Indolizine compounds, preparation method and use thereof

1. An indolizine compound represented by formula I, a pharmaceutically acceptable salt, an enantiomer, or a diastereomer thereof,

wherein,

R 1 is selected from the group consisting of

R 10 is selected from the group consisting of H, halogen, —NH 2 , —NO 2 , optionally substituted C1-C6 alkyl and optionally substituted C1-C4 alkoxy;

R 2 is selected from the group consisting of H, halogen, cyano and optionally substituted C1-C6 alkyl;

R 3 is

R 6 and R 6′ are each independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl, and at least one of R 6 and R 6′ is H;

X is an optionally substituted saturated or unsaturated 4-7 membered cyclic hydrocarbyl group or an optionally substituted 4-7 membered saturated or unsaturated heterocyclic group, and the heterocyclic group contains 1-2 heteroatoms selected from O, N, S and P;

R 4 and R 5 are independently selected from the group consisting of H, halogen, —COOH, —CN, optionally substituted C1-C6 alkyl, optionally substituted 6-16 membered aryl, optionally substituted 5-16 membered heteroaryl, optionally substituted 4-8 membered saturated or unsaturated cycloalkyl, optionally substituted 4-8 membered saturated or unsaturated heterocyclic group, optionally substituted C1-C6 alkylcarbonyl, optionally substituted —C(O)O—(C1-C6 alkyl), —C(O)(NR a R b ), dihydroxyboryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C6 alkyl sulfonyl group, optionally substituted C1-C6 alkyl sulfoxide group and optionally substituted C1-C6 alkyl mercapto group; wherein, the heteroaryl or heterocyclic group contains 1-3 heteroatoms selected from N, O, S, P; wherein, R a and R b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl, and optionally substituted 4-8 membered heterocyclic group, or R a and R b are connected together with N to form an optionally substituted 4-8 membered heterocyclic ring; wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, S and P;

R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl;

R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium and optionally substituted C1-C6 alkyl;

the optionally substituted substituents in R 2 , R 7 , R 8 , R 9 , R 10 , R a and R b include one or more substituents selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, —OH, amino, methoxy and dimethylamino.

2. The indolizine compound represented by formula I of claim 1 , the pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein,

R 1 is

R 10 is selected from the group consisting of H, halogen, —NH 2 , —NO 2 , optionally substituted C1-C6 alkyl and optionally substituted C1-C4 alkoxy;

R 2 is selected from the group consisting of H, halogen, cyano and optionally substituted C1-C6 alkyl; R 2 is optionally substituted C1-C4 alkyl; further R 2 is methyl;

R 3 is

R 6 and R 6′ are each independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl, and at least one of R 6 and R 6′ is H;

X is selected from the group consisting of an optionally substituted saturated or unsaturated 4-7 membered cyclic hydrocarbyl group, and an optionally substituted 4-7 membered saturated or unsaturated heterocyclic group; wherein, the heterocyclic group contains 1-2 heteroatoms selected from O, N, S, P; the substituent in X is selected from the group consisting of —OH, halogen, tert-butyloxycarbonyl, —NR s R t , C1-C4 alkyl substituted with 1-3 R x s, C1-C4 alkoxy substituted with 1-3 R x s, C1-C4 alkylcarbonyl substituted with 1-3 R x s, C1-C4 alkoxycarbonyl substituted with 1-3 R x s and C1-C4 alkylsulfonyl substituted with 1-3 R x s; each R x is independently selected from the group consisting of H, halogen, methylamino, dimethylamino, amino, —OH, methoxy and ethoxy;

R s and R t are each independently selected from the group consisting of: H, C1-C4 alkyl, C1-C4 haloalkyl,

R 4 and R 5 are each independently selected from the group consisting of H, halogen, —COOH, —CN, optionally substituted C1-C6 alkyl, optionally substituted 6-16 membered aryl, optionally substituted 5-16 membered heteroaryl, optionally substituted 4-8 membered saturated or unsaturated cycloalkyl, optionally substituted 4-8 membered saturated or unsaturated heterocyclic group, optionally substituted C1-C6 alkylcarbonyl, optionally substituted —C(O)O—(C1-C6 alkyl), —C(O)(NR a R b ), dihydroxyboryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C6 alkyl sulfonyl group, optionally substituted C1-C6 alkyl sulfoxide group and optionally substituted C1-C6 alkyl mercapto group; the heteroaryl or heterocyclic group contains 1-3 heteroatoms selected from N, O, S, P; and the substituents in R 4 and R 5 are selected from the group consisting of halogen, —CN, R 45 (C1-C4 alkyl), R 45 (C1-C4 alkoxy), R 45 (C1-C4 alkyl) acyl, R 45 (C1-C4 alkyl) sulfonyl, R 45 (C3-C8 cycloalkyl), R 45 (4-8 membered heterocyclic group) and —NR c R d ; the heterocyclic group is a heterocyclic group containing 1-2 heteroatoms selected from N and O;

each R 45 is independently selected from the group consisting of H, —OH, halogen, tert-butyloxycarbonyl, halogenated C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 acyl, dimethylamino, methylamino, diethylamino, methylethylamino, ethylamino,

and R 451 is selected from the group consisting of H, C1-C4 alkyl; wherein, R a and R b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl and optionally substituted 4-8 membered heterocyclic group, or Ra and Rb are connected together with N to form optionally substituted 4-8 membered heterocyclic ring;

wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, S and P;

R c and R d are each independently selected from the group consisting of: H, C1-C4 alkyl, C1-C4 haloalkyl,

R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl;

R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium and optionally substituted C1-C6 alkyl;

the substituents in R 2 , R 7 , R 8 , R 9 , R 10 , R a , and R b include one or more substituents selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, —OH, amino, methoxy and dimethylamino.

3. The indolizine compound represented by formula I of claim 1 , the pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein,

R 3 is selected from the group consisting of:

where R h is selected from the group consisting of H, C1-C4 alkyl substituted with 1-3 R x s, C1-C4 alkylcarbonyl substituted with 1-3 R x s, C1-C4 alkoxycarbonyl substituted with 1-3 R x s, C1-C4 alkylsulfonyl substituted with 1-3 R x s and tert-butyloxycarbonyl;

R j is selected from the group consisting of —OH, halogen, C1-C4 alkyl substituted with 1-3 R x s, C1-C4 alkoxy substituted with 1-3 R x s, and —NR s R t ;

R x is selected from the group consisting of H, halogen and —OH;

R s and R t are each independently selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl,

R 6 and R 6′ are each independently selected from the group consisting of H, methyl and ethyl, and at least one of R 6 and R 6′ is H;

R 3 is selected from the group consisting of:

where R h is selected from the group consisting of H and R x (C1-C3 alkyl);

R j is selected from the group consisting of —OH, halogen, R x (C1-C3 alkyl), R x (C1-C3 alkoxy) and —N(C1-C3 alkyl) 2 ;

R x is selected from the group consisting of H, halogen, trifluoromethyl and difluoromethyl;

R 6 and R 6′ are each independently selected from the group consisting of H, methyl and ethyl, and at least one of R 6 and R 6′ is H;

R 3 is selected from the group consisting of:

R h is selected from C1-C3 alkyl substituted with fluorine;

R 6 and R 6′ are each independently selected from H and methyl, and at least one of R 6 and R 6′ is H.

4. The indolizine compound represented by formula I of claim 1 , the pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein,

R 4 or R 5 are each independently selected from the group consisting of: H, R 55 C1-C4 alkyl, —CN, halogen, R 55 C1-C4 alkylcarbonyl, R 55 (C1-C4 alkoxy) carbonyl, —COOH, —C(O)(NR a R b ),

and R 55 C1-C3 alkynyl;

n is the number of R 55 substituents, and is selected from 1, 2 and 3;

R 55 is selected from the group consisting of H, R 551 C1-C4 alkyl, R 551 C3-C8 cycloalkyl, halogen, —CN, —NR c R d , (R 551 C1-C4 alkyl)O—, R 551 C1-C4 alkyl sulfonyl group,

R 551 (C1-C6 alkyl)OC(O)—, —COOH and —C(O)(NR a R b ); wherein R 551 is H, —OH, halogen, halogenated C1-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, amino, dimethylamino, methylamino, diethylamino, methylethylamino, ethylamino,

R a and R b are each independently selected from the group consisting of H, C1-C4 alkyl, Rb″(C1-C4)alkyl, phenyl, halophenyl, and R b′ substituted heterocyclic group; or R a and R b are connected together with N to form a 4-8 membered heterocyclic group substituted with R b′ , the heterocyclic group contains 1-2 heteroatoms selected from N and O;

R b″ is selected from the group consisting of H, —OH, C1-C3 alkoxy, dimethylamino,

R b′ is selected from the group consisting of H, C1-C4 alkyl, tert-butyloxycarbonyl and C1-C4 acyl;

R 4 or R 5 are each independently selected from the group consisting of H,

n is the number of R 55 substituents, and is selected from 1 and 2;

R 55 is selected from the group consisting of H, C1-C4 alkyl, halogen, —NH 2 , (C1-C2 alkyl)NH— and dimethylamino.

5. The indolizine compound represented by formula I of claim 1 , the pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein,

R 3 is

R 6 and R 6′ are each independently selected from the group consisting of H, methyl, ethyl and propyl, and at least one of R 6 and R 6′ is H;

X is selected from the group consisting of optionally substituted pyranyl, optionally substituted piperidinyl, optionally substituted piperazinyl and optionally substituted morpholinyl, and the substituent in X is selected from the group consisting of C1-C4 alkyl and halogenated C1-C4 alkyl;

the substituent in X is trifluoroethyl;

R 2 is methyl;

R 10 is selected from the group consisting of unsubstituted or halogenated C1-C4 alkyl and unsubstituted or halogenated C1-C4 alkoxy;

R 4 , R 5 are each independently selected from the group consisting of H, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazolyl, optionally substituted triazolyl and optionally substituted pyrrolopyridyl;

the substituents in R 4 and R 5 are selected from the group consisting of H, C1-C4 alkyl, halogen and —NR c R d ;

R c and R d are each independently selected from the group consisting of H, C1-C4 alkyl and halogenated C1-C4 alkyl.

6. The indolizine compound represented by formula I of claim 1 , the pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein,

R 2 is methyl;

R 3 is

R 6 and R 6′ are each independently selected from H and methyl, and at least one of R 6 and R 6′ is H;

X is selected from the group consisting of morpholinyl, trifluoroethylpiperazinyl and trifluoroethylpiperidinyl; further morpholinyl, 2,2,2-trifluoroethylpiperazinyl or 2,2,2-trifluoroethyl piperidinyl;

R 4 and R 5 are each independently selected from the group consisting of H, dimethylaminopyridine and methylaminopyridine; further H, 2-dimethylaminopyridine or 2-methylaminopyridine;

R 7 , R 8 and R 9 are hydrogen;

R 10 is methoxy.

7. The indolizine compound represented by formula I of claim 1 , the pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein the indolizine compound represented by Formula I is selected from the following compounds:

8. A method for preparing the indolizine compound represented by Formula I of claim 1 or the pharmaceutically acceptable salt thereof, the method comprising one of the following methods:

(1) in the presence of a base, compound a is reacted with compound b via a condensation reaction to produce compound c;

(2) in the presence of a Lewis acid, compound c is reacted with secondary amine via dehydration reaction to produce enamine compound d;

(3) compound d is hydrolyzed to produce compound e;

(4) compound e is reacted with amine f via condensation reaction to produce compound I-1,

wherein, R 1 , R 2 , R 4 , R 5 , R 6 , R 6′ , R 7 , R 8 and R 9 are as defined in claim 1 , and R k is a C1-C4 linear or branched alkyl group; circle X is an optionally substituted 4-7 membered saturated or unsaturated heterocyclic group, and the heterocyclic group contains at least one N atom, and the optional substituent thereof is defined as the substituent in X as defined in claim 1 ;

(5) in the presence of titanium trichloride or titanium tetrachloride and a reducing agent, compound c is reacted with a corresponding ketone in an inert solvent via McMurry reaction to produce compound g;

(6) compound g undergoes a hydrolysis reaction to produce compound h;

(7) compound g is reacted with amine f via condensation reaction to produce compound 1-2;

wherein, R 1 , R 2 , R 4 , R 5 , R 6 , R 6′ , R 7 , R 8 and R 9 are as defined in claim 1 , and R k is a C1-C4 linear or branched alkyl group; circle Y is an optionally substituted saturated or unsaturated 4-7 membered cyclic hydrocarbyl group or optionally substituted 4-7 membered saturated or unsaturated heterocyclic group, and the heterocyclic group contains 1-2 heteroatoms selected from O, N, S and P, and the optional substituent thereof is defined as the substituent in X as defined in claim 1 .

9. A pharmaceutical composition, comprising:

an active component in a therapeutically effective amount, the active component is selected from the indolizine compound represented by formula I of claim 1 , the pharmaceutically acceptable salt, enantiomer, or diastereomer thereof; and

a pharmaceutically acceptable carrier.