阅读说明：本技术 双杂环取代的吡啶-2(1h)-酮衍生物、其制法与医药上的用途 (Biheterocyclic substituted pyridine-2 (1H) -ketone derivative, preparation method and medical application thereof ) 是由 胡斌 朱经峰 方志华 杨斐 林崇懒 华默嘉 刘洋 关慧平 于 2019-11-11 设计创作，主要内容包括：提供双杂环取代的吡啶-2(1H)-酮衍生物、其制法与医药上的用途。具体地,提供式(Ⅱ)化合物或其药学上可接受的盐、立体异构体或溶剂化物,及其制备方法和应用。<Image he="370" wi="700" file="DDA0002643286580000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Provides a bi-heterocyclic substituted pyridine-2 (1H) -ketone derivative, a preparation method and a medical application thereof. Specifically, provided are compounds of formula (II) or pharmaceutically acceptable salts, stereoisomers or solvates thereof, and methods of preparation and use thereof.)

A compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

in the formula (I), the compound is shown in the specification,

R₃is-L₁-R_c；L₁Is a bond, C (O) or (CR)₃₁R₃₂)_q；R_cIs hydrogen, phenyl, C_3-8Cycloalkyl (preferably C)_3-6Cycloalkyl), C_1-8Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy), -NR₁₁R₁₂、-CONR₂₁R₂₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl), -SO₂NR₁₁R₁₂、-CONR₁₃SO₂R₀、-SO₂NR₁₃COC_1-10Alkyl (preferably-SO)₂NR₁₃COC_1-6Alkyl, more preferably-SO₂NR₁₃COC_1-3Alkyl), -NR-₁₁(CH₂)_pNHR₁₄、-NR₁₁(CH₂)_pCONR₁₅R₁₆、-NR₁₁(CH₂)_pCR₁₅R₁₆(ii) a Said phenyl group, C_3-8Cycloalkyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy group), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂、-COC_1-10Alkyl (preferably-COC)_1-6Alkyl, more preferably-COC_1-3Alkyl), -CONR₁₁R₁₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂NR₁₁R₁₂or-SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl groups);

R₄is hydrogen or C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl groups);

or R₃、R₄Taken together with the attached carbon atom to form a 3-to 6-membered saturated monocyclic heterocycle or a 3-to 6-membered saturated monocyclic ring; the 3-to 6-membered saturated monocyclic ring or the 3-to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of: halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy group), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl groups);

R₀₁、R₀₂、R₀₃each is independentThe site is hydrogen, halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy), optionally substituted C_1-10Alkyl (preferably optionally substituted C)_1-6Alkyl, more preferably optionally substituted C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl) or halo C_1-10Alkoxy (preferably halo C)_1-6Alkoxy, more preferably halo C_1-3Alkoxy) and R₀₁、R₀₂、R₀₃At least one of which is not hydrogen; said optionally substituted means unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: c_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy), -NR₁₁R₁₂、-CONR₂₁R₂₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl), -SO₂NR₁₁R₁₂；

wherein Z₁Is NR₅S or CR₅R₆；

Z₂Is N or CR₆；

Z₃Is a bond, C (O), C (R)₇R₈) Or S (O)₂；

Z₄Is N or CR₆；

Z₅Is CR₉；

Z₆Is N or CR₆；

Z₇Is NR₅S or CR₅R₆；

Z₈Is a bond, C (O), C (R)₇R₈) Or S (O)₂；

Ring B is a 4-to 6-membered saturated or unsaturated monocyclic ring, a 5-to 6-membered monocyclic heteroaryl ring or a benzene ring;

ring C taken together with the fused heterocycle forms a 9-to 10-membered bicyclic heteroaryl ring;

ring D is a 4-to 6-membered saturated or unsaturated monocyclic ring, a 5-to 6-membered monocyclic heteroaryl ring, or a benzene ring;

R₅、R₆、R₇、R₈、R₉each independently hydrogen, halogen (preferably F or Cl), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl group), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂、-COC_1-10Alkyl (preferably-COC)_1-6Alkyl, more preferably-COC_1-3Alkyl), -CONR₁₁R₁₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂NR₁₁R₁₂or-SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl groups);

R₃₁、R₃₂each independently hydrogen, halogen (preferably F or Cl), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl group), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂、-NR₁₃COC_1-10Alkyl (preferably-NR)₁₃COC_1-6Alkyl, more preferably-NR₁₃COC_1-3Alkyl), -NR-₁₃SO₂R₀；

R_bIs halogen (preferably F or Cl), CN, carboxyl, -NR₁₁R₁₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl), -SO₂NR₁₁R₁₂、-P(O)(OC_1-10Alkyl radical)₂(preferably-P (O) (OC)_1-6Alkyl radical)₂More preferably-P (O) (OC)_1-3Alkyl radical)₂)、-P(O)(OH)₂、-CONR₁₁R₁₂、-CONR₁₃SO₂R₀、-SO₂NR₁₃COC_1-10Alkyl (preferably-SO)₂NR₁₃COC_1-6Alkyl, more preferably-SO₂NR₁₃COC_1-3Alkyl), -NR-₁₁(CH₂)_pNHR₁₄、-NR₁₁(CH₂)_pCONR₁₅R₁₆、-NR₁₁(CH₂)_pCR₁₅R₁₆Halogen substituted C_1-10Alkyl-substituted hydroxymethyl or halogeno C_1-10An alkyl-substituted hydroxyethyl group; r₀Is C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), -NR-₁₁R₁₂、C_3-8Cycloalkyl (preferably C)_3-6Cycloalkyl groups);

R₁₄is-SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl), -COC_1-10Alkyl radical(preferably-COC)_1-6Alkyl, more preferably-COC_1-3Alkyl groups);

R₁₅、R₁₆each independently is hydrogen or C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl groups); or R₁₅、R₁₆Form a 5-to 6-membered saturated monocyclic heterocyclic ring with the attached nitrogen or carbon atom; the 5-to 6-membered saturated mono-heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of: halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy group), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂；

R₂₁、R₂₂Each independently is hydrogen or R₂₁、R₂₂And the attached nitrogen atoms together form a 5-to 6-membered saturated monocyclic heterocycle; said 5-to 6-membered saturated mono-heterocyclic ring being unsubstituted or substituted by 1-3-NR₁₁R₁₂Or C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl) substituted;

R₁₁、R₁₂、R₁₃each independently is hydrogen, C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl) or halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl groups);

p is 0, 1,2 or 3;

q is 1,2 or 3;

m is 0, 1,2,3 or 4;

R_ais halogen (preferably F or Cl), CN, C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl) or halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl groups);

n is 0, 1,2,3 or 4.

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R is₀₁、R₀₃Is hydrogen; r₀₂Is halogen (preferably F or Cl) or C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy, most preferably methoxy).

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein in formula (a), Z is₁Is NR₅S or CR₅R₆；Z₂Is N or CR₆；Z₃Is a bond;is a single bond or a double bond; ring B is a 4-to 6-membered saturated or unsaturated monocyclic ring, a 5-to 6-membered monocyclic heteroaryl ring or a benzene ring.

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein in formula (a), Z is₁Is NR₅；Z₂Is N or CR₆；Z₃Is C (O), C (R)₇R₈) Or S (O)₂；

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein in formula (B), Z is₄Is N or CR₆；Z₅Is CR₉(ii) a C ring and said heterocyclic ring together form 9-to 10-membered bicyclic heteroarylAnd (4) a ring.

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein in formula (C), Z is₆Is N or CR₆；Z₇Is NR₅S or CR₅R₆；Z₈Is a bond;

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein in formula (C), Z is₆Is N or CR₆；Z₇Is NR₅；Z₈Is C (O), C (R)₇R₈) Or S (O)₂；

A compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

in the formula (I), the compound is shown in the specification,

R₃is-L₁-R_c；L₁Is a bond, C (O) or (CR)₃₁R₃₂)_q；R_cIs hydrogen, phenyl, C_3-8Cycloalkyl (preferably C)_3-6Cycloalkyl), C_1-8Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy), -NR₁₁R₁₂、-CONR₂₁R₂₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl), -SO₂NR₁₁R₁₂、-CONR₁₃SO₂R₀、-SO₂NR₁₃COC_1-10Alkyl (preferably-SO)₂NR₁₃COC_1-6Alkyl, more preferably-SO₂NR₁₃COC_1-3Alkyl), -NR-₁₁(CH₂)_pNHR₁₄、-NR₁₁(CH₂)_pCONR₁₅R₁₆、-NR₁₁(CH₂)_pCR₁₅R₁₆(ii) a Said phenyl group, C_3-8Cycloalkyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy group), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂、-COC_1-10Alkyl (preferably-COC)_1-6Alkyl, more preferably-COC_1-3Alkyl), -CONR₁₁R₁₂、 -C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂NR₁₁R₁₂or-SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl groups);

R₄is hydrogen or C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl groups);

or R₃、R₄With the carbon atom bound theretoTogether form a 3-to 6-membered saturated monocyclic heterocycle or 3-to 6-membered saturated monocyclic ring; the 3-to 6-membered saturated monocyclic ring or the 3-to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of: halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy group), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl groups);

R₀₁、R₀₃is hydrogen; r₀₂Is halogen (preferably F or Cl) or C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy, most preferably methoxy);

is a structure shown in formula (A) or formula (C):

wherein Z₁Is NR₅S or CR₅R₆；

Z₂Is N or CR₆；

Z₃Is a bond;

Z₆is N or CR₆；

Z₇Is NR₅S or CR₅R₆；

Z₈Is a bond;

ring B is a 4-to 6-membered saturated or unsaturated monocyclic ring, a 5-to 6-membered monocyclic heteroaryl ring or a benzene ring;

ring D is a 4-to 6-membered saturated or unsaturated monocyclic ring, a 5-to 6-membered monocyclic heteroaryl ring, or a benzene ring;

is a single bond or a double bond;

R₅、R₆each independently hydrogen, halogen (preferably F or Cl), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl group), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂、-COC_1-10Alkyl (preferably-COC)_1-6Alkyl, more preferably-COC_1-3Alkyl), -CONR₁₁R₁₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂NR₁₁R₁₂or-SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl groups);

R₃₁、R₃₂each independently hydrogen, halogen (preferably F or Cl), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl group), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂、-NR₁₃COC_1-10Alkyl (preferably-NR)₁₃COC_1-6Alkyl, more preferably-NR₁₃COC_1-3Alkyl), -NR-₁₃SO₂R₀；

R_bIs halogen (preferably F or Cl), CN, carboxyl, -NR₁₁R₁₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl), -SO₂NR₁₁R₁₂、-P(O)(OC_1-10Alkyl radical)₂(preferably-P (O) (OC)_1-6Alkyl radical)₂More preferably-P (O) (OC)_1-3Alkyl radical)₂)、-P(O)(OH)₂、-CONR₁₁R₁₂、-CONR₁₃SO₂R₀、-SO₂NR₁₃COC_1-10Alkyl (preferably-SO)₂NR₁₃COC_1-6Alkyl, more preferably-SO₂NR₁₃COC_1-3Alkyl), -NR-₁₁(CH₂)_pNHR₁₄、-NR₁₁(CH₂)_pCONR₁₅R₁₆、-NR₁₁(CH₂)_pCR₁₅R₁₆Halogen substituted C_1-10Alkyl-substituted hydroxymethyl or halogeno C_1-10An alkyl-substituted hydroxyethyl group; r₀Is C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), -NR-₁₁R₁₂、 C_3-8Cycloalkyl (preferably C)_3-6Cycloalkyl groups);

R₁₄is-SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl), -COC_1-10Alkyl (preferably-COC)_1-6Alkyl, more preferably-COC_1-3Alkyl groups);

R₁₅、R₁₆each independently is hydrogen or C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl groups); or R₁₅、R₁₆Form a 5-to 6-membered saturated monocyclic heterocyclic ring with the attached nitrogen or carbon atom; the 5-to 6-membered saturated mono-heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of: halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy group), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂；

R₂₁、R₂₂Each independently is hydrogen or R₂₁、R₂₂And the attached nitrogen atoms together form a 5-to 6-membered saturated monocyclic heterocycle; said 5-to 6-membered saturated mono-heterocyclic ring being unsubstituted or substituted by 1-3-NR₁₁R₁₂Or C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl) substituted;

R₁₁、R₁₂、R₁₃each independently is hydrogen, C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl) or halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl groups);

p is 0, 1,2 or 3;

q is 1,2 or 3;

m is 0, 1,2,3 or 4;

R_ais halogen (preferably F or Cl), CN, C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl) or halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl groups);

n is 0, 1,2,3 or 4.

The compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R is_bIs halogen, CN, carboxyl, NH₂、-C(O)OC_1-3Alkyl, -SO₂C_1-3Alkyl, -SO₂NH₂、-P(O)(OC_1-3Alkyl radical)₂、-P(O)(OH)₂、-CONH₂、-CONHSO₂C_1-3Alkyl, -CONHSO₂NH₂、-CONHSO₂N(CH₃)₂、-CONHSO₂C_3-6Cycloalkyl, -SO₂NHCOC_1-10Alkyl, -C (CF)₃)₂OH、-NHCH₂CONH₂、-NH(CH₂)₂CONH₂、-NH(CH₂)₃CONH₂、-NH(CH₂)₃NHSO₂C_1-3Alkyl, -NH (CH)₂)₂NHSO₂C_1-3Alkyl, -NHCH₂NHSO₂C_1-3Alkyl, -NHCH₂NHCOC_1-3Alkyl, -NH (CH)₂)₂NHCOC_1-3Alkyl, -NH (CH)₂)₃NHCOC_1-3Alkyl, -NHCHR₁₅R₁₆or-NHCONR₁₅R₁₆；R₁₅、R₁₆Form a 5-to 6-membered saturated mono-heterocyclic ring with the nitrogen atom to which it is attached; the 5-to 6-membered saturated mono-heterocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of: halogen, C_1-3Alkoxy radical, C_1-3Alkyl, halo C_1-3Alkyl, NH₂Or N (CH)₃)₂。

The compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein m is 0, 1, or 2.

The compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein formula (a) or formula (C) is selected from the group consisting of:

the compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein formula (a) or formula (C) is selected from the group consisting of:

the compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein formula (a) or formula (C) is selected from the group consisting of:

the compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein formula (a) or formula (C) is selected from the group consisting of:

the compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein formula (a) or formula (C) is selected from the group consisting of:

the compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein formula (B) is selected from the following group of structures:

the compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein formula (B) is selected from the following group of structures:

the compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R is₃is-CH₂-L₁；L₁Is phenyl; said phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy group), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl), -NR-₁₁R₁₂、-COC_1-10Alkyl (preferably-COC)_1-6Alkyl, more preferably-COC_1-3Alkyl), -CONR₁₁R₁₂、-C(O)OC_1-10Alkyl (preferably-C (O) OC_1-6Alkyl, more preferably-C (O) OC_1-3Alkyl), -SO₂NR₁₁R₁₂or-SO₂C_1-10Alkyl (preferably-SO)₂C_1-6Alkyl, more preferably-SO₂C_1-3Alkyl groups); r₄Is hydrogen.

The compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein R is₃、R₄Taken together with the attached carbon atom to form a 3-to 6-membered saturated monocyclic heterocycle or a 3-to 6-membered saturated monocyclic ring; the 3-to 6-membered saturated monocyclic ring or the 3-to 6-membered saturated monocyclic ring is unsubstituted or selected by 1-3Substituent of group (b): halogen (preferably F or Cl), C_1-10Alkoxy (preferably C)_1-6Alkoxy, more preferably C_1-3Alkoxy group), C_1-10Alkyl (preferably C)_1-6Alkyl, more preferably C_1-3Alkyl), halo C_1-10Alkyl (preferably halogenated C)_1-6Alkyl, more preferably halogenated C_1-3Alkyl groups).

The compound of claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein n is 1.

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, selected from table a, table B, table C, or table D.

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, selected from table B, table C, or table D.

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, selected from table B or table C.

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, selected from the structures:

a pharmaceutical composition comprising a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; and a pharmaceutically acceptable carrier.

Use of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a pharmaceutical composition according to claim 25, in the manufacture of an inhibitor of XIa.

Use of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a pharmaceutical composition according to claim 25, in the manufacture of a medicament for inhibiting factor XIa.

Use of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a pharmaceutical composition according to claim 25, for the manufacture of a medicament for the prevention and/or treatment of a factor XIa-mediated disease.

Use of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a pharmaceutical composition according to claim 25, for the manufacture of a medicament for the prevention and/or treatment of cardiovascular and cerebrovascular diseases.

Use according to claim 29, wherein the cardiovascular and cerebrovascular disease is preferably a thromboembolic disease, more preferably myocardial infarction, angina pectoris, reocclusion and restenosis following angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

A method for preventing and/or treating a factor XIa-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a pharmaceutical composition of claim 25.

A method for the prevention and/or treatment of cardiovascular and cerebrovascular diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and optionally another therapeutically active agent.

The method according to claim 32, wherein the cardiovascular disease, preferably a thromboembolic disease, more preferably myocardial infarction, angina, reocclusion and restenosis following angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.

A compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

in the formula (I), the compound is shown in the specification,

R₃is-L₁-R_c；L₁Is a bond, C (O) or (CR)₃₁R₃₂)_q；R_cIs a 5 to 6 membered monocyclic heteroaryl ring or a 3 to 6 membered saturated monocyclic heterocycle; the 5-to 6-membered monocyclic heteroaryl ring, the 3-to 6-membered saturated monocyclic heterocycle are unsubstituted or substituted with 1-3 substituents selected from the group consisting of: halogen, C_1-10Alkoxy radical, C_1-10Alkyl, halo C_1-10Alkyl, -NR₁₁R₁₂、-COC_1-10Alkyl, -CONR₁₁R₁₂、-C(O)OC_1-10Alkyl, -SO₂NR₁₁R₁₂or-SO₂C_1-10An alkyl group;

the other groups are as defined in claim 8.

The compound of claim 34, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, selected from table E.