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CN-121991060-A - Phenylpropionic acid compound, preparation method, intermediate and application thereof

CN121991060ACN 121991060 ACN121991060 ACN 121991060ACN-121991060-A

Abstract

The invention discloses a phenylpropionic acid compound, and a preparation method, an intermediate and application thereof. The invention provides a compound shown as a formula I, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a solvate of the pharmaceutically acceptable salt. The phenylpropionic acid compound provided by the invention has a good inhibition effect on alpha 4 beta 7 cells.

Inventors

  • DUAN SHUDONG
  • WU XUNIAN
  • LI CONG
  • QIN JIHONG

Assignees

  • 上海汇伦医药股份有限公司

Dates

Publication Date
20260508
Application Date
20251031
Priority Date
20241101

Claims (11)

  1. 1. A compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof, Wherein the carbon atom represented by "+" means that when it is a chiral carbon atom, the carbon atom is in the R configuration, S configuration, or mixtures thereof; The carbon atom represented by "#" means that when it is a chiral carbon atom, the carbon atom is in the R configuration, S configuration, or a mixture thereof; L 1 is a bond or-NR a -C (O) -, wherein the carbonyl group is attached to ring A; R a is hydrogen or C 1-6 alkyl; ring A is a 6 membered heterocyclyl, 7-12 membered heterocyclyl or 5-12 membered heteroaryl; The types of the hetero atom groups in the 5-6 membered heteroaryl and the 5-6 membered heterocyclic groups are independently selected from one, two or three of N, O or S, and the number of the hetero atom groups is independently 1, 2 or 3; R 1 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl independently being optionally substituted with one or more R 1-1 ; Or R 1 、R a together with the atoms to which it is attached form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl optionally being substituted with one or more R 1-1 ; R 1-1 is each independently halogen, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl being independently optionally substituted by one or more R 1-1a ; R 1-1a is each independently halogen, C 1-6 alkyl, -O-C 1-6 alkyl or halogenated C 1-6 alkyl; R 2 is hydrogen, C 1-6 alkyl, -O-C 1-6 alkyl or-NR a1 R a2 , said C 1-6 alkyl and-O-C 1-6 alkyl independently optionally substituted with one or more R 2-1 ; Each R 2-1 is independently-NR a1 R a2 ; R a1 and R a2 are independently hydrogen or C 1-6 alkyl, or R a1 、R a2 together with the N atom to which they are attached are linked to form a 3-6 membered heterocyclyl, said 3-6 membered heterocyclyl optionally being substituted with one or more R a1-1 ; R a1-1 is each independently halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl or-O-C 1-6 alkyl; R 3 and R 4 are hydrogen, halogen, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl independently being optionally substituted with one or more R 3-1 ; R 3-1 is independently halogen, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl being independently optionally substituted with one or more R 3-1a , R 3-1a is independently halogen; R 5 is each independently halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl or-O-halo C 1-6 alkyl; R 6 is each independently halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, -O-C 1-6 alkyl or-O-halo C 1-6 alkyl; x and t are each independently 0 or 1, y is 0,1, 2 or 3;z is 1, 2, 3 or 4; The types of the hetero atom groups in the 6-membered heterocyclic group, the 3-6-membered heterocyclic group, the 5-10-membered heterocyclic group and the 7-12-membered heterocyclic group are independently selected from one, two, three or four of N, O, S or C (O), and the number of the hetero atom groups is independently 1, 2, 3, 4 or 5; The types of the hetero atom groups in the 5-12 membered heteroaryl are one, two or three of N, O or S, and the number of the hetero atom groups is 1,2, 3, 4 or 5; And the compound shown as the formula I meets any one of the following conditions: in condition (1), ring A is L 1 is a bond, R 1 is C 1-6 alkyl, said C 1-6 alkyl being substituted by one or more R 1-1 , R 1 -1 are each independently C 3-6 cycloalkyl, said C 3-6 cycloalkyl being substituted by one or more R 1-1a , R 1-1a are each independently halogen, C 1-6 alkyl, -O-C 1-6 alkyl or halogenated C 1-6 alkyl; and (2) the condition that the ring A is 6-membered heterocyclic group, 7-12-membered heterocyclic group or 5-12-membered heteroaryl, the type of the hetero atom group of the 6-membered heterocyclic group is one, three or four of N, O, S or C (O), and the number of the hetero atom groups is independently 1, 3 or 4.
  2. 2. A compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in claim 1 which meets one or more of the following conditions: (1) C 1-6 alkyl of the C 1-6 alkyl, -O-C 1-6 alkyl, C 1-6 alkyl of the halogenated C 1-6 alkyl and C 1-6 alkyl of the-O-halogenated C 1-6 alkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (2) In ring A, the 6-membered heterocyclic group is a partially saturated 6-membered heterocyclic group, the kinds of hetero atom groups in the partially saturated 6-membered heterocyclic group are selected from two of N and C (O), the number of the hetero atom groups is independently 2, 3 or 4, for example 2 or 4, and for example the 6-membered heterocyclic group is (3) In ring A, the 7-12 membered heterocyclyl is a partially saturated 7-12 membered heterocyclyl, which 7-12 membered heterocyclyl may be bicyclic or tricyclic, for example, a 5-6 membered cycloalkyl-partially saturated 5-8 membered heterocyclyl, a 5-6 membered heterocycloalkyl-partially saturated 5-8 membered heterocyclyl, a 5-6 membered heteroaryl-partially saturated 5-8 membered heterocyclyl or a phenyl-partially saturated 5-8 membered heterocyclyl, a further example, a cyclopentyl-partially saturated 6-membered heterocyclyl, a cyclohexyl-partially saturated 6-membered heterocyclyl, a 5-6 membered heterocycloalkyl-partially saturated 6-membered heterocyclyl, a partially saturated 5-6-membered heterocyclyl, a 6-membered heteroaryl-partially saturated 7-membered heterocyclyl, a phenyl-partially saturated 5-membered heterocyclyl or a phenyl-partially saturated 7-membered heterocyclyl; The 5-6 membered cycloalkyl group may be cyclopentyl or cyclohexyl, for example The hetero atom groups in the 5-6 membered heterocycloalkyl group may be independently selected from one or both of N and O, and the number of hetero atom groups is independently 1 or 2, such as an azacyclopentyl group or an azacyclohexyl group, and further such as The type of heteroatom group in the partially saturated 5-6 membered heterocyclic group may be independently selected from one, two or three of N, O and S, the number of heteroatom groups is independently 1,2 or 3, for example, the partially saturated 5-6 membered heterocyclic group is The types of the hetero atom groups in the partially saturated 5-8 membered heterocyclic group can be independently selected from one, two or three of N, O and C (O), the number of the hetero atom groups is independently 1, 2,3 or 4, the partially saturated 5-8 membered heterocyclic group can be a single ring or a double ring, and the double ring can be a spiro ring, for example, the partially saturated 5-8 membered heterocyclic group The hetero atom groups in the 5-6 membered heteroaryl group may be independently selected from one or both of N, O and S, the number of hetero atom groups being 1 or 2, e.g. pyridyl, further e.g (4) In ring A, the 5-12 membered heteroaryl is a 5-10 membered heteroaryl, the 5-10 membered heteroaryl may be a monocyclic ring or a bicyclic ring, the bicyclic ring may be a fused ring, e.g., a benzo 5-6 membered heteroaryl, a 5-6 membered heteroaryl and a 5-6 membered heteroaryl, further, e.g., the 5-10 membered heteroaryl is pyridinyl, thiazolyl, pyrazinyl, benzopyrazolyl, benzoxazolyl, benzothiazolyl, pyridinyl-pyrrolyl, pyrimidinyl-pyrazolyl or benzopyrrolyl, e.g. (5) The C 3-6 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (6) The 3-6 membered heterocyclic group is 3-6 membered heterocycloalkyl, the kind of the hetero atom group in the 3-6 membered heterocycloalkyl may be selected from one, two or 3 of N, O and S, the number of the hetero atom group is 1,2 or 3, for example, azetidine, further for example (7) The 5-10 membered heterocyclic group in the 5-10 membered heterocyclic group formed by R 1 、R a and the atom to which it is attached is a 5-10 membered heterocycloalkyl group, the kind of the heteroatom group in the 5-10 membered heterocyclic group may be selected from one, two or three of N, O and S, the number of the heteroatom groups is 1, 2 or 3, the 5-10 membered heterocyclic group may be a single ring or a double ring, for example, a double ring, the double ring may be a merging ring, for example, a 5-6 membered heterocycloalkyl group and a 3-6 membered cycloalkyl group, for example (8) The halogen, halogen in the halo-C 1-6 alkyl, and halogen in the-O-halo-C 1-6 alkyl are independently F, cl, br, or I, such as F or Cl; (9) The "plurality" is independently 2 or 3.
  3. 3. A compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in claim 1 which meets one or more of the following conditions: (1) R a is hydrogen; (2) Ring A is a partially saturated 6-membered heterocyclic group, e.g. pyridonyl or Or ring A is a partially saturated 7-12 membered heterocyclyl or 5-12 membered heteroaryl, preferably, the ring A is pyridinyl, thiazolyl, pyrazinyl, cyclopentylthio, partially saturated 6-membered heterocyclyl, cyclohexylo partially saturated 6-membered heterocyclylalkyl and partially saturated 6-membered heterocyclyl, partially saturated 5-6-membered heterocyclylao and partially saturated 6-membered heterocyclyl, 6-membered heteroarylo partially saturated 7-membered heterocyclyl, phenylo partially saturated 5-membered heterocyclyl, phenylo partially saturated 7-membered heterocyclyl, 5-6-membered heteroarylo 5-6-membered heteroaryl or benzo5-6-membered heteroaryl; (3) Ring B and ring C are phenyl; (4) R 1 is C 1-6 alkyl, said C 1-6 alkyl optionally substituted with one or more R 1-1 ; (5) R 1-1 is each independently C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl being independently optionally substituted by one or more R 1-1a , preferably R 1-1 is each independently C 3-6 cycloalkyl, said C 3-6 cycloalkyl being optionally substituted by one or more R 1-1a ; (6) R a1 and R a2 are independently C 1-6 alkyl; (7) R 3 is hydrogen, halogen, hydroxy, C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl being independently optionally substituted by one or more R 3-1 groups, preferably R 3-1 is selected from halogen, C 1-6 alkyl or C 3-6 cycloalkyl; (8) R 4 is hydrogen or C 1-6 alkyl, said C 1-6 alkyl optionally substituted with one or more R 3-1 , preferably R 3-1 are each independently C 3-6 cycloalkyl, said C 3-6 cycloalkyl optionally substituted with one or more R 3-1a ; (9) Each R 5 is independently halogen or C 1-6 alkyl; (10) Is that Wherein the "2" position is attached to ring C; (11) Each R 6 is independently halogen or C 1-6 alkyl; (12) Is that
  4. 4. The compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein ring a is pyridinyl, thiazolyl, pyrazinyl, The carbon atom indicated by ". Times." indicates that when it is a chiral carbon atom, the carbon atom is in the R configuration, S configuration, or mixtures thereof; Independently represents a single bond or a double bond; Z 1 、Z 2 and Z 3 are each independently CH 2 , CH, C, NH, N, O or S; y 1 、Y 2 、Y 3 and Y 4 are each independently CH 2 or NH; X 1 、X 2 、X 3 or X 4 are each independently CH, N, CH 2 or O; preferably, Z 1 、Z 2 and Z 3 are each independently CH 2 , CH, C, NH or N; or, one of Y 1 、Y 2 、Y 3 and Y 4 is NH; Or, X 1 、X 2 、X 3 or X 4 are each independently CH, N, or CH 2 ; More preferably, the process is carried out, Is that The carbon atom indicated by ". Times." indicates that when it is a chiral carbon atom, the carbon atom is in the R configuration, S configuration, or mixtures thereof; can be Or a mixture of both.
  5. 5. The compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula I is a compound of formula I-a; Preferably, the compound shown in the formula I is a compound shown in the formula I-b: Ring a is a 5-12 membered heteroaryl; or the compound shown in the formula I is a compound shown in the formula I-c: ring A is a 7-12 membered heterocyclyl; more preferably, the compound shown in the formula I-b is the compound shown in the formula I-b-1: or the compound shown in the formula I-c is a compound shown in the formula I-c-1: the carbon atom indicated by ". Times." indicates that when it is a chiral carbon atom, the carbon atom is in the R configuration, S configuration, or mixtures thereof.
  6. 6. A compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in claim 1 which meets one or more of the following conditions: (1) R 1 is (2) L 1 is Or a single bond; (3) Ring A is (4) R 2 is H, Methyl or methoxy, (5) R 3 is H, hydroxy, F, cl, methyl, ethyl, -CF 3 , methoxy group, (6) R 4 is H, methyl, ethyl, n-propyl, (7) R 5 and R 6 are independently methyl or F; Preferably, the compound shown in the formula I meets one or more of the following conditions: (1) Is that (2) Is that Wherein the "2" position is attached to ring C; (3) Is that
  7. 7. The compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein the compound of formula I is any one of: Preferably, the compound shown in the formula I is any one of the following compounds: Preferably, the mobile phase of the chromatographic separation consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is formic acid aqueous solution, the volume percent of formic acid in the mobile phase A is 0.1%, the mobile phase B is acetonitrile, the flow rate is 20mL/min, the elution gradient is that the volume percent of the mobile phase B in the mobile phase is increased from 32% to 42%, the elution time is 17 minutes, and more preferably, the chromatographic column is SunFire C18,19 x 250mm and 10um, and the retention time of the peak-first compound is 8.9 minutes; Preferably, the mobile phase of the chromatographic separation consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is formic acid aqueous solution, the volume percent of formic acid in the mobile phase A is 0.1%, the mobile phase B is acetonitrile, the flow rate is 20mL/min, the elution gradient is that the volume percent of the mobile phase B in the mobile phase is increased from 32% to 42%, the elution time is 17 minutes, and more preferably, the chromatographic column is SunFire C18,19 x 250mm and 10um, and the retention time of the compound with the rear peak is 10 minutes; Preferably, the mobile phase of the chromatographic separation consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is a formic acid aqueous solution, the volume percent of formic acid in the mobile phase A is 0.1%, the mobile phase B is acetonitrile, the flow rate is 20mL/min, the elution gradient is that the volume percent of the mobile phase B in the mobile phase is increased from 32% to 42%, the elution time is 17 minutes, and more preferably, the chromatographic column is SunFire C18,19 x 250mm and 10um, and the retention time of the first-come peak compound is 7 minutes; The chromatographic separation column is a C18 reverse chromatographic column, and/or 1 H NMR(400MHz,MeOD-d 4 ) is δ7.12-7.10(m,1H),6.88-6.78(m,3H),6.27(s,1H),5.28-5.27(m,1H),5.04-5.01(m,1H),3.24-3.15(m,3H),3.10-3.00(m,2H),2.75-2.69(m,1H),2.61-2.57(m,7H),2.48-2.42(m,3H),2.29-2.28(m,6H),2.10(s,3H),2.00(s,3H), preferably the mobile phase of the chromatographic separation consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is formic acid aqueous solution, the volume percent of formic acid in the mobile phase A is 0.1%, the mobile phase B is acetonitrile, the flow rate is 20mL/min, the elution gradient is that the volume percent of the mobile phase B in the mobile phase is increased from 32% to 42%, the elution time is 17 minutes, and more preferably the chromatographic column is SunFire C18,19 x 250mm and 10um, and the retention time of the compound with the rear peak is 15 minutes.
  8. 8. A pharmaceutical composition, the pharmaceutical composition comprising: (1) The compound of formula I, stereoisomer thereof, solvate thereof, pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, and, (2) Pharmaceutical excipients.
  9. 9. Use of a compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 or a pharmaceutical composition as claimed in claim 8 in the preparation of an α4β7 integrin inhibitor; Or a compound of formula I, a stereoisomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 or a pharmaceutical composition as claimed in claim 8 for use in the manufacture of a medicament for the prophylaxis and/or treatment of a disease, disorder or condition; the disease, disorder or condition may be a disease, disorder or condition mediated by α4β7 integrin; the disease and the disease mediated by the α4β7 integrin independently may be inflammatory bowel disease, colitis, ulcerative colitis, gastroenteritis, crohn's disease or esophagitis.
  10. 10. A compound of formula II or formula III, a stereoisomer thereof, a solvate thereof, an acceptable salt thereof or a solvate of an acceptable salt thereof: r 7 is C 1-6 alkyl, such as ethyl; Definition of "," # ", ring a, ring B, ring C, L 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , y, z, x and t is as defined in any one of claims 1-7; preferably, the compound shown in the formula II is any one of the following compounds: The compound shown in the formula III is any one of the following compounds:
  11. 11. a preparation method of a compound shown in a formula I is characterized by comprising the following steps of carrying out hydrolysis reaction of a compound shown in a formula III in a solvent under the action of alkali to obtain the compound shown in the formula I Definition of "," # ", ring a, ring B, ring C, L 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , y, z, x and t is as defined in any one of claims 1-7, R 7 is as defined in claim 10; preferably, the hydrolysis reaction is performed under a nitrogen atmosphere, the base may be lithium hydroxide, and the solvent may be a mixed solution of an alcoholic solvent and water, for example, methanol and water.

Description

Phenylpropionic acid compound, preparation method, intermediate and application thereof Technical Field The invention relates to the field of medicines, in particular to a phenylpropionic acid compound, and a preparation method, an intermediate and application thereof. Background Integrins (Integrin) are a class of heterophilic cell adhesion molecules that are ubiquitous on vertebrate cell surfaces, depending on Ca 2+ or Mg 2+. As an important adhesive protein for connecting cells and cells with extracellular matrix (ECM), the integrin is used as an extracellular matrix receptor, and can connect extracellular matrix with intracellular actin skeleton into a whole, so that the function of bidirectional connection is achieved. Integrins are transmembrane heterodimers whose molecules consist of 2 non-covalently bound transmembrane glycoprotein subunits, termed α and β. It has now been found that 18 alpha subunits and 8 beta subunits, together 24 integrin dimers. Integrins are the major receptors for most extracellular matrix proteins (including collagen, fibronectin and laminin) in animal cells, binding their ligands with lower affinity. In addition to adhesion, integrins also have the effect of transmitting extracellular signals into cells, involved in regulating a variety of physiological processes. Inflammatory Bowel Disease (IBD) has a complex pathogenesis and dysfunction of the intestinal mucosal immune system is closely related to disease progression. For immune cells such as T cells and B cells, the integrins alpha 4 beta 7 on the cell membrane interact with MAdCAM-1 (mucosa addressee cell adhesion molecule-1) on the high endothelial venules, so that the immune cells can be adhered to enter the related immune tissues of the intestinal tract from the vascular endothelial gap, and an immune response is started. IBD is roughly classified clinically into Ulcerative Colitis (UC) and Crohn's Disease (CD) based on the phenotype and mechanism of pathogenesis. Under IBD conditions, elevated MAdCAM-1 levels on the surface of endothelial cells of the high endothelial venules lead to increased intestinal homing T cells, which accelerate the development of colonic inflammation. Clinical studies have demonstrated the efficacy of α4β7 targeted drugs in IBD patients. Up to now, 3 drugs targeting α4β7 have been marketed, including vedelizumab (vedolizumab), natalizumab (Natalizumab) and the chemical AJM300. Wherein, natalizumab and AJM300 are both alpha 4 beta 7/alpha 4 beta 1 double-target inhibitors, and vedelizumab is an alpha 4 beta 7 single-target inhibitor. It was found that administration of vedelizumab increased the risk of patients suffering from Progressive Multifocal Leukoencephalopathy (PML), the mechanism of which is presumably related to blocking immune cell intra-brain homing. PML risk was not found temporarily compared to clinical administration of vedelizumab. In addition, considering normal physiological functions such as the mediation of immune cells to the central nervous system and conjunctival migration of eyes, and the differentiation and proliferation of precursor B cells, the improvement of the selectivity of the medicine to the alpha 4 beta 1 can reduce the side effects of the medicine. Disclosure of Invention The invention aims to solve the technical problem that the alpha 4 beta 7 integrin small molecule inhibitor in the prior art has fewer varieties, and therefore, the invention provides a phenylpropionic acid compound, and a preparation method, an intermediate and application thereof. The phenylpropionic acid compound provided by the invention has a good inhibition effect on alpha 4 beta 7 cells. The invention provides a compound shown in a formula I, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a solvate of the pharmaceutically acceptable salt, Wherein the carbon atom represented by "+" means that when it is a chiral carbon atom, the carbon atom is in the R configuration, S configuration, or mixtures thereof; The carbon atom represented by "#" means that when it is a chiral carbon atom, the carbon atom is in the R configuration, S configuration, or a mixture thereof; L 1 is a bond or-NR a -C (O) -, wherein the carbonyl group is attached to ring A; R a is hydrogen or C 1-6 alkyl; ring A is a 6 membered heterocyclyl, 7-12 membered heterocyclyl or 5-12 membered heteroaryl; The types of the hetero atom groups in the 5-6 membered heteroaryl and the 5-6 membered heterocyclic groups are independently selected from one, two or three of N, O or S, and the number of the hetero atom groups is independently 1, 2 or 3; R 1 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl independently being optionally substituted with one or more R 1-1; Or R 1、Ra together with the atoms to which it is attached form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl optionally being substituted with o