phenyl) -1H-pyrrole-2-carbonitrile (0.37 g) as a solid product in 60% yield.
Step 5, 3-amino-4-cyclopentyl-1- (4- (((1, 3-dioxoisoindol-2-yl) methyl) phenyl) -1H-pyrrole-2-carbonitrile (0.35 g) is weighed, trifluoroacetic acid (3 mL) is added, concentrated sulfuric acid (0.2 mL) is added dropwise under stirring, the reaction is heated to 60 ℃ and stirred overnight, TLC detection is completed, the reaction is cooled and placed in an ice bath, water is added and sodium carbonate solid is carefully added and stirred to neutralize until the solution is slightly alkaline, extraction is performed with ethyl acetate, the ethyl acetate layer is separated and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating under reduced pressure is purified 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 (0.28 g), and the yield is 78%.
Step 6, 3-amino-4-cyclopentyl-1- (4- (((1, 3-dioxoisoindol-2-yl) methyl) phenyl) -1H-pyrrole-2-carboxamide (0.27 g) was dissolved in 5mL of ethanol, hydrazine hydrate (0.15 mL) was added, the reaction was heated to reflux for 2 hours, TLC was monitored to completion, cooled to room temperature, extracted 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-1- (4- (aminomethyl) phenyl) -4-cyclopentyl-1H-pyrrole-2-carboxamide (0.16 g) as a solid product in 85% yield.
Step 7, 3-amino-1- (4- (aminomethyl) phenyl) -4-cyclopentyl-1H-pyrrole-2-carboxamide (0.12 g) and 2-methoxybenzoic acid (80 mg) were dissolved in 3mL of anhydrous DMF, HATU (0.3 g) and DMAP (5 mg) were added and the reaction was stirred at room temperature for about 6 hours, TLC was monitored for completion, the reaction was completed, extracted 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-methoxybenzamide) methyl) phenyl) -1H-pyrrole-2-carboxamide (0.13 g) as a solid product in 75% yield, LC-MS (ESI-MS) 433[ M+H ] ] + 。
Referring to the synthetic methods of the examples above, the following compounds can be synthesized using similar synthetic routes and methods:
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example 75: BTK WT & BTK C481S kinase activity assay
1. Compound formulation
Test compounds shown in Table 1 were dissolved in 100% DMSO to prepare 10mM stock solutions, which were stored in a nitrogen cabinet in the dark.
2. Kinase reaction process
(1) 1 XKinase buffer was prepared.
(2) Preparing a compound concentration gradient: test compounds were tested at an initial concentration of 1000nM, diluted 100-fold final concentration of 100% DMSO in 384source plates, 5-fold dilution, 7 concentrations, and single well assay. 250nl of 100-fold final concentration of compound was transferred to the destination plate 384-well-plate using a dispenser Echo 550. Positive and negative control wells were added with 250nl DMSO.
(3) A2.5-fold final concentration of Kinase solution was prepared using a 1 XKinase buffer.
(4) Adding 10 μl of 2.5-fold final concentration kinase solution to each of the compound wells and positive control wells; mu.l of 1 XKinase buffer was added to the negative control wells.
(5) Centrifugation at 1000rpm for 30 seconds, the reaction plate was shaken and mixed well and incubated at room temperature for 10 minutes.
(6) A5/3-fold final concentration of a mixed solution of ATP and Kinase substrate 2 was prepared using a 1 XKinase buffer.
(7) The reaction was initiated by adding 15. Mu.l of a 5/3-fold final concentration of the mixed solution of ATP and substrate.
(8) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and after shaking and mixing, incubated at room temperature for 30 minutes.
(9) The kinase reaction was stopped by adding 30. Mu.l of stop detection solution, centrifuging at 1000rpm for 30 seconds, and shaking and mixing.
(10) The conversion was read with Caliper EZ Reader.
(11) Fitting curve calculation IC 50 . The results are shown in Table 1.
Example 76: tumor cell proliferation inhibition Activity assay
By passing throughThe inhibition of OCI-LY10 and Mino cell proliferation by the compounds was measured and the antitumor efficacy of the compounds was examined. OCI-LY10 and Mino cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Digesting the cells, inoculating the cells into a 96-well plate according to the cell concentration of OCI-LY10 and Mino 10000/well, and 5% CO at 37 DEG C 2 Incubate overnight. Different concentrations (1000 nM, 4-fold dilution, 8 concentrations) of compound were added to 96-well plates at 37℃with 5% CO 2 After 72 hours incubation, 20uL MTS per well was added. After 2h incubation, the reaction was stopped by adding 25. Mu.l of 10% SDS per well. The absorbance at 490nm and 650nm was measured with a microplate reader. Calculation of IC with GraphPad Prism 5.0 50 . The results are shown in Table 1.
Kinase and tumor cell proliferation inhibitory Activity data for the Compounds of Table 1
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+:IC 50 <3nM；++:3nM<IC 50 <30nM；+++:30nM<IC 50 <300nM；++++:300nM<IC 50
The results in Table 1 show that the compounds of the invention have strong inhibition effects on both BTK WT (wild type) and BTK C481S (mutant type); meanwhile, the compound can inhibit proliferation of OCI-LY10 and Mino tumor cells, and has anti-tumor 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. 90 microliters per well was added to a 96-well plate at 37℃with 5% CO 2 Incubator to incubateCulturing for 30min;
3. adding different concentration compounds into each hole, and adding 5% CO at 37deg.C 2 Incubating in an incubator for 60min;
4. 10uL of anti-IgM is added to each well outside the control group, the temperature is 37 ℃, and the CO content is 5% 2 Incubating for 16h in an incubator;
5. adding 5 microliters of anti-CD19 and anti-CD69 streaming antibodies into each hole, and dyeing for 30min at normal temperature;
6. adding erythrocyte lysate into each hole to break red blood cells;
7. streaming on-machine detection CD19&CD69 double positive cell proportion and IC was calculated 50 。
TABLE 2 Compound B cell activating Activity
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+:IC 50 <3nM；++:3nM<IC 50 <30nM；+++:30nM<IC 50 <300nM；++++:300nM<IC 50
The results in Table 2 show 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, 163:1827-1837).
The specific method comprises the following steps: on day 0, female Balb/c mice were injected intravenously with 100mg/kg of the Chemico mAb cocktail against type II collagen and on day 1, 1.25mg/kg of lipopolysaccharide was injected intraperitoneally. On days 2 to 12, the compound was administered at 10mg/kg orally 1 time per day. After the 13 th day of abdominal anesthesia, femoral artery blood is taken for about 4ml, centrifugation is carried out for 20min at 3000r/min, serum is taken, and a kit is used for detecting IL-1 beta, and meanwhile, related tissue samples are observed.

Claims (12)

1. A compound having the structure of formula IIIa:
or a pharmaceutically acceptable salt thereof; wherein:
ring a is selected from the following heterocyclic structures:
Y 1 、Y 2 independently selected from CR 7 、N；
m is selected from 0, 1, 2, 3, 4;
n is selected from 0, 1, 2;
R 1 selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxy, C 3 -C 5 Cycloalkyl;
R 2 selected from: c (C) 1 -C 10 Alkyl, C 3 -C 7 Cycloalkyl, quaternary to seven membered heterocyclyl, C 3 -C 7 Cycloalkenyl, C 6 -C 10 Aryl, five to ten membered heteroaryl;
r is as described above 2 Can be further substituted with 1-5R X Substituted, each R X Independently selected from: d, C 1 -C 3 Alkyl, halogen, amino, nitro, hydroxy, oxo, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, -C (O) C 1 -C 3 Alkyl, -C (O) O-C 1 -C 3 Alkyl, -C 1 -C 3 Alkylamino, halo C 1 -C 3 Hydroxyalkyl, halo C 1 -C 3 Alkylamino, C 3 -C 5 Cycloalkyl, quaternary to six membered heterocycloalkyl;
R 3 selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halo C 1 -C 6 Alkoxy, C 3 -C 5 Cycloalkyl;
R 12 ，R 14 ，R 15 ，R 16 ，R 17 each independently selected from: h, D, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 ～C 5 Cycloalkyl, C 3 -C 7 Cycloalkenyl, quaternary to seven membered heterocyclyl, C 6 -C 10 Aryl, five-to ten-membered heteroaryl, halogen, nitro, cyano, ORa, SRa, NH (CH) 2 )Ra，C(O)Ra，S(O)Ra，SO 2 Ra, C (O) ORa, OC (O) Ra, NRbRc, C (O) N (Rb) Rc, N (Rb) C (O) Rc, -P (O) RbRc; the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl groups may be further substituted with 1 or more Rd;
ra, rb, rc are each independently selected from: h, D;
rd is selected from: h, D;
R 7 selected from: h, D, halogen, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl;
when ring A is selected from (I), R 2 Selected from C 6 -C 10 Aryl, five to ten membered heteroaryl;
when ring A is selected from (J), R 2 Selected from C 6 -C 10 Aryl, five to ten membered heteroaryl;
when ring A is selected from (A), R 2 Not substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted ternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 A cycloalkenyl group.
2. The compound of claim 1, having a structure of formula IIIa:
or a pharmaceutically acceptable salt thereof; wherein:
ring a of IIIa is selected from one of rings (a) (C) (D) (F) (G) (I) (J) (P) (Q);
when the general structural formula is selected from IIIa and the ring A is selected from one of (A), (C), (D), (F), (G), R 2 Not substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted ternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 A cycloalkenyl group;
when the general structural formula is selected from IIIa and ring A is selected from one of (I) (J), R 2 Selected from C 6 -C 10 Aryl, five to ten membered heteroaryl.
3. The compound of claim 1, having a structure of formula IVa:
or a pharmaceutically acceptable salt thereof; wherein:
ring a of IVa is selected from one of rings (a) (Q) (I) (J);
when the general structural formula is selected from IVa and the ring A is selected from (A), R 2 Not substituted or unsubstituted C 3 -C 7 Cycloalkyl, substituted or unsubstituted ternary to seven membered heterocyclyl, substituted or unsubstituted C 3 -C 7 A cycloalkenyl group;
when the general structural formula is selected from IVa and the ring A is selected from (I) (J), R 2 Selected from C 6 -C 10 Aryl, five to ten membered heteroaryl.
4. The compound of claim 1, having the structure represented by formulas Va-Vd:
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, -OMe, -OEt, -OiPr, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl, -OCF 3 3-to 5-membered cycloalkyl;
R 2 selected from: c (C) 1 -C 3 Alkyl, phenyl, five to seven membered heteroaryl, wherein alkyl, phenyl, heteroaryl may be further substituted with one or more substituents selected from the group consisting of: d, C 1 -C 3 Alkyl, halogen, amino, nitro, hydroxy, oxo, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyalkyl, -C (O) C 1 -C 3 Alkyl, -C (O) O-C 1 -C 3 Alkyl, -C 1 -C 3 Alkylamino, halo C 1 -C 3 Hydroxyalkyl, halo C 1 -C 3 Alkylamino, C 3 -C 5 Cycloalkyl, quaternary to six membered heterocycloalkyl;
when the structure is selected from Vb or Vc, R 2 Selected from phenyl, five-membered to seven-membered heteroaryl.
5. The compound of claim 1, having a structure of formula VIe:
or a pharmaceutically acceptable salt thereof;
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from: h, D, halogen, hydroxy, amino, cyano, carboxy, -OMe, -OEt, -OiPr, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl, OCF 3 3-to 5-membered cycloalkyl;
R 2 selected from:
6. a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising one or more of the compounds as claimed in any one of claims 1 to 6.
8. Use of a compound as defined in any one of claims 1 to 6 in the manufacture of a medicament for the sole treatment of a disease, disorder or condition benefiting from inhibition of bruton's tyrosine kinase activity.
9. The use of claim 8, wherein the disease, disorder or condition is one that would benefit from inhibiting a bruton's tyrosine kinase mutation.
10. The use according to claim 8, wherein the disease is selected from the group consisting of B-cell proliferative diseases and autoimmune diseases.
11. The use according to claim 10, wherein the B-cell proliferative disorder is selected from diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma/waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, burkitt's lymphoma/leukemia, or lymphomatoid granulomatosis.
12. The use of claim 10, wherein the autoimmune disease is selected from the group consisting of inflammatory bowel disease, arthritis, lupus, stell's disease, diabetes, myasthenia gravis, hashimoto's thyroiditis, graves ' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronal inflammation, acute disseminated encephalomyelitis, addison's disease, ocular clonus-myoclonus syndrome, compulsive spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, goodpasture's syndrome, immune thrombocytopenic purpura, optic neuritis, primary biliary cirrhosis, leiter's syndrome, takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis, psoriasis, systemic dehairing, behcet's disease, chronic fatigue, familial dysfunctions, endometrium, interstitial myopic, jetlag, myotonic neuralgia, and graft versus chronic.
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