Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof

文档序号：1623668 发布日期：2020-01-14 浏览：22次中文

阅读说明：本技术 一种新型磷酸肌醇3-激酶抑制剂及其制备方法和用途 (Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof ) 是由张龙宋国伟于 2018-05-31 设计创作，主要内容包括：本发明属于药物化学领域,涉及一种新型磷酸肌醇3-激酶抑制剂及其制备方法和用途。具体而言,本发明提供了一种具有式I结构的化合物,其可以作为高效的PI3K抑制剂,具有抗肿瘤、抗神经退行性疾病(如阿尔茨海默病)、抗炎等多种药理活性。(The invention belongs to the field of pharmaceutical chemistry, and relates to a novel phosphoinositide 3-kinase inhibitor, and a preparation method and application thereof. Specifically, the invention provides a compound with a structure shown in formula I, which can be used as a high-efficiency PI3K inhibitor and has various pharmacological activities such as anti-tumor, anti-neurodegenerative diseases (such as Alzheimer disease), anti-inflammation and the like.)

1. A compound having the structure of formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion thereof, wherein:

R₁、R₃、R₄and R₆Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)₇) (ii) a And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₀is-CH₂-、-C(＝R₂)-、-S(＝R₂)_n-or-P (═ R)₂)(R₀)-；

X₁、X₂、X₃、X₅、X₆、X₇、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄Each independently is CH, CR₇Or N; or X₇And R₄May form a 3-6 membered ring;

X₄and X₈Each independently is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

Or X₄And X₅Form a double bond therebetween, wherein: x₅Is C, X₄Is CH, CR₇Or N;

R₀is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is₀When not hydrogen, R₀Hydrogen in (a) is optionally substituted with deuterium or halogen;

R₂and R₅Each independently is NH, NR₇NOH, S or O;

each R₇Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;

each n is independently 0, 1 or 2.

2. The compound of claim 1, having the structure of formula I, wherein: which are compounds of formula IA:

wherein:

X₁、X₂、X₃、X₄、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each R₇Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, alkylamido, amino, alkanoyl,An alkanoyloxy group, an alkoxycarbonyl group, an alkylsulfonamido group, a cyano group, or a hydroxyl group;

each n is independently 0, 1 or 2.

3. The compound of claim 1, having the structure of formula I, wherein: which are compounds of formula IB:

wherein:

X₁、X₂、X₃、X₄、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

4. The compound of claim 1, having the structure of formula I, wherein: which is a compound of formula IC:

wherein:

R₁、R₃、R₄and R₆Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇An alkoxycarbonyl group,-NHS(＝O)R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)₇) (ii) a And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃、X₄、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂Is NH, NR₇NOH, S or O;

R₅NH, NR, NOH or S;

each n is independently 0, 1 or 2.

5. The compound of claim 1, having the structure of formula I, wherein: which is a compound of formula ID:

wherein:

R₃is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is₃Optionally substituted with at least one R₇Substitution;

R₁、R₄and R₆Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)₇) (ii) a And R is₁、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃、X₄、X₆、X₇、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N; or X₇And R₄May form a 3-6 membered ring;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂Optionally independently NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2;

if and only if X₆Is N, X₇Is CH, X₈is-NH-or-NR₇-, and R₂When is O, R₁And R₃At least one group selected from spiro ring group, hetero-spiro ring group, bridged ring group, hetero-bridged ring group, - (CH)₂)_nSF₅Substituted or unsubstituted phosphoryl, SF₅Substituted aryl or heteroaryl, substituted or unsubstituted phosphoryl-substituted aryl or heteroaryl.

6. The compound of claim 1, having the structure of formula I, wherein: which is a compound of formula IE:

wherein:

R₁、R₃、R₄and R₆Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)₇) (ii) a And R is₁、R₃、R₄And R₆The hydrogen in (1) can optionally be substituted with 0 to more than one R₇Substitution;

X₀is-CH₂-、-C(＝R₂)-、-S(＝R₂)_n-or-P (═ R)₂)(R₀)-；

X₁、X₂、X₃、X₅、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄Each independently is CH, CR₇Or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₀Is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and when R is₀When not hydrogen, R₀Hydrogen in (a) is optionally substituted with deuterium or halogen;

R₂and R₅Each independently is NH, NR₇NOH, S or O;

each R₇Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclic ringAn alkoxy group, an alkylamido group, an amino group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylsulfonamido group, a cyano group, or a hydroxyl group;

each n is independently 0, 1 or 2.

7. The compound of claim 1, having the structure of formula I, wherein: which are compounds of formula IF:

wherein:

R₁、R₃、R₄and R₆Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)₇) (ii) a And R is₁、R₃、R₄And R₆The hydrogen in (1) can optionally be substituted with 0 to more than one R₇Substitution;

X₁、X₂、X₃、X₅、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₄and X₈Each independently is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

8. A compound having the structure of formula I according to claim 1, comprising:

9. a process for the preparation of a compound having the structure of formula I according to any one of claims 1 to 7, comprising:

1) a method for preparing a compound having the structure of formula IA comprises the following steps:

s1: replacement of X in Compound IA-1-1 with R₃To obtain compound IA-1-2;

s2: reacting compound IA-1-2 with compound IA-a to obtain compound IA-1-3;

s3: reacting compound IA-1-3 with compound IA-b to obtain compound IA-1-4;

s4: reacting compound IA-1-4 with compound IA-c to obtain a compound having the structure of formula IA;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅、R₆And R₇A compound of formula IA as defined in claim 2; or

The specific steps are as follows:

s1: by replacing X in compound IA-2-1 with R₃To obtain compound IA-2-2;

s2: reacting the compound 1A-2-2 with a compound IA-a to obtain a compound IA-2-3;

s3: reacting the compound IA-2-3 with the compound IA-d to obtain a compound IA-2-4;

s4: performing ring closing reaction on the compound IA-2-4 under the nitro reduction condition to obtain a compound IA-2-5;

s5: reacting compound IA-2-5 with compound IA-c to obtain a compound having the structure of formula IA;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅And R₆A compound of formula IA as defined in claim 2;

2) the preparation method of the compound with the structure of the formula IB comprises the following specific steps:

s1: replacement of X in Compound IB-1-1 by R₃To obtain a compound IB-1-2;

s2: reacting the compound IB-1-2 with the compound IB-a to obtain a compound IB-1-3;

s3: reacting the compound IB-1-3 with the compound IB-b to obtain a compound IB-1-4;

s4: reacting the compound IB-1-4 with a compound IB-c to obtain a compound with a structure of a formula IB;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅、R₆And R₇A compound of formula IB as defined in claim 3; or

The specific steps are as follows:

s1: replacement of X in Compound IB-2-1 with R₃To obtain a compound IB-2-2;

s2: reacting the compound 1B-2-2 with a compound IB-a to obtain a compound IB-2-3;

s3: reacting the compound IB-2-3 with a compound IB-d to obtain a compound IB-2-4;

s4: performing ring closing reaction on the compound IB-2-4 under the nitro reduction condition to obtain a compound IB-2-5;

s5: reacting the compound IB-2-5 with a compound IB-c to obtain a compound with a structure of a formula IB;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅And R₆A compound of formula IB as defined in claim 3;

3) the preparation method of the compound with the structure of formula IC comprises the following steps:

s1: replacement of X in Compound IC-1-1 by R₃To obtain a compound IC-1-2;

s2: reacting the compound IC-1-2 with the compound IC-a to obtain a compound IC-1-3;

s3: reacting the compound IC-1-3 with the compound IC-b to obtain a compound IC-1-4;

s4: reacting the compound IC-1-4 with a compound IC-c to obtain a compound with a formula IC structure;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅、R₆And R₇A compound of formula IC as defined in claim 4; or

The specific steps are as follows:

s1: replacement of X in Compound IC-2-1 by R₃To obtainCompound IC-2-2;

s2: reacting the compound 1C-2-2 with a compound IC-a to obtain a compound IC-2-3;

s3: reacting the compound IC-2-3 with the compound IC-d to obtain a compound IC-2-4;

s4: performing ring closing reaction on the compound IC-2-4 under the nitro reduction condition to obtain a compound IC-2-5;

s5: reacting the compound IC-2-5 with a compound IC-c to obtain a compound with a formula IC structure;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆A compound of formula IC as defined in claim 4;

4) the preparation method of the compound with the structure shown in the formula ID comprises the following specific steps:

s1: replacement of X in Compound ID-1-1 by R₃To obtain compound ID-1-2;

s2: under the action of the compound ID-a, the compound ID-1-2 undergoes a ring closure reaction to obtain a compound ID-1-3;

s3: introduction of R into Compound ID-1-3₁To obtain compound ID-1-4;

s4: reacting the compound ID-1-4 with the compound ID-b to obtain a compound ID-1-5;

s5: reacting the compound ID-1-5 with the compound ID-c to obtain a compound ID-1-6;

s6: reacting the compound ID-1-6 with the compound ID-d to obtain a compound ID;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₄、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₆And R₇A compound of formula ID as defined in claim 5; or

The specific steps are as follows:

s1: replacement of X in Compound ID-2-1 by R₃To obtain compound ID-2-2;

s2: reacting the compound ID-2-2 with the compound ID-e to obtain a compound ID-2-3;

s3: reacting the compound ID-2-3 with the compound ID-f to obtain a compound ID-2-4;

s4: reacting the compound ID-2-4 with a Lawson reagent and a compound ID-g to obtain a compound ID-2-5;

s5: reacting the compound ID-2-5 with the compound ID-c to obtain a compound with a structure shown in a formula ID;

wherein: x is chlorine, bromine or iodine; r is H, OH or R₇；X₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₆And R₇A compound of formula ID as defined in claim 5;

5) the preparation method of the compound with the structure of the formula IE comprises the following specific steps:

s1: the compound IE-1-1 reacts with the compound IE-a to obtain a compound IE-1-2;

s2: the compound IE-1-2 reacts with the compound IE-b to obtain a compound IE-1-3;

s3: the compound IE-1-3 reacts with the compound IE-c to obtain a compound IE-1-4;

s4: carrying out ammonolysis reaction on the compound IE-1-4 to obtain a compound IE-1-5;

s5: replacement of X in Compound IE-1-5 by R₃To obtain a compound IE-1-6;

s6: reacting the compound IE-1-6 with the compound IE-d to obtain a compound IE;

wherein: x is chlorine, bromine or iodine; r is alkyl; x₁、X₂、X₃、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆A compound of formula IE as defined in claim 6; and

6) the preparation method of the compound with the structure of the formula IF comprises the following specific steps:

s1: reacting the compound IF-1-1 with the compound IF-a to obtain a compound IF-1-2;

s2: reacting the compound IF-1-2 with the compound IF-b to obtain a compound IF-1-3;

s3: reacting the compound IF-1-3 with the compound IF-c to obtain a compound IF-1-4;

s4: replacement of X in Compound IF-1-4 by R₃To obtain a compound IE-1-5;

s5: carrying out amino reaction on the compound IF-1-5 to obtain a compound IF-1-6;

s6: reacting compound IF-1-6 with compound IF-d to obtain compound IF;

wherein: x is chlorine, bromine or iodine; r is alkyl; x₁、X₂、X₃、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆A compound of formula IF as defined in claim 7.

10. A pharmaceutical composition comprising a compound having the structure of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion.

11. A compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any ratio or a pharmaceutical composition according to claim 10 for use as a PI3K inhibitor.

12. Use of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any ratio, or a pharmaceutical composition according to claim 10, as an inhibitor of PI 3K.

13. Use of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition according to claim 10, for the preparation of a medicament for the prevention and/or treatment of a disease which is mediated at least in part by PI 3K.

14. A method for the prevention and/or treatment of a disease mediated at least in part by PI3K, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition according to claim 10.

15. A pharmaceutical combination comprising a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition according to claim 10 and at least one additional cancer therapeutic.

16. A method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition according to claim 10, and at least one additional cancer therapeutic.

Technical Field

The invention belongs to the field of medicinal chemistry, and relates to a potent phosphoinositide 3-kinase (PI3K) inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and a medical application thereof, in particular to an application in preparing a medicament for preventing and/or treating diseases at least partially mediated by PI 3K.

Background

Phosphoinositide 3-kinases (PI3K) are a large class of enzymes whose primary function is phosphorylation of the inositol ring of phosphoinositides. Based on structural similarity, the type of regulatory subunit and the specificity of various phosphoinositide substrates, PI3K is divided into three classes (I, II and III) (Marone R, et al, Biochim. Biophys. acta, 2008; 1784: 159. sub.185), with the most extensive studies on class I PI 3K. All members of this class are composed of a catalytic subunit and an associated regulatory component for the catalytic phosphorylation of phosphatidylinositol 4, 5-bisphosphate (PIP2) to produce the signal molecule phosphatidylinositol 3,4, 5-trisphosphate (PIP 3). In addition, there is some evidence that this type can act as a protein kinase, although the exact nature and physiological significance of the substrate is still being explored (Backer JM., et al, nat. cell. biol., 2005; 7: 773. su. 774). This type is further divided into two subgroups (IA and IB). Three subtypes, the group IA members PI3K α, PI3K β, and PI3K γ, are activated by cellular signaling events involving tyrosine phosphorylation. PI3K α and PI3K β are widely expressed and play a role in cell growth, division and survival (Thomas M, et al, Curr. Opin. Pharmacol., 2008; 8: 267-274). The role of these two kinases in many biological functions is enhanced by embryonic lethality observed in mice lacking PI3K α or PI3K β. Due to their role in homeostasis, clinical evaluation of PI3K α and PI3K β is limited to the field of oncology, and some compounds are also in different stages of clinical development. The PI3K δ subtype, which differs in its behavior, appears to be expressed primarily in hematopoietic cells and may play an important role in the inflammatory response. As such, the recently emerging PI3K δ selective compounds have attracted more attention.

The PI3K γ subtype is expressed in immune cells and has limited expression in normal or malignant epithelial and connective tissue cells. The results of studies in PI3K γ knockout mice indicate that PI3K γ is important for cell activation and migration of some chemokines (Sasaki T., et al, Science, 2000; 287: 1040-. PI3K γ signaling is particularly important for myeloid cell function, downstream of G protein-coupled receptors (GPCRs), such as chemokine receptors, and RAS. In addition, in these cells, PI3K γ can be activated in response to tissue hypoxia. PI3K γ plays a key role in unique myeloid cells, which form a key component of the immunosuppressive tumor microenvironment, as demonstrated in PI3K γ deletion and kinase death knock-in studies. For example, mouse syngeneic tumors grow slowly when transplanted into immunocompetent mice with inactivated PI3K γ gene (Schmid M.C., et al, cancer cell, 2011; 19: 715-. This growth delay is due to the elimination of tumor-associated bone marrow, and the immunosuppressive tumor microenvironment in which these cells promote tumor growth is well known (Gunderson A.J., et al., Cancer Discovery, 2016; 6: 270-285). Furthermore, tumor-associated bone marrow cells are hypothesized to support tumor regeneration following radiation or chemotherapy and to be able to metastasize to spread (De Palma m., et al, j.med.chem., 2012; 55: 8559-8581). These preclinical studies highlight a key role for PI3K γ in myeloid cell biology and suggest that PI3K γ inhibition in tumor-associated myeloid cells may be effective in preventing tumor growth in a variety of settings.

Although PI3K γ inhibitors have been reported in the last decade, there are still few reports of highly selective PI3K γ inhibitors in vivo (WO2017214269, WO2016054491, CN106456628, WO 2015051241). Therefore, from the existing data analysis, the development of the high-selectivity PI3K gamma inhibitor has huge theoretical and clinical values.

Disclosure of Invention

Problems to be solved by the invention

The invention aims to provide a series of novel compounds with a regulating or inhibiting effect on the activity of PI3K, a preparation method of the series of compounds, a pharmaceutical composition containing the series of compounds and medical application of the series of compounds.

Means for solving the problems

In a first aspect, the present invention provides a compound having the structure of formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion thereof, wherein:

X₀is-CH₂-、-C(＝R₂)-、-S(＝R₂)_n-or-P (═ R)₂)(R₀)-；

X₁、X₂、X₃、X₅、X₆、X₇、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄Each independently is CH, CR₇Or N;

X₄and X₈Each independently is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

Or X₄And X₅Form a double bond therebetween, wherein: x₅Is C, X₄Is CH, CR₇Or N;

R₂and R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In a second aspect, the present invention provides a compound having the structure of formula I as described above, comprising:

(1) 2-amino-N- (1- (8- (dimethylphosphoryl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(2) (R) -2-amino-N- (1- (8- (dimethylphosphoryl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(3) (S) -2-amino-N- (1- (8- (dimethylphosphoryl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(4) 2-amino-N- (1- (1-oxo-8- (pentafluoro-lambda)⁶-sulfanyl) -2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a]Pyrimidine-3-carboxamides;

(5) (R) -2-amino-N- (1- (1-oxo-8- (pentafluoro-lambda)⁶-sulfanyl) -2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a]Pyrimidine-3-carboxamides;

(6) (S) -2-amino-N- (1- (1-oxo-8- (pentafluoro-lambda)⁶-sulfanyl) -2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a]Pyrimidine-3-carboxamides;

(7) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1,2] thiazin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(8) (R) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1,2] thiazin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(9) (S) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1,2] thiazin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(10) 2-amino-N- (1- (8- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(11) (R) -2-amino-N- (1- (8- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(12) (S) -2-amino-N- (1- (8- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(13) 2-amino-N- (1- (8- (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(14) (R) -2-amino-N- (1- (8- (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(15) (S) -2-amino-N- (1- (8- (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(16) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydro-2, 6-naphthyridin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(17) (R) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydro-2, 6-naphthyridin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(18) (S) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydro-2, 6-naphthyridin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(19) 2-amino-N- (1- (4- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5-oxo-6-phenyl-5, 6-dihydro-1, 6-naphthyridin-7-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(20) (R) -2-amino-N- (1- (4- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5-oxo-6-phenyl-5, 6-dihydro-1, 6-naphthyridin-7-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(21) (S) -2-amino-N- (1- (4- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5-oxo-6-phenyl-5, 6-dihydro-1, 6-naphthyridin-7-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(22) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(23) (R) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(24) (S) -2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(25) 2-amino-N- (1- (2- (1-adamantyl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(26) (R) -2-amino-N- (1- (2- (1-adamantyl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(27) (S) -2-amino-N- (1- (2- (1-adamantyl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(28)3- (4- (2-aminopyrazolo [1,5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;

(29) (S) -3- (4- (2-aminopyrazolo [1,5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;

(30) (R) -3- (4- (2-aminopyrazolo [1,5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;

(31) 2-amino-N- (2- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) propan-2-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(32) 2-amino-N '-methyl-N' - (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid hydrazide;

(33) 2-amino-N' -hydroxy-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamidine;

(34) (R) -2-amino-N' -hydroxy-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamidine;

(35) (S) -2-amino-N' -hydroxy-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamidine;

(36)3- (3-amino-4- (2-aminopyrazolo [1,5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;

(37) (S) -3- (3-amino-4- (2-aminopyrazolo [1,5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;

(38) (R) -3- (3-amino-4- (2-aminopyrazolo [1,5-a ] pyrimidin-3-yl) -4-oxobutan-2-yl) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -2-phenylisoquinolin-1 (2H) -one;

(39) 2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(40) (S) -2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(41) (R) -2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(42) 2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(43) (S) -2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(44) (R) -2-amino-N- (1- (5- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-3-phenyl-3, 4-dihydrophthalazin-2 (1H) -yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(45) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-2-phenyl-1, 2,3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(46) 2-amino-N- ((1R) -1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-2-phenyl-1, 2,3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(47) 2-amino-N- ((1S) -1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 4-dioxo-2-phenyl-1, 2,3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(48) n- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (sulfamoylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(49) (R) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (aminosulfonylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(50) (S) -N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) -2- (aminosulfonylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(51) 2-amino-N- (1- (1- (hydroxyimino) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-2-phenyl-1, 2,3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(52) (R) -2-amino-N- (1- (1- (hydroxyimino) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-2-phenyl-1, 2,3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(53) (S) -2-amino-N- (1- (1- (hydroxyimino) -8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-2-phenyl-1, 2,3, 4-tetrahydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(54) 2-amino-N- (1- (1-imino-8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-2H-benzo [ e ] [1,2] thiazin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(55) 2-amino-N- (1- (1-ethylimino-8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-2H-benzo [ e ] [1,2] thiazin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(56) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-imino-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(57) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-ethylimino-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(58) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamidine;

(59) 2-amino-N' -ethyl-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboximidamide;

(60) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-methyl-1-oxo-2-phenyl-1, 2-dihydrobenzo [ c ] [1,2] azaphenanthroline-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(61) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2- (2- (dimethylphosphoryl) phenyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(62) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2- (4- (pentafluoro- λ)⁶-sulfanyl) phenyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a]Pyrimidine-3-carboxamides;

(63) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carbothioamide;

(64) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1, 1-dioxo-2-phenyl-2H-benzo [ e ] [1,2,4] thiadiazin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(65) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-1-methyl-2-phenyl-1, 2-dihydrobenzo [ c ] [1,5,2] diazaphosphaphenazine-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(66) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-thioxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(67) 2-amino-N' -hydroxy-N- (1- (1-oxo-2-phenyl-8- (phenylethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamidine;

(68) 2-amino-N- (1- (1- (hydroxyimino) -2-phenyl-8- (phenylethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(69) 2-amino-N' -methyl-N- (1- (1-oxo-2-phenyl-8- (phenylethynyl) -1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamidine;

(70) 2-amino-N- (1-deuterated-1- (4-deuterated-8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(71) 2-amino-N- (1- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) cyclopropyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide;

(72) 2-amino-N- (2- (8- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) propan-2-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide.

In a third aspect, the present invention provides a process for the preparation of a compound having the structure of formula I as described above, comprising:

1) a method for preparing a compound having the structure of formula IA comprises the following steps:

s1: replacement of X in Compound IA-1-1 with R₃To obtain compound IA-1-2;

s2: reacting compound IA-1-2 with compound IA-a to obtain compound IA-1-3;

s3: reacting compound IA-1-3 with compound IA-b to obtain compound IA-1-4;

s4: reacting compound IA-1-4 with compound IA-c to obtain a compound having the structure of formula IA;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅、R₆And R₇As defined in the following compounds of formula IA; or

The specific steps are as follows:

s1: by replacing X in compound IA-2-1 with R₃To obtain compound IA-2-2;

s2: reacting the compound 1A-2-2 with a compound IA-a to obtain a compound IA-2-3;

s3: reacting the compound IA-2-3 with the compound IA-d to obtain a compound IA-2-4;

s4: performing ring closing reaction on the compound IA-2-4 under the nitro reduction condition to obtain a compound IA-2-5;

s5: reacting compound IA-2-5 with compound IA-c to obtain a compound having the structure of formula IA;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅And R₆As defined in the following compounds of formula IA;

2) the preparation method of the compound with the structure of the formula IB comprises the following specific steps:

s1: replacement of X in Compound IB-1-1 by R₃To obtain a compound IB-1-2;

s2: reacting the compound IB-1-2 with the compound IB-a to obtain a compound IB-1-3;

s3: reacting the compound IB-1-3 with the compound IB-b to obtain a compound IB-1-4;

s4: reacting the compound IB-1-4 with a compound IB-c to obtain a compound with a structure of a formula IB;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅、R₆And R₇As defined in compounds of formula IB below; or

The specific steps are as follows:

s1: replacement of X in Compound IB-2-1 with R₃To obtain a compound IB-2-2;

s2: reacting the compound 1B-2-2 with a compound IB-a to obtain a compound IB-2-3;

s3: reacting the compound IB-2-3 with a compound IB-d to obtain a compound IB-2-4;

s4: performing ring closing reaction on the compound IB-2-4 under the nitro reduction condition to obtain a compound IB-2-5;

s5: reacting the compound IB-2-5 with a compound IB-c to obtain a compound with a structure of a formula IB;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅And R₆As defined in the following formula IB compound；

3) The preparation method of the compound with the structure of formula IC comprises the following steps:

s1: replacement of X in Compound IC-1-1 by R₃To obtain a compound IC-1-2;

s2: reacting the compound IC-1-2 with the compound IC-a to obtain a compound IC-1-3;

s3: reacting the compound IC-1-3 with the compound IC-b to obtain a compound IC-1-4;

s4: reacting the compound IC-1-4 with a compound IC-c to obtain a compound with a formula IC structure;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅、R₆And R₇As defined in the following formula IC compounds; or

The specific steps are as follows:

s1: replacement of X in Compound IC-2-1 by R₃To obtain a compound IC-2-2;

s2: reacting the compound 1C-2-2 with a compound IC-a to obtain a compound IC-2-3;

s3: reacting the compound IC-2-3 with the compound IC-d to obtain a compound IC-2-4;

s4: performing ring closing reaction on the compound IC-2-4 under the nitro reduction condition to obtain a compound IC-2-5;

s5: reacting the compound IC-2-5 with a compound IC-c to obtain a compound with a formula IC structure;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆As defined in the following formula IC compounds;

4) the preparation method of the compound with the structure shown in the formula ID comprises the following specific steps:

s1: replacement of X in Compound ID-1-1 by R₃To obtain compound ID-1-2;

s2: under the action of the compound ID-a, the compound ID-1-2 undergoes a ring closure reaction to obtain a compound ID-1-3;

s3: introduction of R into Compound ID-1-3₁To obtain compound ID-1-4;

s4: reacting the compound ID-1-4 with the compound ID-b to obtain a compound ID-1-5;

s5: reacting the compound ID-1-5 with the compound ID-c to obtain a compound ID-1-6;

s6: reacting the compound ID-1-6 with the compound ID-d to obtain a compound ID;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₄、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₆And R₇As defined in the following formula ID compounds; or

The specific steps are as follows:

s1: replacement of X in Compound ID-2-1 by R₃To obtain compound ID-2-2;

s2: reacting the compound ID-2-2 with the compound ID-e to obtain a compound ID-2-3;

s3: reacting the compound ID-2-3 with the compound ID-f to obtain a compound ID-2-4;

s4: reacting the compound ID-2-4 with a Lawson reagent and a compound ID-g to obtain a compound ID-2-5;

s5: reacting the compound ID-2-5 with the compound ID-c to obtain a compound with a structure shown in a formula ID;

wherein: x is chlorine, bromine or iodine; r is H, OH or R₇；X₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₆And R₇As defined in the following formula ID compounds;

5) the preparation method of the compound with the structure of the formula IE comprises the following specific steps:

s1: the compound IE-1-1 reacts with the compound IE-a to obtain a compound IE-1-2;

s2: the compound IE-1-2 reacts with the compound IE-b to obtain a compound IE-1-3;

s3: the compound IE-1-3 reacts with the compound IE-c to obtain a compound IE-1-4;

s4: carrying out ammonolysis reaction on the compound IE-1-4 to obtain a compound IE-1-5;

s5: replacement of X in Compound IE-1-5 by R₃To obtain a compound IE-1-6;

s6: reacting the compound IE-1-6 with the compound IE-d to obtain a compound IE;

wherein: x is chlorine, bromine or iodine; r is alkyl; x₁、X₂、X₃、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆As defined in the following formula IE compound;

6) the preparation method of the compound with the structure of the formula IF comprises the following specific steps:

s1: reacting the compound IF-1-1 with the compound IF-a to obtain a compound IF-1-2;

s2: reacting the compound IF-1-2 with the compound IF-b to obtain a compound IF-1-3;

s3: reacting the compound IF-1-3 with the compound IF-c to obtain a compound IF-1-4;

s4: replacement of X in Compound IF-1-4 by R₃To obtain a compound IE-1-5;

s5: carrying out amino reaction on the compound IF-1-5 to obtain a compound IF-1-6;

s6: reacting compound IF-1-6 with compound IF-d to obtain compound IF;

wherein: x is chlorine, bromine or iodine; r is alkyl; x₁、X₂、X₃、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆As defined in the following compounds of formula IF.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound having the structure of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or mixture thereof, in any proportion.

In a fifth aspect, the present invention provides a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any ratio, or a pharmaceutical composition as described above, for use as a PI3K inhibitor.

In a sixth aspect, the present invention provides the use of a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition thereof, as described above, as an inhibitor of PI 3K.

In a seventh aspect, the present application provides a use of the above compound having a structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any ratio, or the above pharmaceutical composition, in the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by PI 3K.

In an eighth aspect, the present invention provides a method for preventing and/or treating a disease mediated at least in part by PI3K, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above.

In a ninth aspect, the present invention provides a pharmaceutical combination comprising a compound having the structure of formula I as described above or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent.

In a tenth aspect, the present invention provides a method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic.

ADVANTAGEOUS EFFECTS OF INVENTION

The invention provides a compound of formula I with a novel structure, which can be used as a high-efficiency PI3K inhibitor and has various pharmacological activities of resisting tumors, neurodegenerative diseases (such as Alzheimer disease), inflammation, infection and the like. The synthesis method is mild, simple and easy to operate, easy to derivatize and suitable for industrial mass production.

Drawings

FIG. 1 is a compound of the present invention having the structure of formula I.

FIG. 2 is a synthetic route for Compound 1 of the present invention.

FIG. 3 is a scheme for the synthesis of compound 7 of the present invention.

FIG. 4 is a scheme for the synthesis of compound 10 of the present invention.

FIG. 5 is a scheme for the synthesis of compound 32 of the present invention.

FIG. 6 is a scheme showing the synthesis of compound 42 of the present invention.

FIG. 7 is a scheme for the synthesis of compound 51 of the present invention.

Detailed Description

Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[ definition of terms ]

Unless otherwise indicated, the following terms have the following meanings.

"pharmaceutically acceptable salt" refers to salts of compounds having the structure of formula I that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or inorganic/organic base, such salts also being referred to as acid addition salts or base addition salts. Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like, common organic acids include, but are not limited to, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, common inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, and the like, and common organic bases include, but are not limited to, diethylamine, triethylamine, ethambutol, and the like.

The term "solvate" refers to a substance formed by the binding of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to at least one solvent molecule by non-covalent intermolecular forces. The term "solvate" includes "hydrate". Common solvates include, but are not limited to, hydrates, ethanolates, acetonates, and the like.

The term "hydrate" refers to a substance formed by the non-covalent intermolecular binding of a compound of the present invention or a pharmaceutically acceptable salt thereof with water. Common hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

The term "isomers" refers to compounds having the same number and type of atoms and thus the same molecular weight, but differing in the spatial arrangement or configuration of the atoms.

The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, and includes both "configurational isomers" and "conformational isomers". The term "configurational isomers" refers to isomers resulting from different spatial arrangements of atoms in a molecule, and includes both "cis-trans isomers" and "optical isomers". The term "cis-trans isomer" refers to isomers in which the atoms (or groups) on both sides of a double bond or ring system are in different positions relative to a reference plane, in the cis isomer the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer the atoms (or groups) are on the opposite side of the double bond or ring system, wherein "double bond" refers generally to a carbon-carbon double bond and also includes a carbon-nitrogen double bond and a nitrogen-nitrogen double bond. The term "optical isomer" refers to a stable isomer having a perpendicular asymmetric plane due to having at least one chiral factor (including a chiral center, a chiral axis, a chiral plane, etc.) so that plane polarized light can be rotated. Because of the presence of asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention and their salts comprise asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, mixtures of enantiomers and diastereomers. Generally, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds may be prepared or isolated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity. gtoreq.98%,. gtoreq.95%,. gtoreq.93%,. gtoreq.90%,. gtoreq.88%,. gtoreq.85% or. gtoreq.80%). As described hereinafter, individual stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. The starting compounds of a particular stereochemistry are either commercially available or may be prepared according to the methods described hereinafter and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "isotopic label" refers to a compound formed by replacing a particular atom in a structure with its isotopic atom. Unless otherwise indicated, compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as²H(D)、³H(T)、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶S and³⁷Cl。

the term "prodrug" refers to a derivatized compound that, upon application to a patient, is capable of providing, directly or indirectly, a compound of the invention. Particularly preferred derivative compounds or prodrugs are those which, when administered to a patient, increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

The term "independently of each other" means that at least two groups (or ring systems) present in the structure in the same or similar range of values may have the same or different meaning in a particular case. For example, X and Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when X is hydrogen, Y is either hydrogen or halogen, hydroxy, cyano, alkyl or aryl; similarly, when Y is hydrogen, X may be hydrogen, or may be halogen, hydroxy, cyano, alkyl or aryl.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) located in main group VII of the periodic Table of the elements.

The term "hypophosphoryl" refers to a monovalent group formed by hypophosphorous acid upon loss of the hydroxyl group and attached to the parent (-P (═ O) H) by a single bond to the phosphorus atom₂). The phosphoryl group can be attached in unsubstituted form to the structural parent nucleus of the compounds of the formula I according to the invention, or the hydrogen atom can be replaced by other substituents. Common substituted phosphoryl groups include, but are not limited to, dialkylphosphoryl (-P (═ P) phosphoryl groupsO)(Alk)₂E.g. dimethylphosphoryl), diarylphosphoryl (- ═ O) (Ar)₂E.g. diphenylphosphinyl), alkylarylphosphinylphosphinyl (-P (═ O) (Alk) (Ar), e.g. methylphenylphosphinyl), dialkoxyphosphinyl (-P (═ O) (OAlk)₂Such as dimethoxyphosphoryl) and the like.

The term "phosphoryl" refers to a monovalent group formed by the loss of a hydroxyl group from a phosphoric acid and attached to the parent (-P (═ O) (OH) by a single bond to the phosphorus atom₂)。

The term "alkyl" refers to a monovalent straight or branched chain alkane group consisting of carbon and hydrogen atoms, containing no unsaturation, and attached to the parent nucleus by a single bond, preferably C₁-C₆Alkyl, more preferably C₁-C₄An alkyl group; common alkyl groups include, but are not limited to, methyl (-CH)₃) Ethyl (-CH)₂CH₃) N-propyl (-CH)₂CH₂CH₃) Isopropyl (-CH (CH)₃)₂) N-butyl (-CH)₂CH₂CH₂CH₃) Sec-butyl (-CH (CH)₃)CH₂CH₃) Isobutyl (-CH)₂CH(CH₃)₂) T-butyl (-C (CH))₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) Neopentyl (-CH)₂C(CH₃)₃) And the like.

The term "alkenyl" refers to a monovalent straight or branched chain alkene group consisting of only carbon and hydrogen atoms, containing at least one double bond, and connected to the parent nucleus by a single bond, preferably C₂-C₆An alkenyl group; common alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) 1-propen-1-yl (-CH ═ CH-CH)₃) 1-buten-1-yl (-CH ═ CH-CH)₂-CH₃) 1-penten-1-yl (-CH ═ CH-CH)₂-CH₂-CH₃)1, 3-butadien-1-yl (-CH ═ CH)₂)1, 4-pentadien-1-yl (-CH ═ CH-CH)₂-CH＝CH₂) And the like.

The term "alkynyl" refers to a radicalA linear or branched alkyne radical of valency, consisting exclusively of carbon and hydrogen atoms, containing at least one triple bond and being linked to the parent nucleus by a single bond, preferably C₂-C₆An alkynyl group; common alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propyn-1-yl (i.e., propynyl) (-C.ident.C-CH)₃) 1-butyn-1-yl (i.e. butynyl)

Pentyn-1-yl

1, 3-diacetylene-1-yl (-C.ident.C-C.ident.CH), 1, 4-pentadiyne-1-yl

And the like.

The term "alkoxy" refers to a monovalent straight or branched chain radical consisting solely of carbon, hydrogen and oxygen atoms, which may contain unsaturation, and which is attached to the parent nucleus by a single bond to the oxygen atom, preferably C₁-C₄An alkoxy group; common alkoxy groups include, but are not limited to, methoxy (-OCH)₃) Ethoxy (-OCH)₂CH₃) N-propoxy group (-OCH)₂CH₂CH₃) I-propoxy (-OCH (CH)₃)₂) N-butoxy (-OCH)₂CH₂CH₂CH₃) Sec-butoxy (-OCH (CH)₃)CH₂CH₃) Isobutoxy (-OCH)₂CH(CH₃)₂) T-butoxy (-OC (CH))₃)₃) N-pentyloxy (-OCH)₂CH₂CH₂CH₂CH₃) Neopentyloxy (-OCH)₂C(CH₃)₃) And the like.

The term "alkanoyl" refers to a monovalent straight or branched chain radical consisting only of carbon, hydrogen and oxygen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the carbonyl group, preferably C₁-C₄An alkyl acyl group; common alkyl acyl packetsIncluding, but not limited to, formyl (-C (═ O) H), acetyl (-C (═ O) CH₃) N-propionyl (-C (═ O) CH₂CH₃) N-butyryl (-C (═ O) CH₂CH₂CH₃) Isobutyryl group (-C (═ O) CH (CH)₃)₂) N-pentanoyl (-C (═ O) CH₂CH₂CH₂CH₃) Pivaloyl (-C (═ O) C (CH)₃)₃) And the like.

The term "alkylamido" refers to a monovalent straight or branched chain radical consisting of only carbon, hydrogen, oxygen and nitrogen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the nitrogen atom, preferably C₁-C₄An alkylamido group; common alkylamido groups include, but are not limited to, formylamino (-NHC (═ O) H), acetamido (-NHC (═ O) CH₃) N-propionylamino (-NHC (═ O) CH₂CH₃) N-butylamido (-NHC (═ O) CH₂CH₂CH₃) Isobutyramido (-NHC (═ O) CH (CH)₃)₂) N-pentanoylamino (-NHC (═ O) CH₂CH₂CH₂CH₃) Pivaloylamino (-NHC (═ O) C (CH)₃)₃) And the like.

The term "alkanoyloxy" refers to a monovalent straight or branched chain radical consisting of only carbon, hydrogen and oxygen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the oxygen atom, preferably C₁-C₄An alkyl acyloxy group; common alkanoyloxy groups include, but are not limited to, formyloxy (-OC (═ O) H), acetyloxy (-OC (═ O) CH₃) N-propionyloxy (-OC (═ O) CH₂CH₃) N-butyryloxy (-OC (═ O) CH₂CH₂CH₃) Isobutyroyloxy (-OC (═ O) CH (CH)₃)₂) N-valeryloxy (-OC (═ O) CH₂CH₂CH₂CH₃) Pivaloyloxy (-OC (═ O) C (CH)₃)₃) And the like.

The term "alkoxycarbonyl" refers to a monovalent straight or branched chain radicalA group consisting of carbon, hydrogen and oxygen atoms only, containing no unsaturation other than the carbonyl group in its structure, and being linked to the parent nucleus by a single bond to the carbonyl group, preferably C₁-C₄An alkoxycarbonyl group; common alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl (-C (═ O) OCH₃) Ethoxycarbonyl (-C (═ O) OCH₂CH₃) N-propoxycarbonyl (-O) OCH₂CH₂CH₃) Iso-propoxycarbonyl (-C (═ O) OCH (CH)₃)₂) N-butoxycarbonyl (-C (═ O) OCH₂CH₂CH₂CH₃) T-butyloxycarbonyl (-C (═ O) OC (CH)₃)₃) And the like.

The term "cycloalkyl" refers to a monovalent monocyclic, non-aromatic ring system consisting only of carbon and hydrogen atoms, containing no unsaturation, and connected to the parent nucleus by a single bond; common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "heterocyclyl" refers to a monovalent monocyclic non-aromatic ring system consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing no unsaturation, and being connected to the parent nucleus by a single bond; common heterocyclyl groups include, but are not limited to, oxiranyl, oxetan-3-yl, azetidin-3-yl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidin-4-yl, and the like.

The term "spirocyclic group" refers to a monovalent non-aromatic ring system in which two single rings share a carbon atom, which consists only of carbon and hydrogen atoms, contains no unsaturation, and is connected to the parent nucleus by a single bond; according to the number of spiro atoms, they can be classified into mono-spiro compounds, di-spiro compounds, tri-spiro compounds, etc.; common spirocyclic groups include, but are not limited to, spiro [2.4] heptan-1-yl, spiro [3.5] nonan-2-yl, spiro [4.5] decan-2-yl, dispiro [5.2.5.2] hexadecan-3-yl, and the like.

The term "heterospirocyclic" refers to a monovalent non-aromatic ring system of two monocyclic rings sharing a single carbon atom, consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing no unsaturation, and being linked to the parent nucleus by a single bond; common heterospirocyclic groups include, but are not limited to, 6-oxaspiro [3.3] heptan-2-yl, 7-methyl-7-azaspiro [3.5] nonan-2-yl, 7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl, 9-methyl-9-phosphaspiro [5.5] undecan-3-yl, and the like.

The term "bridged cyclic group" refers to a monovalent non-aromatic ring system in which any two monocyclic rings share two carbon atoms that are not directly connected, are composed of only carbon and hydrogen atoms, contain no unsaturation, and are connected to the parent nucleus by a single bond; according to the number of constituent rings, they can be classified into bicyclic compounds, tricyclic compounds, tetracyclic compounds, etc.; common bridging groups include, but are not limited to, decahydronaphthalen-1-yl, bicyclo [ 3.2.1%]Octane-1-yl, tricyclo [2.2.1.0^2.6]Heptane-1-yl, 1-adamantyl, and the like.

The term "heterobridged cyclic group" refers to a monovalent non-aromatic ring system in which any two monocyclic rings share two carbon atoms not directly connected, are composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, contain no unsaturation, and are connected to the parent nucleus by a single bond; common heterobridged cyclic groups include, but are not limited to, 1, 4-diazabicyclo [2.2.2] octan-2-yl, 2, 8-diazabicyclo [4.3.0] nonan-8-yl, and the like.

The term "aryl" refers to a monovalent monocyclic or polycyclic (including fused forms) aromatic ring system consisting of only carbon and hydrogen atoms and being linked to the parent nucleus by a single bond; common aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.

The term "arylalkyl" refers to a monovalent straight or branched chain alkyl radical consisting solely of carbon and hydrogen atoms, containing at least one aryl group, and connected to the parent nucleus by a single bond, preferably C₆-C₁₀aryl-C₁-C₆Alkyl, more preferably C₆-C₁₀aryl-C₁-C₄An alkyl group; common arylalkyl groups include, but are not limited to, benzyl, β -phenylethyl, α -phenylethyl, naphthylmethyl, and the like.

The term "arylalkenyl" refers to a monovalent straight or branched chain alkene group consisting of only carbon and hydrogen atoms, containing at least one double bond and at least one aryl group, and being connected to the parent nucleus by a single bond, preferably C₆-C₁₀aryl-C₂-C₆An alkenyl group; common arylalkenyl groups include, but are not limited to, 1-styryl (-CPh ═ CH)₂) 2-styryl (-CH ═ CHPh), 3-phenyl-1-propen-1-yl (-CH ═ CH-CH)₂Ph), 2-phenyl-1-propen-1-yl (-CH ═ CPh-CH)₃) 4-phenyl-1, 3-butadien-1-yl (-CH ═ CHPh), 4-diphenyl-1, 3-butadien-1-yl (-CH ═ CH-CH ═ CPh)₂) And the like.

The term "arylalkynyl" refers to a monovalent straight or branched chain alkyne group consisting of only carbon and hydrogen atoms, containing at least one triple bond and at least one aryl group, and connected to the parent nucleus by a single bond, preferably C₆-C₁₀aryl-C₂-C₆An alkynyl group; common arylalkynyl groups include, but are not limited to, phenylethynyl (-C ≡ CPh), 3-phenyl-1-propyn-1-yl (-C ≡ C-CH)₂Ph), 3-diphenyl-1-propyn-1-yl (-C.ident.C-CHPh)₂) And 4-phenyl-1, 3-diacetylene-1-yl (-C.ident.C-C.ident.CPh).

The term "heteroaryl" refers to a monovalent monocyclic or polycyclic (including fused forms) aromatic ring system composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, and connected to the parent nucleus by a single bond; common heterocyclyl groups include, but are not limited to, benzopyrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, acridinyl, carbazolyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, indazolyl, indolizinyl, indolyl, quinolinyl, isoquinolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, purinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl, tetrazolyl, and the like.

The term "heteroarylalkyl" refers to a monovalent straight or branched chain alkyl radical consisting of carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur and phosphorusContaining at least one heteroaryl group and being linked to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C₁-C₆Alkyl, more preferably 5-10 membered heteroaryl-C₁-C₄An alkyl group; common heteroarylalkyl groups include, but are not limited to, pyrrol-2-ylmethyl, furan-2-ylmethyl, thiophen-2-ylmethyl, 1H-pyrazol-3-ylmethyl, quinolin-4-ylmethyl, and the like.

The term "heteroarylalkenyl" refers to a monovalent straight or branched chain alkene group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one double bond and at least one heteroaryl group, and connected to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C₂-C₆An alkenyl group; common heteroarylalkenyl groups include, but are not limited to, 2- (pyrrol-2-yl) vinyl, 2- (furan-2-yl) vinyl, 2- (thiophen-2-yl) vinyl, 4- (1H-pyrazol-3-yl) -1, 3-butan-1-yl, and the like.

The term "heteroarylalkynyl" refers to a monovalent straight or branched chain alkyne group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one triple bond and at least one heteroaryl group, and connected to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C₂-C₆An alkynyl group; common heteroarylalkynyls include, but are not limited to, (pyrrol-2-yl) ethynyl, (furan-2-yl) ethynyl, (thiophen-2-yl) ethynyl, (1H-pyrazol-3-yl) ethynyl, (1H-pyrazol-4-yl) ethynyl, (1-methyl-1H-pyrazol-4-yl) ethynyl, and the like.

The term "ureido" refers to a monovalent group formed from urea after one hydrogen atom has been lost and which is attached to the parent (-NHC (═ O) NH via a single bond₂). The term "alkylureido" refers to a monovalent group formed by the replacement of a hydrogen atom in an ureido group with an alkyl group (the site of substitution is typically on a nitrogen atom in another amino group) and is attached to the parent nucleus (-NHC (═ O) NHAlk or-NHC (═ O) NAlk by a single bond₂)。

The term "pentafluoro- λ⁶-thioalkyl "(also known as" sulfur pentafluoride ") means a monovalent group consisting of only a sulfur atom and a fluorine atom, and is bonded to the parent nucleus by a single bond(-SF₅)。

[ Compound of the general formula ]

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion thereof, wherein:

X₀is-CH₂-、-C(＝R₂)-、-S(＝R₂)_n-or-P (═ R)₂)(R₀)-；

X₁、X₂、X₃、X₅、X₆、X₇、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄Each independently is CH, CR₇Or N;

X₄and X₈Each independently is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

Or X₄And X₅Form a double bond therebetween, wherein: x₅Is C, X₄Is CH, CR₇Or N;

R₂and R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IA:

wherein:

R₁、R₃、R₄and R₆Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro-ring, heterospiro-ring, bridged ring, heterobridged ring, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroArylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)₇) (ii) a And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃、X₄、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IB:

wherein:

X₁、X₂、X₃、X₄、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IC:

wherein:

X₁、X₂、X₃、X₄、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂Is NH, NR₇NOH, S or O;

R₅NH, NR, NOH or S;

each n is independently 0, 1 or 2.

In some preferred embodiments of the invention, the compound of formula I above is a compound of formula ID:

wherein:

X₁、X₂、X₃、X₄、X₆、X₇、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N; or X₇And R₄May form a 3-6 membered ring;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂Optionally independently NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2;

In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IE:

wherein:

X₀is-CH₂-、-C(＝R₂)-、-S(＝R₂)_n-or-P (═ R)₂)(R₀)-；

X₁、X₂、X₃、X₅、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄Each independently is CH, CR₇Or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂and R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IF:

wherein:

X₁、X₂、X₃、X₅、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₄and X₈Each independently is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the present invention, in the compounds of formula I or formula IA above:

R₁is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, more preferably aryl or heteroaryl;

R₃is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;

R₄is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;

R₆is hydrogen, alkyl, heteroalkyl, alkenyl, alkynylCycloalkyl, heterocyclyl, spirocyclyl, heterospirocyclyl, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR₇Amino, -NHS (═ O) R₇Spiro-, hetero-spiro-, bridged-or heterobridged-ring groups, more preferably amino or-NHS (═ O) R₇；

And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃and X₄Each independently is CH, CR₇Or N, preferably CH or CR₇More preferably CH;

X₆is N;

X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N, preferably X₉、X₁₃、X₁₄Is N, more preferably X₉、X₁₃And X₁₄And is N at the same time;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-, preferably-NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the above compound of formula I or formula IB:

R₀is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, heteroaryl or heteroarylalkyl, and when R is₀When not hydrogen, R₀Hydrogen in (a) is optionally substituted with deuterium or halogen; preferably hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; more preferably hydrogen, alkyl, cycloalkyl or heterocyclyl;

R₃is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclic, arylAlkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;

R₄is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;

R₆is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR₇Amino, -NHS (═ O) R₇Spiro-, hetero-spiro-, bridged-or heterobridged-ring groups, more preferably amino or-NHS (═ O) R₇；

And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃and X₄Each independently is CH, CR₇Or N, preferably CH or CR₇More preferably CH;

X₆is N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-, preferably-NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the compounds of formula I or formula IC above:

R₃is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro, -SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido radicals, preferably hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkylHeterocyclyl, spiro-cyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, substituted or unsubstituted hypophosphoryl, phosphoryl or alkylureido groups, more preferably alkenyl, alkynyl, cycloalkyl, heterocyclic, spiro-cyclic, bridged cyclic, aryl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkenyl, heteroarylalkynyl, phosphoryl or substituted or unsubstituted hypophosphoryl;

R₄is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;

And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃and X₄Each independently is CH, CR₇Or N, preferably CH or CR₇More preferably CH;

X₆is N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-, preferably-NH-or-NR₇-；

R₂Is NH, NR₇NOH, S or O;

R₅is NH, NR₇NOH or S;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:

R₃is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, or- (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Phosphoryl or substituted or unsubstituted phosphoryl hypo;

R₄is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;

R₆is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR₇Amino, -NHS (═ O) R₇Spiro-, hetero-spiro-, bridged-or hetero-bridged ring groups, more preferably hydrogen, alkyl, -NHCOR₇Amino or-NHS (═ O) R₇；

And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃and X₄Each independently is CH, CR₇Or N, preferably CH or CR₇More preferably CH;

X₆is N;

X₇is CH, CR₇Or N; or X₇And R₄May form a 3-6 membered ring;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-, preferably-CH₂-、-CHR₇-, -NH-or-NR₇-；

R₂Is NH, NR₇NOH, S or O;

each R₇Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclic oxygen radicalA group, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano, or hydroxy;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:

R₃is spiro ring group, bridged ring group, hetero spiro ring group, hetero bridged ring group, -SF₅Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is₃The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃、X₄、X₆、X₇、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N; or X₇And R₄May form a 3-6 membered ring;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂Is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:

R₃is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Phosphoryl or substituted or unsubstituted phosphoryl hypo; and when R is₃When not hydrogen, R₃The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

R₁is spiro ring group, hetero spiro ring group, bridged ring group, hetero bridged ring group, aryl or heteroaryl; and R is₁The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

R₄and R₆Each independently is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxy, nitro,-SO₂R₇、-NHSO₂R₇、-OP(＝O)(OR₇)₂Substituted OR unsubstituted hypophosphoryl, phosphoryl, alkylureido OR-OC (═ O) (OR)₇) (ii) a And R is₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃、X₄、X₆、X₇、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N; or X₇And R₄May form a 3-6 membered ring;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂Is NH, NR₇NOH, S or O;

each R₇Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, hetero-spiro, bridged, hetero-bridged, aryl (including substituted aryl, such as phenyl substituted with sulfur pentafluoride, dimethylphosphinyl, or phosphoryl), arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Heterocyclyloxy, alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano or hydroxy;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:

R₃is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Phosphoryl or substituted or unsubstitutedA phosphoryl group of (a); and R is₃The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂、X₃、X₄、X₆、X₇、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N; or X₇And R₄May form a 3-6 membered ring;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-or-C (═ R)₂)-；

R₂Is NH, NR₇NOH, S or O;

each R₇Each independently is deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂A heterocyclyloxy group,Alkylamido, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, cyano, or hydroxy;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the compounds of formula I or formula ID above:

R₃is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, spiro, hetero-spiro, bridged, hetero-bridged, - (CH)₂)_nSF₅、-(CH₂)_nNHSO₂NH₂Phosphoryl or substituted or unsubstituted phosphoryl hypo; and R is₃Optionally substituted by 0 to multiple R₇Substitution;

X₁、X₂、X₃、X₄、X₆、X₉、X₁₀、X₁₁、X₁₂、X₁₃and X₁₄Each independently is CH, CR₇Or N;

X₇is CR₇Or N; or X₇And R₄May form a 3-6 membered ring;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-；

R₂Is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the above compound of formula I or formula IE:

R₄is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;

R₆is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR₇Amino, -NHS (═ O) R₇Spiro-, hetero-spiro-, bridged-or hetero-bridged ring groups, more preferably hydrogen, alkyl, -NHCOR₇Amino or-NHS (═ O) R₇；

And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₀is-CH₂-、-C(＝R₂)-、-S(＝R₂)_n-or-P (═ R)₂)(R₀) -, preferably-C (═ R)₂) -or-S (═ R)₂)_n-；

X₁、X₂And X₃Each independently is CH, CR₇Or N, preferably CH or CR₇More preferably CH;

X₅and X₆Each independently is CH, CR₇Or N, preferably CH or N;

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-, preferably-NH-or-NR₇-；

R₂and R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In some more preferred embodiments of the invention, in the compounds of formula I or formula IF above:

R₁is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, bridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or heterocyclyloxy, preferably hydrogen, alkyl, heteroalkyl, alkenyl, alkynylA group, cycloalkyl, heterocyclyl, spirocyclyl, bridged cyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, more preferably aryl or heteroaryl;

R₄is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkoxy;

R₆is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, -NHCOR₇Amino group, -COR₇、-OCOR₇Alkoxycarbonyl, -NHS (═ O) R₇Halogen, cyano, hydroxyl, nitro or alkylureido, preferably hydrogen, alkyl, alkynyl, cycloalkyl, alkoxy, -NHCOR₇Amino, -NHS (═ O) R₇Spiro-, hetero-spiro-, bridged-or hetero-bridged ring groups, more preferably hydrogen, alkyl, -NHCOR₇Amino or-NHS (═ O) R₇；

And R is₁、R₃、R₄And R₆The hydrogen in (1) may optionally be replaced by 0 to more than one R₇Substitution;

X₁、X₂and X₃Each independently is CH, CR₇Or N, preferably CH or CR₇More preferably CH;

X₅and X₆Each independently is CH, CR₇Or N, preferably CH or N, more preferably N;

X₄is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-, preferably-CH₂-or-CHR₇-；

X₈is-CH₂-、-CHR₇-、-C(R₇)₂-、-C(＝R₂) -, -NH-or-NR₇-, preferably-NH-or-NR₇-；

R₂And R₅Each independently is NH, NR₇NOH, S or O;

each n is independently 0, 1 or 2.

In addition, the invention also provides the compound of the formula I, wherein the specific structure and name are shown in the following table:

[ production method ]

The present invention provides a process for the preparation of a compound of formula I as described above, which comprises:

1) the preparation method of the compound of the formula IA comprises the following steps:

s1: replacement of X in Compound IA-1-1 with R₃(preferably by coupling or substitution) to give compound IA-1-2;

s2: reacting compound IA-1-2 with compound IA-a, preferably by condensation, to give compound IA-1-3;

s3: reaction of compound IA-1-3 with compound IA-b (preferably in the presence of a Grignard reagent and a metalorganic compound, more preferably in the presence of isopropyl magnesium chloride and n-butyl lithium) to provide compound IA-1-4;

s4: reacting compound IA-1-4 with compound IA-c, preferably by condensation, to give a compound of formula IA;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅、R₆And R₇As defined above for compounds of formula IA (preferably X)₄Is CH, X₆Is N, X₈is-NH-); or

The specific steps are as follows:

s1: by replacing X in compound IA-2-1 with R₃(preferably by coupling or substitution) to give compound IA-2-2;

s2: reacting compound 1A-2-2 with compound IA-a (preferably by condensation) to give compound IA-2-3;

s3: reacting compound IA-2-3 with compound IA-d, preferably by condensation, to give compound IA-2-4;

s4: performing ring closing reaction on the compound IA-2-4 under a nitro reduction condition (preferably a zinc powder/acetic acid condition) to obtain a compound IA-2-5;

s5: reacting compound IA-2-5 with compound IA-c, preferably by condensation, to give a compound of formula IA;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅And R₆As defined above for compounds of formula IA (preferably X)₆Is N, X₈is-NH-);

2) the preparation method of the compound shown in the formula IB comprises the following specific steps:

s1: replacement of X in Compound IB-1-1 by R₃(preferably by coupling or substitution) to give compound IB-1-2;

s2: reacting compound IB-1-2 with compound IB-a (preferably by condensation) to give compound IB-1-3;

s3: reacting compound IB-1-3 with compound IB-b (preferably in the presence of a Grignard reagent and a metal organic compound, more preferably in the presence of isopropyl magnesium chloride and n-butyl lithium) to provide compound IB-1-4;

s4: reacting compound IB-1-4 with compound IB-c (preferably by condensation) to give a compound of formula IB;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅、R₆And R₇As defined above for compounds of formula IB (preferably X)₄Is CH, X₆Is N, X₈is-NH-); or

The specific steps are as follows:

s1: replacement of X in Compound IB-2-1 with R₃(preferably by coupling or substitution) to give compound IB-2-2;

s2: reacting compound 1B-2-2 with compound IB-a (preferably by condensation) to give compound IB-2-3;

s3: compound IB-2-3 is reacted (preferably by condensation) with compound IB-d to provide compound IB-2-4;

s4: performing ring closing reaction on the compound IB-2-4 under a nitro reduction condition (preferably a zinc powder/acetic acid condition) to obtain a compound IB-2-5;

s5: compound IB-2-5 is reacted (preferably by condensation) with compound IB-c to provide a compound of formula IB;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₂、R₃、R₄、R₅And R₆As defined above for compounds of formula IB (preferably X)₆Is N, X₈is-NH-);

3) the preparation method of the compound of the formula IC comprises the following specific steps:

s1: replacement of X in Compound IC-1-1 by R₃(preferably by coupling or substitution) to give compound IC-1-2;

s2: reacting compound IC-1-2 with compound IC-a (preferably by condensation) to give compound IC-1-3;

s3: reacting compound IC-1-3 with compound IC-b (preferably in the presence of a Grignard reagent and an organolithium compound, more preferably in the presence of isopropyl magnesium chloride and n-butyllithium) to give compound IC-1-4;

s4: reacting compound IC-1-4 with compound IC-c, preferably by condensation, to give a compound of formula IC;

wherein: x is chlorine, bromine or iodine; x₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅、R₆And R₇As defined above for compounds of formula IC (preferably X)₆Is N, X₈is-NH-); or

The specific steps are as follows:

s1: replacement of X in Compound IC-2-1 by R₃(preferably by coupling or substitution) to give compound IC-2-2;

s2: compound 1C-2-2 is reacted (preferably by condensation) with compound IC-a to give compound IC-2-3;

s3: reacting compound IC-2-3 with compound IC-d, preferably by condensation, to give compound IC-2-4;

s4: performing ring closing reaction on the compound IC-2-4 under the nitro reduction condition (preferably zinc powder/acetic acid condition) to obtain a compound IC-2-5;

s5: reacting compound IC-2-5 with compound IC-c, preferably by condensation, to give a compound of formula IC;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆As defined above for compounds of formula IC (preferably X)₆Is N, X₈is-NH-);

4) the preparation method of the compound shown in the formula ID comprises the following specific steps:

s1: replacement of X in Compound ID-1-1 by R₃(preferably by coupling or substitution) to give compound ID-1-2;

s2: under the action of a compound ID-a (preferably sodium methoxide/methanol), carrying out a ring closing reaction on the compound ID-1-2 to obtain a compound ID-1-3;

s3: introduction of R into Compound ID-1-3₁(preferably by substitution) to give compound ID-1-4;

s4: reaction of compound ID-1-4 with compound ID-b (preferably by a substitution reaction) gives compound ID-1-5;

s5: reaction of compound ID-1-5 with compound ID-c (preferably by condensation) gives compound ID-1-6;

s6: reaction of compound ID-1-6 with compound ID-d (preferably by a substitution reaction) to give compound ID;

wherein: x is chlorine, bromine or iodine; x₁、X₂、X₃、X₄、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₆And R₇As defined above for compounds of formula ID (preferably X)₄Is CH); or

The specific steps are as follows:

s1: replacement of X in Compound ID-2-1 by R₃(preferably by coupling or substitution) to give compound ID-2-2;

s2: compound ID-2-2 is reacted (preferably by condensation) with compound ID-e to give compound ID-2-3;

s3: reacting compound ID-2-3 with compound ID-f (preferably in the presence of a Grignard reagent and an organolithium compound, more preferably in the presence of isopropyl magnesium chloride and n-butyllithium) to give compound ID-2-4;

s4: reacting the compound ID-2-4 with a Lawson reagent and a compound ID-g to obtain a compound ID-2-5;

s5: compound ID-2-5 is reacted with compound ID-c (preferably in the presence of a Grignard reagent and an organolithium compound, more preferably in the presence of isopropyl magnesium chloride and n-butyllithium) to give a compound of formula ID;

wherein: x is chlorine, bromine or iodine; r is H, OH or R₇；X₄Is CH or CR₇；X₁、X₂、X₃、X₆、X₈、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₆And R₇As defined above for compounds of formula ID (preferably X)₆Is N, X₈is-NH-);

5) the preparation method of the compound with the structure of the formula IE comprises the following specific steps:

s1: the compound IE-1-1 reacts with the compound IE-a to obtain a compound IE-1-2;

s2: reaction of compound IE-1-2 with compound IE-b, preferably by a substitution reaction, to give compound IE-1-3;

s3: reaction of compound IE-1-3 with compound IE-c (preferably by chlorination) to give compound IE-1-4;

s4: carrying out ammonolysis reaction on the compound IE-1-4 to obtain a compound IE-1-5;

s5: replacement of X in Compound IE-1-5 by R₃(preferably by coupling or substitution) to give compound IE-1-6;

s6: reacting (preferably by condensation) compound IE-1-6 with compound IE-d to give compound IE;

wherein: x is chlorine, bromine or iodine; r is alkyl; x₁、X₂、X₃、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆As defined above for the compound of formula IE;

6) the preparation method of the compound with the structure of the formula IF comprises the following specific steps:

s1: reacting compound IF-1-1 with compound IF-a (preferably in the presence of a catalyst, more preferably in the presence of polymethoxysilane/tin (II) trifluoromethanesulfonate/oxygen) to give compound IF-1-2;

s2: reacting compound IF-1-2 with compound IF-b (preferably by substitution) to give compound IF-1-3;

s3: reaction of compound IF-1-3 with compound IF-c (preferably by chlorination) affords compound IF-1-4;

s4: replacement of X in Compound IF-1-4 by R₃(preferably by coupling or substitution) to give compound IF-1-5;

s5: carrying out ammonolysis reaction on the compound IF-1-5 to obtain a compound IF-1-6;

s6: reacting compound IF-1-6 with compound IF-d (preferably by condensation) to give compound IF;

wherein: x is chlorine, bromine or iodine; r is alkyl; x₁、X₂、X₃、X₉、X₁₀、X₁₁、X₁₂、X₁₃And X₁₄And R₁、R₃、R₄、R₅And R₆As defined above for compounds of formula IF.

In some embodiments of the present invention, the Coupling Reaction in the above preparation method includes, but is not limited to, Suzuki Reaction (Suzuki Reaction), Heck Reaction (Heck Reaction), stele Reaction (Stille Reaction), germ Coupling Reaction (Sogonoshira Coupling), panda Coupling Reaction (Kumada Coupling), root-shore Coupling (Negishi Coupling), juniper Coupling (Hiyama Coupling), and the like. It will be appreciated that the experimental conditions for the above-described coupling reaction are well known to those skilled in the art.

When the compound of the formula I has a specific configuration, the invention also provides a corresponding preparation method so as to obtain the compound with the specific configuration. These compounds having a specific configuration and the process for their preparation are likewise part of the present invention.

[ pharmaceutical composition ]

The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and not deleterious to the subject, including, but not limited to, diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, preservatives, antioxidants, pH adjusters, solvents, co-solvents, surfactants, and the like.

The present invention provides a pharmaceutical composition comprising a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion.

In some embodiments of the present invention, the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[ medical use ]

Whether a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or mixture thereof, in any proportion, or a pharmaceutical composition as described above, is useful as an inhibitor of PI 3K. Accordingly, the present invention provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above, as an inhibitor of PI 3K.

In addition, the present application also provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any proportion, or a pharmaceutical composition as described above, for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by PI 3K.

The term "a disease mediated at least in part by PI 3K" refers to a disease that involves at least a portion of the factors associated with PI3K in its pathogenesis, including, but not limited to, cancer (e.g., cervical cancer), neurodegenerative disease (e.g., alzheimer's disease), viral infection (e.g., AIDS), bacterial infection (e.g., streptococcal infection), ocular disease (e.g., cataract), autoimmune disease (e.g., rheumatoid arthritis), depression, anxiety, and psychological disorders.

[ method of treatment ]

The present invention provides a method for the prevention and/or treatment of a disease mediated at least in part by PI3K, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above.

The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., a patient).

The term "administering" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the invention) to a patient or a cell, tissue, organ, biological fluid, etc. site thereof, such that the pharmaceutically active ingredient or pharmaceutical composition contacts the patient or the cell, tissue, organ, biological fluid, etc. site thereof. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.

The term "in need thereof refers to a judgment by a physician or other caregiver that a patient needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors of the physician or other caregiver in their area of expertise.

The term "patient" (or subject) refers to a human or non-human animal (e.g., a mammal).

[ combination drug ]

The present invention provides a pharmaceutical combination comprising a compound of formula I as described above or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent.

The term "cancer" refers to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth at an ectopic site. Common cancers include, but are not limited to, brain, liver, gall bladder, bronchial, lung, bladder, ovarian, cervical, testicular, lip, tongue, hypopharynx, larynx, esophageal, stomach, intestinal (e.g., colon, rectum), thyroid, salivary gland, pancreatic, breast, prostate, blood (or leukemia), lymph (or lymphoma), bone, and skin cancers.

The term "cancer therapeutic agent" refers to a pharmaceutical composition or pharmaceutical formulation that is effective in controlling and/or combating cancer. Common cancer therapeutic agents include, but are not limited to, anti-puring agents (e.g., pentostatin, etc.), anti-pyrimidinium agents (e.g., fluorouracil), antifolate agents (e.g., methotrexate), DNA polymerase inhibitors (e.g., cytarabine), alkylating agents (e.g., cyclophosphamide), platinum-based complexes (e.g., cisplatin), DNA-destroying antibiotics (e.g., mitomycin), topoisomerase inhibitors (e.g., camptothecin), intercalating DNA interfering nucleic acid synthesizers (e.g., epirubicin), anti-feed drugs (e.g., asparaginase), interfering tubulin forming agents (e.g., paclitaxel), interfering ribosome function agents (e.g., cephalotaxine), cytokines (e.g., IL-1), thymopeptides, tumor cell proliferation viruses (e.g., adenovirus ONYX-015), and the like.

In addition, the present invention provides a method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic.

The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. If the experimental procedures in the following examples do not specify particular conditions, conventional conditions or conditions recommended by the manufacturer are generally followed. Unless otherwise indicated, percentages and parts appearing in the following examples are by weight.

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Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof

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