WO2018171602A1 - Urea compound as dual inhibitor of ido and tdo - Google Patents

Abstract

Provided are a urea compound having a dual inhibitory activity against IDO and TDO and being represented by the formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and pharmaceutical composition thereof, and a use of the same in treating an immunosuppressive disease mediated by IDO or TDO.

Description

Urea compounds for dual inhibitors of IDO and TDO Technical field

The invention belongs to the technical field of medicine, relates to urea compounds of dual inhibitors of IDO and TDO, a preparation method thereof, a pharmaceutical composition containing the same, and the activity thereof in regulating IDO and TDO and treating diseases and disorders mediated by them the use of.

Background technique

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-oxygenase (TDO) are two important enzymes that break down tryptophan in various tumor cells and surrounding microenvironmental cells. In the expression, by degrading tryptophan in local tissues, producing a tryptophan depletion environment and increasing the concentration of local metabolite kynurenine to affect the immune function of T cells, inducing host immune defense, inhibiting T cell immunity and resistance Both tumor immunity, induction of maternal fetal immune tolerance, and graft immune tolerance play important metabolic immunomodulatory effects.

Abnormal increases in IDO expression or activity have been shown to be closely related to the pathogenesis of diseases such as depression, Alzheimer's disease, cataracts, and cancer. Therefore, IDO inhibitors may be an effective treatment for these diseases. Although research on IDO inhibitors has been conducted for decades at home and abroad, there are still no IDO inhibitors listed as drugs. Currently available IDO inhibitors are mainly classified into the following categories: 1) competitive inhibitors such as tryptophan derivatives 1-MT; 2) non-competitive inhibitors such as phenylimidazole; 3) anti-competitive Inhibitors such as alkaloids exiguamine A; 4) inhibitors through other mechanisms of action. These types of inhibitors generally have problems such as low inhibition efficiency, inability to permeate the cell membrane, and production of anthracycline metabolites. In the 1990s, 1-methyl-tryptophan (1-MT), a derivative obtained by structural modification of IDO's substrate tryptophan as a template, is currently used in vitro and in vivo. The IDO inhibitor had a inhibition constant (Ki) of 34 μM. Up to now, the NLG919 compound of Newlink Genetics of the United States and the INCB024360 compound of Incyte of the United States have entered clinical trials.

Recent studies have also found that TDO is expressed in a variety of tumor cells, resulting in increased survival and migration of tumor cells and inhibition of the immune system's ability to respond to tumor cells. The effect of TDO on tumor cells and immunosuppression has made it a new anti-tumor drug target. Therefore, screening new IDO/TDO inhibitors and studying their in vivo activities, pharmacokinetics, therapeutic effects and adverse reactions are still a field worth exploring.

Summary of the invention

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

among them,

Ring A is absent or ring A is a benzene ring or contains 1, 2 or 3 5-6 membered heteroaryl rings selected from N, O or S atoms;

Ring B is a five-membered aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, specifically,

i) Y and V are N, Z and W are CH, and X is C;

Ii) Y, Z, V and W are N and X is C;

Iii) X and V are N, Z and W are CH, and Y is C;

Iv) Y, Z and V are N, W is CH and X is C;

v) X, Z and V are N, W is CH, and Y is C;

Vi) X is N, Z, V and W are CH, and Y is C;

Vii) Y is N, Z, V and W are CH, and X is C;

Viii) Z is NH, V and W are CH, and X and Y are C;

Ix) V is NH, Z and W are CH, and X and Y are C;

x) W is NH, V and Z are CH, and X and Y are C;

Xi) V and W are N or NH, Z is CH, and X and Y are C;

Xii) V and Z are N or NH, W is CH, and X and Y are C;

Xiii) Z and W are N or NH, V is CH, and X and Y are C;

Xiv) Y and W are N, V and Z are CH, and X is C;

Xv) X and W are N, V and Z are CH, and Y is C;

Xvi) X and Z are N or NH, V and W are CH, and Y is C;

Xvii) Y and Z are N, V and W are CH, and X is C;

Xviii) Y, V and W are N, Z is CH, and X is C;

Xix) Z, V and W are N or NH, X and Y are C;

Xx) X, W and V are N, Z is CH, and Y is C;

Xxi) Y, Z and W are N, V is CH, X is C; or

Xxii) X, Z, V and W are N and Y is C;

P is C(R ⁶ ) or N;

Q is O or S;

D is selected from NH, O, S or CH ₂ ;

E is selected from NH, O or CH ₂ ;

L is selected from the group consisting of a single bond, S, SO, SO ₂ , CO, C(O)O, S(O)O or S(O) ₂ O;

Each R ^{1 is} independently selected from halogen, amino, hydroxy, cyano, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl;

R ^{2 is} selected from C _3-12 cycloalkyl, C _3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R ³ ;

R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, containing 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, containing 1, 2 or 3 5-6 membered heteroaryl CH ₂ -, -OR ⁴ , -SR ⁴ , -N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N from N, O or S atoms R ⁴ ) ₂ , -C(O)R ⁴ , -S(O)R ⁴ , -S(O)OR ⁴ , -S(O)N(R ⁴ ) ₂ , -S(O) ₂ R ⁴ , -S(O) ₂ OR ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -OC(O)R ⁴ , -OC(O)OR ⁴ , -OC(O)N(R ⁴ ) ₂ , -N(R ⁴ )C(O)R ⁴ , -N(R ⁴ )C(O)OR ⁴ , -N(R ⁴ )C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S (O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , Wherein C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, 5-6 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S atoms, aryl CH ₂ - can be any Optionally substituted with one or more groups independently selected from R ⁵ ;

Each R ^{4 is} independently selected from H, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms;

R ^{5 is} selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl;

R ^{6 is} selected from H, halogen, amino, cyano, hydroxy, -COOH or halogenated C _1-3 alkyl;

m is 0, 1, or 2.

It should be noted that when ring A is not present, formula I is

In one embodiment of the compound of formula I of the present invention, ring A is absent or ring A is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine. Ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, tetrazole ring or triazine ring.

In one embodiment of the compounds of formula I of the invention, ring A is absent or ring A is a benzene ring or a pyridine ring.

In one embodiment of the compounds of formula I of the invention, ring A is absent or ring A is

In one embodiment of the compounds of formula I of the present invention, each R ^{1 is} independently selected from halo, halo C _1-3 alkyl or C _1-6 alkyl.

In one embodiment of the compounds of formula I of the present invention, each R ^{1 is} independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or tri Chloromethyl.

In one embodiment of the compounds of formula I of the invention, each R ^{1 is} independently selected from fluoro, chloro or trifluoromethyl.

In one embodiment of the compounds of formula I of the invention, m is 0 or 1.

In one embodiment of the compounds of formula I of the invention, ring B is an aromatic ring wherein i) Y and V are N, Z and W are CH, X is C; ii) Y, Z, V and W are N, X Is C; iii) X and V are N, Z and W are CH, Y is C; iv) Y, Z and V are N, W is CH, X is C; v) X, Z and V are N, W Is CH, Y is C.

选自

In one embodiment of the compounds of formula I of the invention, structural units

Selected from

选自

In one embodiment of the compounds of formula I of the invention, structural units

Selected from

In one embodiment of the compounds of formula I according to the invention, D is selected from NH, O or CH ₂ ; E is selected from NH, O or CH ₂ .

In one embodiment of the compounds of formula I of the invention, -DC(Q)-E- is selected from the group consisting of -NHC(O)NH-, -NHC(S)NH-, -OC(O)NH-, -NHC(O) CH ₂ - or -CH ₂ C(O)NH-.

One embodiment of the compounds of the invention of formula I, L is selected from a single bond or SO _2.

In one embodiment of the compounds of formula I according to the invention, R ^{2 is} selected from C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 or 3 selected from N, O or S atoms 5-6 membered heteroaryl group, which may optionally be substituted with one or more groups independently selected R ³ groups.

苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基、三嗪基，其可任选地被一个或多个独立地选自R ³的基团取代。 In one embodiment of the compounds of formula I of the present invention, R ^{2 is} selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the loss of one hydrogen atom at any position.

Phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetra oxazolyl, triazinyl, which may be optionally substituted with one or more groups independently selected R ³ groups.

苯基、吡啶基或嘧啶基，其可任选地被一个或多个独立地选自R ³的基团取代。 In one embodiment of the compounds of formula I of the present invention, R ^{2 is} selected from cyclohexyl, which loses a hydrogen atom at any position.

Phenyl, pyridyl or pyrimidyl group, which may optionally be substituted with one or more substituents independently selected from R ³ group.

其可任选地被一个或多个独立地选自R ³的基团取代。 In one embodiment of the compounds of formula I of the invention, R ^{2 is} selected from

Which may be optionally substituted with one or more groups independently selected R ³ groups.

In one embodiment of the compounds of formula I of the invention, R ^{2 is} selected from

In one embodiment of the compounds of formula I of the present invention, R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 heterocycloalkyl, containing 1 , 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C _3-6 heterocycloalkyl CH ₂ -, -OR ⁴ , -SR ⁴ , -S(O) ₂ R ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , wherein C _1-6 alkyl, C _3-6 heterocycloalkyl, containing 1, 2 or 3 are selected from The 5-6 membered heteroaryl or C _3-6 heterocycloalkyl CH ₂ - of the N, O or S atom may be optionally substituted by one or more groups independently selected from R ⁵ .

呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基、三嗪基、

其中甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基，任意位置失去一个H原子的

呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基、三嗪基、

可任选地被一个或多个独立地选自R ⁵的基团取代。 In one embodiment of the compounds of formula I according to the invention, R ^{3 is} selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl , trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, -OR ⁴ , -SR ⁴ , -S(O) ₂ R ⁴ ,- S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ , -P(O)(OR ⁴ ) ₂ , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, lose one position at any position H atomic

Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, Triazinyl,

Among them, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, which loses a H atom at any position

Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, Triazinyl,

Optionally substituted with one or more groups independently selected from R ⁵ .

四唑基或

其中甲基、任意位置失去一个氢原子的

四唑基或

可任选地被一个或多个独立地选自R ⁵的基团取代。 One embodiment of the compounds of formula I of the present invention, R ³ is selected from fluoro, chloro, bromo, cyano, nitro, ^{trifluoromethyl, -OR 4, -SR 4, -S} (O) 2 R 4, - S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ , -P(O)(OR ⁴ ) ₂ , methyl, loss of one hydrogen atom at any position

Tetrazolyl or

Where the methyl group, at any position, loses a hydrogen atom

Tetrazolyl or

Optionally substituted with one or more groups independently selected from R ⁵ .

One embodiment of the compounds of formula I of the present invention, R ³ is selected from fluoro, chloro, bromo, cyano, nitro, _{trifluoromethyl, -OCF 3, -SCH 3, -S} (O) 2 CH 3, - S(O) ₂ NH ₂ , -C(O)OCH ₃ , -COOH, -C(O)NHCH ₃ , -C(O)NH ₂ , -NHS(O) ₂ NH ₂ , -P(O) ( CH ₃ ) ₂ , -P(O)(OCH ₂ CH ₃ ) ₂ , -C(OH)(CF ₃ ) ₂ ,

In one embodiment of the compounds of formula I of the present invention, each R4 is independently selected from H, halo _C1-3 alkyl or _C1-6 alkyl.

In one embodiment of the compounds of formula I of the present invention, each R ^{4 is} independently selected from the group consisting of H, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl , tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

In one embodiment of the compounds of formula I of the present invention, each R ^{4 is} independently selected from H, trifluoromethyl, methyl or ethyl.

In one embodiment of the compounds of formula I of the present invention, R ^{5 is} selected from the group consisting of hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl Base, pentafluoroethyl, monochloromethyl, dichloromethyl or trichloromethyl.

One embodiment of the compounds of formula I of the present invention, R ⁵ is selected from hydroxy or trifluoromethyl.

One embodiment of the compounds of formula I of the present invention, R ⁶ is selected from H or halogen.

One embodiment of the compounds of formula I of the present invention, R ⁶ is selected from H or chloro.

In another aspect, the invention provides a compound of Formula II, or a pharmaceutically acceptable salt thereof,

among them,

Ring A is a benzene ring or a 5-6 membered heteroaryl ring containing 1, 2 or 3 atoms selected from N, O or S atoms;

Ring B is an aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, in particular,

i) Y and V are N, Z and W are CH, and X is C;

Ii) Y, Z, V and W are N and X is C;

Iii) X and V are N, Z and W are CH, and Y is C;

Iv) Y, Z and V are N, W is CH and X is C;

v) X, Z and V are N, W is CH, and Y is C;

Vi) X is N, Z, V and W are CH, and Y is C;

Vii) Y is N, Z, V and W are CH, and X is C;

Viii) Z is NH, V and W are CH, and X and Y are C;

Ix) V is NH, Z and W are CH, and X and Y are C;

x) W is NH, V and Z are CH, and X and Y are C;

Xi) V and W are N or NH, Z is CH, and X and Y are C;

Xii) V and Z are N or NH, W is CH, and X and Y are C;

Xiii) Z and W are N or NH, V is CH, and X and Y are C;

Xiv) Y and W are N, V and Z are CH, and X is C;

Xv) X and W are N, V and Z are CH, and Y is C;

Xvi) X and Z are N or NH, V and W are CH, and Y is C;

Xvii) Y and Z are N, V and W are CH, and X is C;

Xviii) Y, V and W are N, Z is CH, and X is C;

Xix) Z, V and W are N or NH, X and Y are C;

Xx) X, W and V are N, Z is CH, and Y is C;

Xxi) Y, Z and W are N, V is CH, X is C; or

Xxii) X, Z, V and W are N and Y is C;

P is C(R ⁶ ) or N;

Q is O or S;

L is selected from the group consisting of a single bond, S, SO, SO ₂ , CO, C(O)O, S(O)O or S(O) ₂ O;

Each R ^{1 is} independently selected from halogen, amino, hydroxy, cyano, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl;

R ^{2 is} selected from C _3-12 cycloalkyl, C _3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R ³ ;

R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, containing 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, containing 1, 2 or 3 5-6 membered heteroaryl CH ₂ -, -OR ⁴ , -SR ⁴ , -N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N from N, O or S atoms R ⁴ ) ₂ , -C(O)R ⁴ , -S(O)R ⁴ , -S(O)OR ⁴ , -S(O)N(R ⁴ ) ₂ , -S(O) ₂ R ⁴ , -S(O) ₂ OR ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -OC(O)R ⁴ , -OC(O)OR ⁴ , -OC(O)N(R ⁴ ) ₂ , -N(R ⁴ )C(O)R ⁴ , -N(R ⁴ )C(O)OR ⁴ , -N(R ⁴ )C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S (O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , Wherein C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, 5-6 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S atoms, aryl CH ₂ - can be any Optionally substituted with one or more groups independently selected from R ⁵ ;

Each R ^{4 is} independently selected from H, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms;

R ^{5 is} selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl;

R ^{6 is} selected from H, halogen, amino, cyano, hydroxy, -COOH or halogenated C _1-3 alkyl;

m is 0, 1, or 2.

In one embodiment of the compound of Formula II of the present invention, Ring A is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a thiazole ring, Isothiazole ring, oxazole ring, isoxazole ring, tetrazole ring or triazine ring.

In one embodiment of the compounds of formula II of the invention, Ring A is a phenyl ring or a pyridine ring.

In one embodiment of the compound of formula II of the invention, ring A is absent or ring A is

In one embodiment of the compounds of formula II of the invention, each R ^{1 is} independently selected from halo, halo C _1-3 alkyl or C _1-6 alkyl.

In one embodiment of the compounds of formula II of the invention, each R ^{1 is} independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or tri Chloromethyl.

In one embodiment of the compounds of formula II of the invention, each R ^{1 is} independently selected from fluoro, chloro or trifluoromethyl.

In one embodiment of the compounds of formula II of the invention, m is 0 or 1.

In one embodiment of the compound of formula II of the invention, ring B is an aromatic ring wherein i) Y and V are N, Z and W are CH, X is C; ii) Y, Z, V and W are N, X Is C; iii) X and V are N, Z and W are CH, Y is C; iv) Y, Z and V are N, W is CH, X is C; v) X, Z and V are N, W Is CH, Y is C.

选自

In one embodiment of the compound of formula II of the invention, the structural unit

Selected from

选自

In one embodiment of the compound of formula II of the invention, the structural unit

Selected from

One embodiment of the compounds of the invention of formula II, L is selected from a single bond or SO _2.

In one embodiment of the compounds of formula II of the invention, R ^{2 is} selected from C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 or 3 selected from N, O or S atoms. 5-6 membered heteroaryl group, which may optionally be substituted with one or more groups independently selected R ³ groups.

苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基、三嗪基，其可任选地被一个或多个独立地选自R ³的基团取代。 In one embodiment of the compound of formula II of the present invention, R ^{2 is} selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a hydrogen atom is lost at any position.

Phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetra oxazolyl, triazinyl, which may be optionally substituted with one or more groups independently selected R ³ groups.

苯基、吡啶基或嘧啶基，其可任选地被一个或多个独立地选自R ³的基团取代。 In one embodiment of the compound of Formula II of the present invention, R ^{2 is} selected from cyclohexyl, which loses a hydrogen atom at any position.

Phenyl, pyridyl or pyrimidyl group, which may optionally be substituted with one or more substituents independently selected from R ³ group.

其可任选地被一个或多个独立地选自R ³的基团取代。 In one embodiment of the compounds of formula II of the invention, R ^{2 is} selected from

Which may be optionally substituted with one or more groups independently selected R ³ groups.

In one embodiment of the compounds of formula II of the invention, R ^{2 is} selected from

In one embodiment of the compound of Formula II of the present invention, R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 heterocycloalkyl, containing 1 , 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C _3-6 heterocycloalkyl CH ₂ -, -OR ⁴ , -SR ⁴ , -S(O) ₂ R ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , wherein C _1-6 alkyl, C _3-6 heterocycloalkyl, containing 1, 2 or 3 are selected from The 5-6 membered heteroaryl or C _3-6 heterocycloalkyl CH ₂ - of the N, O or S atom may be optionally substituted by one or more groups independently selected from R ⁵ .

呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基、三嗪基、

其中甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基，任意位置失去一个H原子的

呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基、三嗪基、

可任选地被一个或多个独立地选自R ⁵的基团取代。 One embodiment of the compounds of the invention of formula II, R ³ is selected from fluoro, chloro, bromo, cyano, nitro, fluoromethyl, difluoromethyl, trifluoromethyl group, a fluoroethyl, difluoro ethyl , trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, -OR ⁴ , -SR ⁴ , -S(O) ₂ R ⁴ ,- S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ , -P(O)(OR ⁴ ) ₂ , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, lose one position at any position H atomic

Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, Triazinyl,

Among them, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, which loses a H atom at any position

Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, Triazinyl,

Optionally substituted with one or more groups independently selected from R ⁵ .

四唑基或

其中甲基、任意位置失去一个氢原子的

四唑基或

可任选地被一个或多个独立地选自R ⁵的基团取代。 One embodiment of the compounds of the invention of formula II, R ³ is selected from fluoro, chloro, bromo, cyano, nitro, ^{trifluoromethyl, -OR 4, -SR 4, -S} (O) 2 R 4, - S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ , -P(O)(OR ⁴ ) ₂ , methyl, loss of one hydrogen atom at any position

Tetrazolyl or

Where the methyl group, at any position, loses a hydrogen atom

Tetrazolyl or

Optionally substituted with one or more groups independently selected from R ⁵ .

One embodiment of the compounds of the invention of formula II, R ³ is selected from fluoro, chloro, bromo, cyano, nitro, _{trifluoromethyl, -OCF 3, -SCH 3, -S} (O) 2 CH 3, - S(O) ₂ NH ₂ , -C(O)OCH ₃ , -COOH, -C(O)NHCH ₃ , -C(O)NH ₂ , -NHS(O) ₂ NH ₂ , -P(O) ( CH ₃ ) ₂ , -P(O)(OCH ₂ CH ₃ ) ₂ , -C(OH)(CF ₃ ) ₂ ,

In one embodiment of the compounds of formula II of the invention, each R ^{4 is} independently selected from H, halo C _1-3 alkyl or C _1-6 alkyl.

In one embodiment of the compounds of formula II of the invention, each R ^{4 is} independently selected from the group consisting of H, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl , tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

One embodiment of the compounds of the invention of formula II, each R ⁴ is independently selected from H, trifluoromethyl, methyl or ethyl.

In one embodiment of the compound of Formula II of the present invention, R ^{5 is} selected from the group consisting of hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl Base, pentafluoroethyl, monochloromethyl, dichloromethyl or trichloromethyl.

One embodiment of the compounds of the invention of formula II, R ⁵ is selected from hydroxy or trifluoromethyl.

One embodiment of the compounds of the invention of formula II, R ^{6 is} selected from H or halogen.

One embodiment of the compounds of the invention of formula II, R ^{6 is} selected from H or chloro.

In another aspect, the present invention provides a compound of Formula II-1, or a pharmaceutically acceptable salt thereof,

Wherein the group or atom is as defined for the compound of formula II.

In another aspect, the invention provides a compound of Formula II-2, or a pharmaceutically acceptable salt thereof,

Wherein the group or atom is as defined for the compound of formula II.

In another aspect, the present invention provides a compound of Formula II-3, or a pharmaceutically acceptable salt thereof,

Wherein the group or atom is as defined for the compound of formula II.

In another aspect, the invention provides a compound of Formula II-4, or a pharmaceutically acceptable salt thereof,

Wherein the group or atom is as defined for the compound of formula II.

In another aspect, the invention provides a compound of Formula II-5, or a pharmaceutically acceptable salt thereof,

Wherein the group or atom is as defined for the compound of formula II.

In another aspect, the invention provides a compound of Formula III, or a pharmaceutically acceptable salt thereof,

among them,

Ring B is an aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, in particular,

i) Y and V are N, Z and W are CH, and X is C;

Ii) Y, Z, V and W are N and X is C;

Iii) X and V are N, Z and W are CH, and Y is C;

Iv) Y, Z and V are N, W is CH and X is C;

v) X, Z and V are N, W is CH, and Y is C;

Vi) X is N, Z, V and W are CH, and Y is C;

Vii) Y is N, Z, V and W are CH, and X is C;

Viii) Z is NH, V and W are CH, and X and Y are C;

Ix) V is NH, Z and W are CH, and X and Y are C;

x) W is NH, V and Z are CH, and X and Y are C;

Xi) V and W are N or NH, Z is CH, and X and Y are C;

Xii) V and Z are N or NH, W is CH, and X and Y are C;

Xiii) Z and W are N or NH, V is CH, and X and Y are C;

Xiv) Y and W are N, V and Z are CH, and X is C;

Xv) X and W are N, V and Z are CH, and Y is C;

Xvi) X and Z are N or NH, V and W are CH, and Y is C;

Xvii) Y and Z are N, V and W are CH, and X is C;

Xviii) Y, V and W are N, Z is CH, and X is C;

Xix) Z, V and W are N or NH, X and Y are C;

Xx) X, W and V are N, Z is CH, and Y is C;

Xxi) Y, Z and W are N, V is CH, X is C; or

Xxii) X, Z, V and W are N and Y is C;

Q is O or S;

D is selected from NH, O, S or CH ₂ ;

E is selected from NH, O, or CH ₂ ;

L is selected from the group consisting of a single bond, S, SO, SO ₂ , CO, C(O)O, S(O)O or S(O) ₂ O;

Each R ^{1 is} independently selected from halogen, amino, hydroxy, cyano, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl;

R ^{2 is} selected from C _3-12 cycloalkyl, C _3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R ³ ;

R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, containing 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, containing 1, 2 or 3 5-6 membered heteroaryl CH ₂ -, -OR ⁴ , -SR ⁴ , -N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N from N, O or S atoms R ⁴ ) ₂ , -C(O)R ⁴ , -S(O)R ⁴ , -S(O)OR ⁴ , -S(O)N(R ⁴ ) ₂ , -S(O) ₂ R ⁴ , -S(O) ₂ OR ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -OC(O)R ⁴ , -OC(O)OR ⁴ , -OC(O)N(R ⁴ ) ₂ , -N(R ⁴ )C(O)R ⁴ , -N(R ⁴ )C(O)OR ⁴ , -N(R ⁴ )C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S (O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , Wherein C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, 5-6 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S atoms, aryl CH ₂ - can be any Optionally substituted with one or more groups independently selected from R ⁵ ;

Each R ^{4 is} independently selected from H, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms;

R ^{5 is} selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl;

m is 0, 1, or 2.

In one embodiment of the compounds of formula III of the invention, each R ^{1 is} independently selected from halo, halo C _1-3 alkyl or C _1-6 alkyl.

In one embodiment of the compounds of formula III of the invention, each R ^{1 is} independently selected from fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or tri Chloromethyl.

In one embodiment of the compounds of formula III of the invention, each R ^{1 is} independently selected from chloro or trifluoromethyl.

In one embodiment of the compounds of formula III of the invention, m is 0 or 1.

In one embodiment of the compound of formula III of the invention, ring B is an aromatic ring wherein i) Y and V are N, Z and W are CH, X is C; ii) X and V are N, Z and W are CH , Y is C.

选自

In one embodiment of the compound of formula III of the invention, the structural unit

Selected from

选自

In one embodiment of the compound of formula III of the invention, the structural unit

Selected from

One embodiment of the compounds of the invention of formula III, D is selected from NH, O or CH _2; E is selected from NH, O or CH _2.

In one embodiment of the compound of formula III of the invention, -DC(Q)-E- is selected from the group consisting of -NHC(O)NH-, -NHC(S)NH-, -OC(O)NH-, -NHC(O) CH ₂ - or -CH ₂ C(O)NH-.

In one embodiment of the compounds of formula III of the invention, L is selected from the group consisting of a single bond.

In one embodiment of the compounds of Formula III of the present invention, R ^{2 is} selected from phenyl or contains 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, which may optionally be one or A plurality of groups independently selected from R ³ are substituted.

In one embodiment of the compounds of formula III of the invention, R ^{2 is} selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl , isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazinyl, which may be optionally substituted with one or more groups independently selected R ³ groups.

One embodiment of the compounds of the invention of formula III, R ² is selected from phenyl, pyridyl or pyrimidyl group, which may optionally be substituted with one or more substituents independently selected from R ³ group.

其可任选地被一个或多个独立地选自R ³的基团取代。 In one embodiment of the compounds of formula III of the invention, R ^{2 is} selected from

Which may be optionally substituted with one or more groups independently selected R ³ groups.

In one embodiment of the compounds of formula III of the invention, R ^{2 is} selected from

One embodiment of the compounds of the invention of formula III, R ³ is selected from halogen or halogenated C _1-3 alkyl.

One embodiment of the compounds of the invention of formula III, R ³ is selected from fluoro, chloro, bromo or trifluoromethyl.

In another aspect, the invention provides a compound of formula III-1, or a pharmaceutically acceptable salt thereof,

Wherein the group or atom is as defined for the compound of formula III.

In another aspect, the invention provides a compound of formula III-2, or a pharmaceutically acceptable salt thereof,

Wherein the group or atom is as defined for the compound of formula III.

The present invention preferably comprises the following compound or a pharmaceutically acceptable salt thereof,

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, a compound of formula II, and a compound of formula III, or a pharmaceutically acceptable salt thereof, of the invention. In some embodiments, the pharmaceutical compositions of the present invention further comprise one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions of the invention may further comprise one or more additional therapeutic agents.

In another aspect, the invention relates to a method of treating a mammalian immunosuppressive disorder mediated by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-oxygenase (TDO), including A mammal, preferably a human in need of such treatment, is administered a therapeutically effective amount of a compound of formula I, a compound of formula II, and a compound of formula III, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the invention relates to a compound of formula I, a compound of formula II, and a compound of formula III, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prophylaxis or treatment of guanamine 2,3-dual addition Uses of oxygenase (IDO) and tryptophan 2,3-oxygenase (TDO) mediated drugs for immunosuppressive diseases. In still another aspect, the present invention relates to a compound of formula I, a compound of formula II, and a compound of formula III, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prophylaxis or treatment of guanamine 2,3-dual plus Use of oxygenase (IDO) and tryptophan 2,3-oxygenase (TDO) mediated immunosuppressive diseases.

In some embodiments of the invention, the immunosuppressive disease is associated with an infectious disease or cancer. As a preferred embodiment, the immunosuppressive disease may be selected from, but not limited to, pneumonia, malignancy, measles, hepatitis, kidney disease or arthritis.

In some embodiments of the invention, the infectious disease is selected from the group consisting of influenza, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), poliovirus , herpes zoster virus, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV) or Coxsackie virus. The cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head or neck cancer, lymphoma, leukemia or melanoma.

Definition and description

In the following description, certain specific details are included to provide a comprehensive understanding of the various disclosed embodiments. However, one skilled in the relevant art will recognize that the embodiments may be practiced without the use of one or more of these specific details, and other methods, components, materials, and the like.

The word "comprise" and its English variants such as "comprises" and "comprising" should be interpreted as open, unless otherwise required by the present invention. Inclusive meaning, including but not limited to.

References to "one embodiment" or "an embodiment" or "in another embodiment" or "in some embodiments" throughout the specification are meant to include in the at least one embodiment The specific reference elements, structures or features described. The appearances of the phrase "in one embodiment" or "in an embodiment" or "in another embodiment" or "in some embodiments" are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It will be understood that the singular articles "a", "the", "the", "the" Regulations. Thus, for example, a reaction including a "catalyst" includes a catalyst, or two or more catalysts. It is also to be understood that the term "or" is generally used in its meaning including "and/or" unless it is specifically defined otherwise.

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence or non-occurrence of the event or circumstance. For example, an ethyl group "optionally" means ethyl substituted with halo may be unsubstituted (CH ₂ CH _3), monosubstituted (e.g., CH ₂ CH ₂ F), polysubstituted (e.g. CHFCH ₂ F, CH ₂ CHF _2, etc.) or completely substituted (CF ₂ CF ₃ ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.

As used herein, C _mn means having mn carbon atoms in this moiety. For example, "C _3-10 cycloalkyl" means that the cycloalkyl group has 3 to 10 carbon atoms. The "C _0-6 alkylene group" means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond. It is easy to understand that when a hetero atom is contained, mn represents the sum of the number of carbon atoms and hetero atoms.

The numerical ranges in this document refer to individual integers in a given range. For example, "C _1-10 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0) (also referred to as an oxo group), it means that two hydrogen atoms are substituted and the ketone substitution does not occur on the aryl group.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When the number of one linking group is 0, such as -(CRR) ₀ -, it indicates that the linking group is a single bond.

When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.

表示其可在环己基或者环己二烯上的任意一个位置发生取代。 When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit

It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.

The term "pharmaceutically acceptable" is for those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive Toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, as a pharmaceutically acceptable salt of a compound of the formula I, formula II and formula III, for example, a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, or a salt formed with a basic or acidic amino acid. Non-limiting examples of metal salts include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting a compound of the free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

The compounds of formula I, formula II and formula III of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. The compounds of formula I of the present invention may exist in polymorph or amorphous form.

The compounds of the formula I, formula II and formula III of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.

Graphical methods for racemates, ambiscalemic and scalemic or enantiomerically pure compounds of the invention are from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds of Formula I, Formula II and Formula III of the present invention contain olefinic double bonds or other centers of geometric asymmetry, they include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of formula I, formula II and formula III of the invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are also included within the scope of the invention.

The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide purity The desired enantiomer. Alternatively, when a molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then known to those skilled in the art. The diastereomeric resolution is carried out by fractional crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).

The compounds of Formula I, Formula II, and Formula III of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). All isotopic compositions of the compounds of Formula I, Formula II, and Formula III of the present invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.

The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

The word "comprise" or "comprise" and its English variants such as "comprises" or "comprising" shall be understood to mean an open, non-exclusive meaning, ie "including but not limited to".

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the invention or a salt thereof and a pharmaceutically acceptable adjuvant. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the invention to an organism.

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl; for example, the term "halo C _1-3 alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoro. Ethyl and 3-bromopropyl and the like. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The term "hydroxy" refers to -OH.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "amino" refers to -NH ₂ , -NH(alkyl) and -N(alkyl) ₂ , and specific examples of the amino group include, but are not limited to, -NH ₂ , -NHCH ₃ , -NHCH(CH ₃ ) ₂ , - N(CH ₃ ) ₂ , -NHC ₂ H ₅ , -N(CH ₃ )C ₂ H ₅ and the like.

The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,壬基, 癸基, etc. The specific alkyl group includes all isomeric forms thereof, for example, the propyl group includes -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , for example, butyl includes -CH ₂ CH ₂ CH ₂ CH ₃ ,- CH(CH ₃ )(CH ₂ CH ₃ ), -C(CH ₃ ) ₃ , -CH ₂ CH(CH ₃ ) ₂ . The term "C _1-8 alkyl" refers to an alkyl group having from 1 to 8 carbon atoms. The term " _C1-6 alkyl" refers to an alkyl group having from 1 to 6 carbon atoms. The term "C _1-4 alkyl" refers to an alkyl group having from 1 to 4 carbon atoms. The term "C _1-3 alkyl" refers to an alkyl group having from 1 to 3 carbon atoms. The "alkyl", "C _1-8 alkyl", "C _1-6 alkyl", "C _1-4 alkyl" or "C _1-3 alkyl" may be unsubstituted or one Or a plurality of substituents selected from a hydroxyl group, a halogen or an amino group.

The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, such as a _C3-20 cycloalkyl group, preferably a _C3-6 cycloalkyl group, such as a cyclopropyl group, Cyclobutyl, cyclopentyl, cyclohexyl and the like. The cycloalkyl group may be unsubstituted or substituted, and the substituent includes, but is not limited to, an alkyl group, an alkyloxy group, a cyano group, a carboxyl group, an aryl group, a heteroaryl group, an amino group, a halogen, a sulfonyl group. , sulfinyl group, phosphoryl group, hydroxyl group and the like.

Unless otherwise specified, the term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, and optionally substituted -C(=O)N (H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5-7 membered ring" means 5-7 atoms arranged around. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenyl, pyridine, and piperidinyl; in another aspect, the term "5-7 membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bicyclic or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, cyclohexylethane, cycloalkylethane, non-limiting examples of 4-membered heterocycloalkyl including, but not limited to, azetidinyl, acetophenan Examples of a cyclic group, a thibutyl group, a 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine Examples of the group, imidazolidinyl group, tetrahydropyrazolyl group, pyrrolinyl group, dihydrofuranyl group, dihydrothienyl group, 6-membered heterocycloalkyl group include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrogen Thianyl, morpholinyl, piperazinyl, 1,4-thiazolidine, 1,4-dioxolyl, thiomorpholinyl, 1,2-dithiaalkyl, 1,4- Examples of dithiaalkyl, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, 7-membered heterocycloalkyl include, but are not limited to, azacycloheptane Base, oxetanyl, thiaheptanyl. Preferred is a monocyclic heterocycloalkyl group having 5 or 6 ring atoms.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, and the like.

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or a plurality of fused rings containing from 6 to 14, especially from 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.

The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.

The pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.

In all methods of administration of the compounds of Formula I, Formula II and Formula III described herein, the daily dose is from 0.01 to 200 mg/kg body weight, preferably from 0.01 to 20 mg/kg body weight, more preferably from 0.01 to 10 mg/ Kg body weight, either alone or in divided doses.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.

The chemical reaction of a particular embodiment of the invention is carried out in a suitable solvent which is suitable for the chemical changes of the invention and the reagents and materials required thereof. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the prior embodiments.

An important consideration in the art of synthetic route planning is the selection of suitable protecting groups for reactive functional groups (such as amino groups in the present invention), for example, reference to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc., all references cited herein are incorporated by reference in their entirety.

Synthetic route formula A:

Wherein the group and the atom are as defined for the compound of formula I.

The compound of the formula 1 is reacted with triphosgene in dichloromethane to give the compound of the formula 2; the compound of the formula 2 is reacted with R ² -L-NH ₂ in pyridine to give the compound of the formula 3.

Synthetic route formula B:

Wherein the group and the atom are as defined for the compound of formula I.

The compound of the formula 1 is reacted with thiophosgene in dichloromethane to give the compound of the formula 4; the compound of the formula 4 is reacted with R ² -L-NH ₂ in pyridine to give the compound of the formula 5.

detailed description

The following specific embodiments are intended to enable those skilled in the art to understand and practice the invention. They should not be considered as limiting the scope of the application, but are merely exemplary and typical representations of the application. Those skilled in the art will appreciate that there are other synthetic routes to form the compounds of the present application, and non-limiting examples are provided below.

Unless otherwise stated, the temperature is Celsius. The reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing Belling Technology Co., Ltd., and these reagents can be used directly without further purification unless otherwise stated. Unless otherwise stated, the following reactions are carried out in an anhydrous solvent, under a positive pressure of nitrogen or argon or using a drying tube; a reaction vessel is provided with a rubber septum to add substrate and reagents via a syringe; glassware is dried and/or Heat and dry.

Unless otherwise stated, the column chromatography was performed using 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; the thin layer chromatography was used to separate the thin layer chromatography silica gel prefabricated panels (HSGF254) produced by Yantai Chemical Industry Research Institute; the measurement of MS was performed by Thermo LCQ. Fleet type (ESI) liquid chromatography-mass spectrometer.

Nuclear magnetic data ( ¹ H-NMR) was run at 400 MHz using a Varian apparatus unless otherwise stated. The solvent used for the nuclear magnetic data is CDCl ₃ , CD ₃ OD, D ₂ O, DMSO-d _{6 ,} etc., based on tetramethylsilane (0.00 ppm) or based on residual solvent (CDCl ₃ : 7.26 ppm; CD ₃ OD : 3.31 ppm; D ₂ O: 4.79 ppm; DMSO-d ₆ : 2.50 ppm). When the peak shape diversity is indicated, the following abbreviations indicate different peak shapes: s (single peak), d (double peak), t (triplet), q (quadruple), m (multiple peak), br (wide peak) ), dd (double doublet), dt (double triplet). If a coupling constant is given, it is in Hertz (Hz).

Unless otherwise stated, eq. represents molar equivalent; NBS stands for N-bromosuccinimide; m-CPBA stands for m-chloroperoxybenzoic acid; NCS stands for N-chlorosuccinimide; DPPA stands for azidophosphate Diphenyl ester; Boc- represents t-butoxycarbonyl; room temperature represents 20-30 °C.

Synthesis formula A

Step 1: Synthesis of Compound 2

To a solution of the compound of the formula 1 (1.0 eq.) in dichloromethane was added phosgene (0.6 eq.), and the mixture was stirred at room temperature for 2 hr. After completion of the reaction, the solvent was concentrated under reduced pressure, and the solid compound of formula 2 was used directly in step 2.

Step 2: Synthesis of Compound 3

The compound of the formula 2 was added portionwise to a solution of R ² -L-NH ₂ (0.5 eq.) in pyridine and stirred at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was poured into water, and ethyl acetate was evaporated.

Synthesis of general formula B:

Step 1: Synthesis of Compound of Formula 4

Sulfur phosgene (1.2 eq.) was added to a dichloromethane solution of the compound of formula 1 (1.0 eq.) at 0 ° C, and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure.

Step 2: Synthesis of Compound of Formula 5

The compound of the formula 4 was added portionwise to a solution of R ² -L-NH ₂ (1.0 eq.) in pyridine and stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate.

Synthesis of intermediate 1: imidazo[5,1-a]isoquinolin-5-amine

Step 1: Synthesis of 3-chloro-1-methylisoquinoline

To a solution of 1,3-dichloroisoquinoline (49.6 g) in tetrahydrofuran (500 mL) was added dropwise a solution of trimethylaluminum in tetrahydrofuran (139 mL, 2M), then tetratriphenylphosphine palladium. (2.9 g), the mixture was heated to 85 ° C and stirred overnight. The reaction was cooled to room temperature, poured into water (200 mL) The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered, evaporated,jjjjjjjjjj g).

Step 2: Synthesis of 1-bromomethyl-3-chloroisoquinoline

To a solution of 3-chloro-1-methylisoquinoline (43.0 g) in carbon tetrachloride (300 mL) was added N-bromosuccinimide (44.0 g) and benzoyl peroxide (6.0 g). The mixture was heated to 80 ° C and stirred overnight. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated. mjjjjjjjjj

Step 3: Synthesis of 1-azidomethyl-3-chloroisoquinoline

To a solution of 1-bromomethyl-3-chloroisoquinoline (50.0 g) in acetone (500 mL) and water (50 mL), sodium azide (18.2 g) was added, and the mixture was stirred at 50 ° C for 2 hours. It was cooled to room temperature, poured into water (100 mL), and evaporated. The organic phase was dried over anhydrous sodium sulfate, filtered, and then evaporated.

Step 4: Synthesis of 1-aminomethyl-3-chloroisoquinoline

Triphenylphosphine (49.8 g) was added to a solution of 1-azidomethyl-3-chloroisoquinoline (35.6 g) in tetrahydrofuran (300 mL) and water (30 mL). The reaction mixture was poured into water (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjj (27.7g).

Step 5: Synthesis of N-((3-chloroisoquinolin-1-yl)methyl)carboxamide

A mixture of 1-aminomethyl-3-chloroisoquinoline (27.7 g) and ethyl formate (300 mL) was heated to 65 ° C and stirred for 8 hours. It was cooled to room temperature and concentrated under reduced pressure to give N-((3-chloroisoquinolin-1-yl)methyl)carboxamide (30.0 g).

Step 6: Synthesis of 5-chloroimidazo[5,1-a]isoquinoline

To a solution of N-((3-chloroisoquinolin-1-yl)methyl)carboxamide (30.0 g) in dichloromethane (500 mL) was added EtOAc (30.7 g). Ethylamine (82.0 g) was stirred at room temperature for 2 h. The reaction mixture was poured into celite, and the mixture was filtered, evaporated, evaporated, evaporated, evaporated. Column purification (petroleum ether: ethyl acetate = 2:1) gave 5-chloroimidazo[5,1-a]isoquinoline (25.0 g).

Step 7: Synthesis of N-(imidazo[5,1-a]isoquinolin-5-yl)-1,1-benzophenone imide

To a solution of 5-chloroimidazo[5,1-a]isoquinoline (23.0 g) in toluene (300 mL) was added benzophenone imine (21.7 g), tris(dibenzylideneacetone) under a nitrogen atmosphere. Di-palladium (4.6 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (6.2 g) and cesium carbonate (71.7 g), and the mixture was heated to 110 ° C and stirred for 12 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjj -1,1-Dibenzophenone imine (25.6 g).

Step 8: Synthesis of imidazo[5,1-a]isoquinolin-5-amine

N-(imidazo[5,1-a]isoquinolin-5-yl)-1,1-benzophenone imine (15.0 g) was dissolved in tetrahydrofuran (200 mL), and hydrochloric acid was added to the obtained solution. (30 mL, 2N), stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 mL), EtOAc (EtOAc m. 1-a] Isoquinoline-5-amine (6.3 g). ¹ H-NMR (400 M, DMSO-d ₆ ): δ 9.38 (s, 1H), 8.55 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 6.70 (brs, 2H), 6.29 (s, 1H).

Intermediate 2: Synthesis of tetrazos[5,1-a]isoquinolin-5-amine

Step 1: Synthesis of 5-chlorotetrazolo[5,1-a]isoquinoline

To a solution of 1,3-dichloroisoquinoline (1.5 g) in N,N-dimethylformamide (50 mL) was sequentially added azidotrimethylsilane (1.8 g) and tetrabutyl fluoride trifluoride. Ammonium (2.4 mg) was heated to 80 ° C and stirred for 12 hours. After cooling to room temperature, the reaction solution was poured into water (200 mL) The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered, evaporated. Isoquinoline (0.8 g).

Step 2: Synthesis of N-(tetrazolo[5,1-a]isoquinolin-5-yl)-1,1-benzophenone imide

Refer to step 7 in the synthesis of intermediate 1.

Step 3: Synthesis of tetrazolo[5,1-a]isoquinoline-5-amine

Refer to step 8 in the synthesis of intermediate 1. LC-MS [M+1] ⁺ = 186.

Synthesis of Intermediate 3: 8-Fluoroimidazo[5,1-a]isoquinoline-5-amine

Step 1: Synthesis of 5-fluoro-2-indolyl-2,3-dihydro-1H-inden-1-one

5-Fluoro-2,3-dihydro-1H-inden-1-one (8.0 g) was dissolved in diethyl ether (150 mL), cooled to 0 ° C, dry hydrogen chloride was passed to the solution for 3 hours, then slowly drip Isoamyl nitrite (12.5 g) was added, and after completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours, solid was formed, filtered, and the filter cake was washed with diethyl ether. The filter cake was dried to give 5-fluoro-2-mercapto-2,3 -Dihydro-1H-inden-1-one (7.0 g).

Step 2: Synthesis of 1,3-dichloro-6-fluoroisoquinoline

5-Fluoro-2-mercapto-2,3-dihydro-1H-inden-1-one (7.0 g) was dissolved in phosphorus oxychloride (120 mL) at 0 ° C, and then three were added thereto in portions. Phosphorous oxychloride (1.5 g) was added to dry hydrogen chloride gas in the solution, and after 3 hours, the aeration was stopped, and the reaction solution was heated to 60 ° C and stirred for 16 hours. After cooling to room temperature, the phosphorus oxychloride was removed by concentration under reduced pressure, and the obtained solid was washed with water and dried in vacuo to give 1,3-dichloro-6-fluoroisoquinoline (6.0 g).

Steps 3, 4, 5, 6, 7, 8, and 9 refer to steps 1, 2, 3, 4, 5, 6, and 7 in the synthesis of Intermediate 1, respectively.

Step 10: Synthesis of 8-fluoroimidazo[5,1-a]isoquinoline-5-amine

Refer to step 8 in the synthesis of intermediate 1. ^{1 H-NMR (400MHz, DMSO} -d 6): δ8.586 (s, 1H), 8.036 (s, 1H), 7.945-7.924 (m, 1H), 7.257-7.204 (m, 2H), 6.746 (s , 2H), 6.093 (s, 1H).

Synthesis of Intermediate 4: 7-Fluoroimidazo[5,1-a]isoquinoline-5-amine

Step 1: Synthesis of 4-fluoro-2-mercapto-2,3-dihydro-1H-inden-1-one

Referring to step 1 in the synthesis of intermediate 3, 5-fluoro-2,3-dihydro-1H-inden-1-one was substituted for 5-fluoro-2,3-dihydro-1H-inden-1-one.

Steps 2, 3, 4, 5, 6, 7, 8, and 9 refer to steps 2, 3, 4, 5, 6, 7, 8, and 9 in the synthesis of Intermediate 3, respectively.

Step 10: Synthesis of 7-fluoroimidazo[5,1-a]isoquinoline-5-amine

Refer to step 10 in the synthesis of intermediate 3. ^{1 H-NMR (400MHz, DMSO} -d 6): δ8.464 (s, 1H), 8.086-8.049 (m, 1H), 7.883 (s, 1H), 7.276-7.243 (m, 1H), 7.036-7.030 (m, 1H), 6.608 (s, 2H), 5.939 (s, 1H).

Synthesis of intermediate 5: 7-fluoroimidazo[5,1-a]isoquinolin-5-amine

Step 1: Synthesis of 3-chloro-1-methyl-5-nitroisoquinoline

3-Chloro-1-methylisoquinoline (8.3 g) was slowly added to concentrated sulfuric acid (100 mL) at 0 ° C, then potassium nitrate (5.7 g) was added portionwise, and the mixture was stirred at 0 ° C for 1 hour. Pour the reaction solution into crushed ice, adjust the pH to 9 with ammonia water, filter, wash the filter cake with water, and dry the filter cake in vacuo to obtain 3-chloro-1-methyl-5-nitroisoquinoline (6.2 g). ^{1 H-NMR (400MHz, DMSO} -d 6): δ8.713-8.692 (m, 1H), 8.662-8.640 (m, 1H), 8.222 (s, 1H), 7.885-7.845 (m, 1H), 2.968 (s, 3H).

Step 2: Synthesis of 3-chloro-1-methyl-5-aminoisoquinoline

3-Chloro-1-methyl-5-nitroisoquinoline (6.0 g) was dissolved in a mixed solvent of methanol and water (1:1, 200 mL), ammonium chloride (14.4 g) was added and heated to 60 After the solution became clear, the reduced iron powder (15.1 g) was added, and the mixture was stirred at 60 ° C for 30 minutes, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove methanol and extracted with ethyl acetate (150 mL × 2). The mixture was washed with brine, dried over anhydrous sodium sulfate -aminoisoquinoline (3.9 g).

Step 3: Synthesis of 3,5-dichloro-1-methylisoquinoline

3-Chloro-1-methyl-5-aminoisoquinoline (3.9 g) was dissolved in concentrated hydrochloric acid (50 mL), cooled to 0 ° C, and sodium nitrite (1.5 g) in water (10 mL) was slowly added dropwise. The dropping temperature kept the temperature of the reaction solution below 5 ° C. After 20 minutes, a solution of cuprous chloride (2.4 g) in concentrated hydrochloric acid (10 mL) was added and stirred at 0 ° C for one hour. The reaction mixture was poured into water and extracted with ethyl acetate (150 mL×2). :ethyl acetate = 20:1) gave 3,5-dichloro-1-methylisoquinoline (4.2 g).

Steps 4, 5, 6, 7, 8, and 9 refer to steps 2, 3, 4, 5, 6, and 7 in the synthesis of Intermediate 1, respectively.

Step 10: Synthesis of 7-fluoroimidazo[5,1-a]isoquinoline-5-amine

Refer to step 8 in the synthesis of intermediate 1. ^{1 H-NMR (400MHz, DMSO} -d 6): δ8.543 (s, 1H), 8.053-8.033 (m, 1H), 8.006 (s, 1H), 7.460-7.440 (m, 1H), 7.208-7.169 (m, 1H), 6.819 (s, 2H), 6.231 (s, 1H).

Synthesis of intermediate 6: [1,2,3]triazolo[5,1-a]isoquinolin-5-amine

Step 1: Synthesis of 2-((trimethylsilyl)ethynyl)benzaldehyde

To a solution of 2-bromobenzaldehyde (18.5 g) in tetrahydrofuran (500 mL) was added trimethylsilylacetylene (19.6 g), cuprous iodide (0.95 g), triethylamine (20.2 g) and Bis-triphenylphosphine palladium dichloride (3.5 g), and the reaction solution was heated to 50 ° C and stirred overnight. After cooling to room temperature, it was poured into water and extracted with ethyl acetate (300 mL×2). Ether: ethyl acetate = 20:1) 2-((trimethylsilyl)ethynyl)benzaldehyde (19.0 g).

Step 2: Synthesis of trimethyl((2(2-nitrovinyl)phenyl)ethynyl)silane

2-((Trimethylsilyl)ethynyl)benzaldehyde (19.0 g) and ammonium acetate (7.2 g) were added to nitromethane (50 mL), and the reaction mixture was heated to 110 ° C, and stirring was continued for 1 hour. The mixture was concentrated with EtOAc (EtOAc)EtOAc. Ether: ethyl acetate = 20:1) gave trimethyl((2(2-nitrovinyl)phenyl)ethynyl)silane (15.3 g). ^{1 H-NMR (400MHz, CDCl} 3): δ8.460-8.426 (d, 1H), 7.835-7.801 (d, 1H), 7.580-7.535 (m, 2H), 7.441-7.361 (m, 2H), 0.295 (s, 9H).

Step 3: Synthesis of [1,2,3]triazolo[5,1-a]isoquinoline

Trimethyl((2(2-nitrovinyl)phenyl)ethynyl)silane (15.3 g) and sodium azide (6.0 g) were dissolved in dimethyl sulfoxide (150 mL), and the reaction liquid was heated. Stir at 110 ° C for 40 minutes. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (300 mL×2). Methyl chloride:methanol = 20:1) [1,2,3]triazolo[5,1-a]isoquinoline (6.8 g) was obtained.

Step 4: Synthesis of 5-bromo-[1,2,3]triazolo[5,1-a]isoquinoline

[1,2,3]triazolo[5,1-a]isoquinoline (2.0g) was dissolved in dry toluene (100 mL) under nitrogen, cooled to -40 ° C, and added dropwise. Base lithium n-hexane solution (2.4 M, 13.9 mmol). After completion of the dropwise addition, the reaction mixture was stirred at -40 ° C for 2 hours, and 1,2-dibromotetrachloroethane (4.6 g) was added thereto, and the mixture was cooled, and the mixture was further stirred for 2 hours, poured into water, and extracted with ethyl acetate (100 mL) ×2), the organic phase was washed with brine, dried over anhydrous sodium sulfate. 1,2,3]triazolo[5,1-a]isoquinoline (0.54 g).

Step 5 and Step 6: Synthesis of [1,2,3]triazolo[5,1-a]isoquinolin-5-amine

Referring to Step 7 and Step 8 in the synthesis of Intermediate 1, respectively, [1,2,3]triazolo[5,1-a]isoquinolin-5-amine was finally obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.459 (s, 1H), 8.70-8.050 (d, 1H), 7.603-7.583 (d, 1H), 7.542-7.501 (m, 1H), 7.424-7.383 (m, 1H), 6.354 (s, 1H), 5.262 (s, 2H).

Intermediate 7: Synthesis of [1,2,4]triazolo[4,3-a]quinolin-4-amine

Step 1: Synthesis of 3-bromoquinoline-1-nitrogen oxide

To a solution of 3-bromoquinoline (10.0 g) in dichloromethane (300 mL), m.p. The reaction mixture was poured into aq. EtOAc. :1) 3-bromoquinoline-1-nitrogen oxide (9.4 g) was obtained.

Step 2: Synthesis of 3-bromo-2-chloroquinoline

3-bromoquinoline-1-nitrogen oxide (4.0 g) and trichloroacetonitrile (5.2 g) were dissolved in toluene (200 mL), then triphenylphosphine (9.4 g) was added and the mixture was heated to 115 ° C. Stir for 4 hours. After cooling to room temperature, the reaction mixture was evaporated. mjjjjjjjj

Step 3: Synthesis of 3-bromo-2-indolylquinoline

3-Bromo-2-chloroquinoline (0.5 g) was added to hydrazine hydrate (25 mL), and the reaction mixture was heated to 140 ° C and stirred for 1 hour. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (100 mL×2). Methyl chloride:methanol = 20:1) gave 3-bromo-2-mercaptoquinoline (0.4 g).

Step 4: Synthesis of 4-bromo-[1,2,4]triazolo[4,3-a]quinoline

3-Bromo-2-indolylquinoline (0.4 g) was added to formic acid (25 mL), and then stirred at room temperature overnight, and the mixture was poured into water and extracted with ethyl acetate (100 mL×2). The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered and evaporated. Zoxao[4,3-a]quinoline (0.32 g).

Step 5 and Step 6: Synthesis of [1,2,4]triazolo[4,3-a]quinoline-4-amine

Referring to Step 7 and Step 8 in the synthesis of Intermediate 1, respectively, [1,2,4]triazolo[4,3-a]quinolin-4-amine was finally obtained. ^{1 H-NMR (400MHz, DMSO} -d 6): δ9.916 (s, 1H), 8.244-8.224 (d, 1H), 7.659-7.637 (d, 1H), 7.424-7.365 (m, 2H), 6.573 (s, 1H), 6.085 (s, 2H).

Intermediate 8: Synthesis of imidazo[1,5-a]pyridine-5-amine

Steps 1, 2, 3, 4, 5, and 6 refer to steps 2, 3, 4, 5, 6, and 7 in the synthesis of Intermediate 1, respectively.

Step 7: Synthesis of imidazo[1,5-a]pyridine-5-amine

Referring to Step 8 in the synthesis of Intermediate 1, an imidazo[1,5-a]pyridine-5-amine is obtained. ^{1 H-NMR (400MHz, DMSO} -d 6): δ8.29 (s, 1H), 7.22 (s, 1H), 6.85 (d, J = 8.8Hz, 1H), 6.71 (dd, J = 8.8Hz, J = 6.8 Hz, 1H), 6.44 (brs, 2H), 5.71 (dd, J = 6.8 Hz, J = 1.2 Hz, 1H).

Intermediate 9: Synthesis of imidazo[1,5-c]quinazolin-5-amine

Step 1: Synthesis of 4-methylquinazolin-2-amine

To a solution of 2-fluoroacetophenone (1.4 g) in N,N-dimethylacetamide (10 mL) was added bismuth carbonate (2.7 g), and the mixture was heated to 130 ° C and stirred for 4 hours. The reaction solution was cooled to room temperature, then added to cold water (20 mL), filtered, and then filtered and washed with petroleum ether and dried to give 4-methyl quinazolin-2-amine (1.1 g).

Step 2: Synthesis of imidazo[1,5-c]quinazolin-5-amine

Under nitrogen, 4-methylquinolin-2-amine (1.1 g), glycine (1.0 g), t-butyl hydroperoxide (3.60 g, 70% aqueous solution), tetrabutylammonium iodide (0.5 g) Dimethyl sulfoxide (10 mL) was added to a mixture with acetic acid (1.3 g), and the reaction mixture was heated to 95 ° C and stirred for 10 hours. After cooling to room temperature, water (30 ml) and ethyl acetate (30 ml) were evaporated, evaporated, evaporated, evaporated. Methanol = 20:1) gave imidazo[1,5-c]quinazolin-5-amine (0.26 g). ^{1 H-NMR (400MHz, DMSO} -d 6): δ8.58 (s, 1H), 7.96 (d, J = 8.0Hz, 1H), 7.83 (s, 1H), 7.58 (s, 2H), 7.37 ( d, J = 3.6 Hz, 2H), 7.19-7.23 (m, 1H).

Intermediate 10: Synthesis of imidazo[5,1-f][1,6]naphthyridin-5-amine

Step 1: Synthesis of 2-(2-ethoxy-2-oxoethyl)nicotinic acid

Ethyl acetoacetate (26.0 g) was slowly added dropwise to a mixture of potassium t-butoxide (33.7 g) and isopropyl alcohol (500 ml) under a nitrogen atmosphere, and the mixture was stirred for 2 hours. Anhydrous copper acetate (5.5 g, 0.03 mol) and 2-chloronicotinic acid (15.8 g) were added to the reaction mixture, and the mixture was stirred at 80 ° C for 4 hours. It was cooled to room temperature and quenched with water (500 mL), then the pH was adjusted to 4 with 2N diluted hydrochloric acid. Ethyl acetate (500 mL) was added, and the mixture was stirred for 20 min, then filtered, and the filtrate was evaporated. -Oxoethyl)nicotinic acid (15.5 g).

Step 2: Synthesis of 1,6-naphthyridin-5,7(6H,8H)-dione

To a solution of 2-(2-ethoxy-2-oxoethyl)nicotinic acid (15.5 g) in tetrahydrofuran (200 mL) was added triethylamine (7.5 g) and ethyl chloroformate (9.6 g). The reaction solution was allowed to warm to room temperature and stirred for 1 hour. Ammonia water (5 mL) was slowly added and stirring was continued for 1 hour. Water (100 mL) was added and the pH was adjusted to 7 with dilute hydrochloric acid. After filtration, 1,6-naphthyridin-5,7(6H,8H)-dione (6.5 g) was obtained.

Step 3: Synthesis of 5,7-dichloro-1,6-naphthyridine

Dissolve 1,6-naphthyridin-5,7(6H,8H)-dione (6.5g) in phosphorus oxychloride (150mL), cool to 0 ° C, add N,N-diisopropylethylamine (10.4 g), then heated to 100 ° C and stirred for 16 hours. After cooling to room temperature, phosphorus oxychloride was removed under reduced pressure, cold water (100 mL) was added, filtered, and dried in vacuo to give 5,7-dichloro-1,6-naphthyridine (4.0 g).

Steps 4, 5, 6, 7, 8, 9, and 10 refer to steps 1, 2, 3, 4, 5, 6, and 7 in the synthesis of Intermediate 1, respectively.

Step 11: Synthesis of imidazo[5,1-f][1,6]naphthyridin-5-amine

Refer to step 8 in the synthesis of intermediate 1. LC-MS [M+1] ⁺ = 185.

Synthesis of intermediate 11: 6-chloroimidazo[5,1-a]isoquinolin-5-amine

Step 1: Synthesis of 4-chloro-1-methylisoquinolin-3-amine

N-chlorosuccinimide (2.7 g) was slowly added to a solution of 1-methylisoquinolin-3-amine (3.2 g) in dichloromethane (50 ml), and the mixture was stirred at room temperature for 1 hour, then cold water was added. The reaction was quenched (5 ml), EtOAcjjjjjjjjj -Methylisoquinolin-3-amine (3.5 g).

Step 2: Synthesis of 2-(4-chloro-1-methylisoquinolin-3-yl)isoindole-1,3-dione

4-Chloro-1-methylisoquinolin-3-amine (3.5 g) and phthalic anhydride (4.0 g) were sequentially added to acetic acid (50 ml) at room temperature, and the mixture was heated to 120 ° C and stirred for 10 hours. Then concentrated under reduced pressure. 100 ml of a saturated aqueous sodium hydrogencarbonate solution was added to the residue and stirred for 1 hour, and filtered to give 2-(4-chloro-1-methylisoquinolin-3-yl)isoindole-1,3-dione (4.8 g) ).

Step 3: Synthesis of 2-(1-(bromomethyl)-4-chloroquinolin-3-yl)isoindole-1,3-dione

2-(4-Chloro-1-methylisoquinolin-3-yl)isoindole-1,3-dione (4.8 g) and N-bromosuccinimide (3.2 g) under nitrogen To the mixture was added benzoyl peroxide (0.36 g) and carbon tetrachloride (200 ml), and the mixture was heated to 80 ° C and stirred overnight. The mixture was cooled to room temperature, filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Isoindole-1,3-dione (3.6 g).

Step 4: Synthesis of 2-(1-(azidomethyl)-4-chloroisoquinolin-3-yl)isoindole-1,3-dione

2-(1-(Bromomethyl)-4-chloroquinolin-3-yl)isoindole-1,3-dione (3.6 g) and sodium azide (0.88 g) were dissolved in acetone and water ( In a mixed solvent of 10:1, 100 mL), the mixture was heated to 65 ° C and stirred for 3 hours. After cooling, it was poured into water (200 ml), EtOAc (EtOAc m. Purification (dichloromethane:methanol = 20:1) afforded 2 to -(1-(azidomethyl)-4-chloroisoquinolin-3-yl)isoindole-1,3-dione ( 2.2g).

Step 5: Synthesis of 2-(1-(aminomethyl)-4-chloroisoquinolin-3-yl)isoindole-1,3-dione

Dissolving 2-(1-(azidomethyl)-4-chloroisoquinolin-3-yl)isoindole-1,3-dione (2.2g) and triphenylphosphine (2.3g) A mixed solvent of tetrahydrofuran and water (10:1, 50 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (100 mL), EtOAc (EtOAc) (Dichloromethane: methanol = 20:1) gave 2-(1-(aminomethyl)-4-chloroisoquinolin-3-yl)isoindole-1,3-dione (1.3 g).

Step 6: Synthesis of 2-(6-chloroimidazo[5,1-a]isoquinolin-5-yl)isoindole-1,3-dione

2-(1-(Aminomethyl)-4-chloroisoquinolin-3-yl)isoindole-1,3-dione (1.3 g) was combined with ethyl formate (100 mL) and then evaporated. The organic layer was concentrated under reduced pressure to dryness crystals crystals crystals crystals crystalsssssssssssssssssssssssssssssssssss The organic layer was concentrated under reduced pressure. EtOAc (EtOAc m. Methanol = 20:1) 2-(6-Chloroimidazo[5,1-a]isoquinolin-5-yl)isoindole-1,3-dione (0.26 g) was obtained.

Step 7: Synthesis of 6-chloro-H-imidazo[5,1-a]isoquinoline-5-amine

Add 2-(6-chloroimidazo[5,1-a]isoquinolin-5-yl)isoindole-1,3-dione (0.26 g) to 50 ml of absolute ethanol and add 5 with stirring. Drop 85% hydrated hydrazine. The reaction solution was then heated to 50 ° C and stirred for 10 minutes. The organic solvent was concentrated under reduced pressure. EtOAc (EtOAc m. :Methanol = 20:1) 6-Chloro-H-imidazo[5,1-a]isoquinolin-5-amine (90.5 mg) was obtained. LC-MS [M+1] ⁺ = 218.

Intermediate 12: Synthesis of H-imidazo[1,5-a]quinoline-4-amine

Step 1: Synthesis of 2-methylquinoline-3-carboxylic acid ethyl ester

To a solution of 2-nitrobenzaldehyde (11.8 g) and ethyl acetoacetate (12.2 g) in acetic acid (150 mL), reduced iron powder (21.9 g) was added portionwise, and then the reaction mixture was heated to 50 ° C and stirred for 2 hours. The reaction mixture was cooled, filtered, and then filtered, evaporated, evaporated,,,,,,,,,,,, The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

Step 2: Synthesis of 2-methylquinoline-3-carboxylic acid

Ethyl 2-methylquinoline-3-carboxylate (13.6 g) was added to a mixed solvent of tetrahydrofuran (50 mL), methanol (50 mL) and water (50 mL), and solid lithium hydroxide monohydrate (5.3) was added to the mixture. g), stirring at room temperature for 4 hours, adjusting the pH to 5 with dilute hydrochloric acid (2M), and then concentrated to remove the organic solvent. The solid obtained was filtered, washed with water and dried to give 2-methylquinoline-3-carboxylic acid (8.1 g).

Step 3: Synthesis of tert-butyl (2-methylquinolin-3-yl)carbamate

Dry tert-butanol (10 mL), triethylamine (21.6 g) and diphenyl azide (13.1 g) were added to the 1,4, 2-methylquinoline-3-carboxylic acid (8.1 g) under nitrogen. In a solution of dioxane (100 mL), the reaction solution was heated to 100 ° C and stirred for 5 hours. The mixture was cooled to room temperature, filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ g).

Step 4: Synthesis of tert-butyl imidazo[1,5-a]quinolin-4-ylcarbamate

Under the protection of nitrogen, (2-methylquinolin-3-yl)carbamic acid tert-butyl ester (1.8 g), glycine (1.0 g), t-butyl hydroperoxide (3.60 g, 70% aqueous solution), tetrabutyl To a mixture of ammonium iodide (0.5 g) and acetic acid (1.3 g), dimethyl sulfoxide (10 mL) was added, and the mixture was stirred at 95 ° C for 10 hours. After cooling to room temperature, water (30 ml) and ethyl acetate (30 ml) were evaporated, evaporated, evaporated, evaporated. Methanol = 20:1) gave tert-butyl imidazo[1,5-a]quinolin-4-ylcarbamate (0.66 g).

Step 5: Synthesis of imidazo[1,5-a]quinolin-4-amine

tert-Butyl imidazo[1,5-a]quinolin-4-ylcarbamate (0.66 g) was added to a solution of hydrochloric acid (20 mL, 4N), then stirred at room temperature for 4 hr. The mixture was extracted with ethyl acetate (100 mL×2). EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjj . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.01 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.45 (m, 1H), 7.23 ( m, 2H), 6.09 (s, 1H), 5.87 (s, 2H).

Synthesis of intermediate 13: 7-chloroimidazo[1,5-a]-5-amine

Step 1: Synthesis of 4-chloro-6-(ethoxycarbonyl)-picolinic acid

A solution of sodium hydroxide (7.76 g) in water (800 mL) was slowly added dropwise to a solution of diethyl 4-chloropyridine-2,6-dicarboxylate (50.0 g) in ethanol (330 mL) at room temperature. Finish, then stir at room temperature overnight. The residue was dissolved in EtOAc (EtOAc) (EtOAc m. 6-(ethoxycarbonyl)-picolinic acid (21.3 g).

Step 2: Synthesis of ethyl 6-(tert-butoxycarbonylamino)-4-chloropicolinate

Dry tert-butanol (10 mL), triethylamine (21.6 g) and diphenyl azide (13.1 g) were added to 4-chloro-6-(ethoxycarbonyl)-picolinic acid under nitrogen. In a solution of 9.94 g of 1,4-dioxane (100 mL), the reaction mixture was heated to 100 ° C and stirred for 5 hours. The mixture was cooled to room temperature, filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 6.1g).

Step 3: Synthesis of (4-chloro-6-(hydroxymethyl)pyridin-2-yl)carbamic acid tert-butyl ester

To a solution of ethyl 6-(tert-butoxycarbonylamino)-4-chloropicolinate (11.5 g) in EtOAc (150 mL) The reaction mixture was slowly added dropwise with 10 mL of water, and the mixture was evaporated to dryness, evaporated, evaporated, evaporated, evaporated, evaporated. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjjjj Ester (9.6 g).

Step 4: Synthesis of (4-chloro-6-(chloromethyl)pyridin-2-yl)carbamic acid tert-butyl ester

To a solution of (4-chloro-6-(hydroxymethyl)pyridin-2-yl)carbamic acid tert-butyl ester (9.6 g) in dichloromethane (200 mL), pyridine (3.8 g) g) The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, then aq. EtOAc EtOAc (EtOAc m. Purification by column chromatography (dichloromethane:methanol = 20:1)ield

Step 5: Synthesis of (4-chloro-6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)carbamic acid tert-butyl ester

Add phthaloyl to a solution of (4-chloro-6-(chloromethyl)pyridin-2-yl)carbamic acid tert-butyl ester (2.8 g) in N,N-dimethylformamide (100 mL) The imine potassium salt (2.0 g) was stirred at room temperature overnight. The reaction mixture was poured into water, EtOAc (EtOAc m. :1) (4-Chloro-6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)carbamic acid tert-butyl ester (2.3 g).

Step 6: Synthesis of (6-(aminomethyl)-4-chloropyridin-2-yl)carbamic acid tert-butyl ester

To a solution of (4-chloro-6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)carbamic acid tert-butyl ester (2.3 g) in ethanol (100 mL) Hydrazine hydrate (0.3 g) was added thereto, and the reaction mixture was heated to 80 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjj Tert-butyl carbamate (1.0 g).

Steps 7 and 8 refer to steps 5 and 6 in the synthesis of Intermediate 1, respectively.

Step 9: Synthesis of 7-chloroimidazo[1,5-a]-5-amine

Refer to step 5 in the synthesis of intermediate 12. ^{1 H-NMR (400MHz, DMSO} -d 6): δ8.46 (s, 1H), 7.64 (d, J = 2.0Hz 1H), 7.39 (s, 1H), 6.55 (d, J = 2.0Hz, 1H ), 6.44 (brs, 2H).

Synthesis of intermediate 14: 6-chloroimidazo[1,5-a]-8-amine

Step 1: Synthesis of 5-chloro-2-methyl-3-nitropyridine

Substituting 1,3-dichloroisoquinoline for 2,5-dichloro-3-nitropyridine, reference is made to step 1 in the synthesis of intermediate 1 to give 5-chloro-2-methyl-3-nitropyridine.

Step 2: 5-Chloro-2-methylpyridin-3-amine

Referring to Step 2 in the synthesis of Intermediate 5, the title compound was obtained.

Step 3: (5-Chloro-2-methylpyridin-3-yl)-tert-butoxyamide

Referring to Step 3 in the synthesis of Intermediate 15, the title compound was obtained.

Step 4: (2-Bromomethyl-5-chloropyridin-3-yl)-tert-butoxyamide

Referring to Step 2 in the synthesis of Intermediate 1, the title compound was obtained.

Step 5: (5-Chloro-2-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)-tert-butoxyamide

Referring to Step 5 in the synthesis of Intermediate 13, the title compound was obtained.

Step 6: (2-Aminomethyl-5-chloropyridin-3-yl)-tert-butoxyamide

Referring to Step 6 in the synthesis of Intermediate 13, the title compound was obtained.

Steps 7 and 8 refer to steps 5 and 6 in the synthesis of Intermediate 1, respectively.

Step 9: Synthesis of 6-chloroimidazo[1,5-a]-8-amine

Refer to step 5 in the synthesis of intermediate 12. ¹ H-NMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.00 (s, 1H), 6.87 (brs, 2H).

Synthesis of intermediate 15: 6-trifluoromethylimidazo[1,5-a]-8-amine

Step 1: Synthesis of 2-chloro-5-(trifluoromethyl)pyridin-3-amine

Add stannous chloride dihydrate (43.9 g) to a solution of 5-trifluoromethyl-3-nitro-2-chloropyridine (10.0 g) in ethyl acetate (250 mL). Stir for 2 hours. The reaction mixture was cooled to room temperature, poured into water, and the mixture was adjusted to pH 8 with a saturated aqueous sodium hydrogen carbonate solution, filtered, and the filtrate was separated, and the organic phase was dried over anhydrous sodium sulfate. -(Trifluoromethyl)pyridin-3-amine (8.3 g).

Step 2: Synthesis of 3-amino-5-(trifluoromethyl)pyridinecarbonitrile

Under nitrogen, 2-chloro-5-(trifluoromethyl)pyridin-3-amine (5.1 g), zinc cyanide (3.9 g), tris(dibenzylideneacetone)dipalladium (1.2 g) and 1, To a mixture of 1 '-binaphthyl-2,2'-bisdiphenylphosphine (1.42 g) was added N,N-dimethylformamide (50 mL). After the reaction mixture was cooled to room temperature, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated :Methanol = 20:1) 3-Amino-5-(trifluoromethyl)pyridinecarbonitrile (2.5 g) was obtained.

Step 3: Synthesis of (2-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamic acid tert-butyl ester

To a solution of 3-amino-5-(trifluoromethyl)pyridinecarbonitrile (2.0 g) in tetrahydrofuran (100 mL), di-tert-butyl dicarbonate (3.5 g), triethylamine (2.16 g) and 4- Methylaminopyridine (0.13 g), and the reaction mixture was stirred at room temperature for 4 hr. The reaction was quenched with EtOAc EtOAc (EtOAc:EtOAc. 1) (2-Cyano-5-(trifluoromethyl)pyridin-3-yl)carbamic acid tert-butyl ester (2.3 g) was obtained.

Step 4: Synthesis of tert-butyl (2-(aminomethyl)-5-(trifluoromethyl)pyridin-3-yl)carbamate

To a solution of (2-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamic acid tert-butyl ester (1.3 g) in ethyl acetate (50 mL), EtOAc (EtOAc) Stir at room temperature overnight under atmospheric pressure of hydrogen. Filtration and concentration of the filtrate under reduced pressure. Tert-butyl formate (0.3 g).

Steps 5 and 6 refer to steps 5 and 6 in the synthesis of Intermediate 1.

Step 7: Synthesis of 6-trifluoromethylimidazo[1,5-a]-8-amine

Refer to step 5 in the synthesis of intermediate 12. ¹ H-NMR (400 MHz, DMSO-d6): δ 8.43 (1H, s), 8.30 (1H, s), 7.65 (1H, s), 6.35 (2H, brs), 5.87 (1H, s).

Synthesis of intermediate 16: 8-chloroimidazo[5,1-a]isoquinolin-5-amine

Steps 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 are referred to the synthesis steps 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 of Intermediate 3, respectively, to give the title compound.

LC-MS [M+1] ⁺ = 218.

Synthesis of the compounds of Examples 1-49 The synthesis of the title compound was obtained by reference to the general formula A. The synthesis of the compound of Example 50-63 was carried out to obtain the title compound, as shown in Table 1:

Table 1: Examples 1-49

Test Example 1: Biological activity assay

1. IDO and TDO protein induced expression and purification methods

First, according to the kit instructions, PCR amplification of IDO (RNA derived from HeLa cells) and TDO (RNA derived from U87MG cells), amplification of the amplified PCR product, and then pET28a plasmid and IDO (TDO) gel recovery product The restriction endonuclease of NotI and EcoRI (BamH1 and Xhol for TDO plasmid construction) was digested (37 ° C, digested for 2 h), and the T4 rapid ligase ligation product was added to E. coli DH5α. (E.coli DH5α) Competent cells were placed on ice for 30 min, heat shocked at 42 °C for 90 s, shaken in LB medium and plated, picked up monoclonal overnight shakes, extracted plasmid and identified by enzyme digestion, and then sent After sequencing, positive clones, ie His-IDO/pET28a and His-TDO/pET28a plasmids were successfully constructed.

The constructed 300 ml E. coli BL21 strain containing His-IDO/pET28a or His-TDO/pET28a plasmid was shaken in LB medium at 37 ° C to OD ₆₀₀ =0.6-0.8, and the final concentration was 0.5 mM. IPTG was induced at 30 ° C for 3.5 h, and after induction, the cells were collected by centrifugation at 6000 rpm for 45 min.

The collected cells were resuspended with lysate (40 mM Tris-HCl, pH 8.0; 110 mM NaCl; 2.2 mM KCl; 10% glycerol; 0.5% Tween-20; 20 mM imidazole; 1 mM DTT). Ultrasonic lysis (power 30%, cleavage on ice for 15 min), the lysed broth was centrifuged at 12000 rpm, 4 ° C for 60 min, and the resulting supernatant was filtered through a 0.22 μM filter to prepare a sample for use. The nickel column was equilibrated with lysate for 5 column volumes, and the prepared supernatant sample was applied to a nickel column. After loading, the eluent (40 mM Tris-HCl, pH 8.0; 110 mM NaCl; 2.2) was used. The protein was eluted with a gradient of mM KCl; 10% glycerol; 20-250 mM imidazole. The eluted protein solution was dialyzed overnight at 4 ° C, concentrated after dialysis, and stored at -80 ° C until use.

2. IDO and TDO enzymatic activity test

The enzymatic activity detection platform of IDO and TDO was established by light absorption method. Compounds were diluted 10 times with 100% DMSO starting from 10 mM (5 concentrations in total), and 4 μL of each concentration was added to 96 μL of reaction buffer. The mixture was mixed in a liquid (50 mM K ₂ HPO ₄ -KH ₂ PO ₄ phosphate buffer, pH 6.5) and used as a 4* compound. 2*IDO enzyme was prepared using reaction buffer at a final concentration of 75 nM (total TDO enzyme concentration of 300 nM), 4* substrate (L-(+)-Absorbate with a final concentration of 20 μM, respectively, purchased from Alfa Aesar, Cat. No. A15613; 10 μM Methylene blue, purchased from Sigma, catalog number M9140-25G; 0.2 mg/ml Catalase was purchased from Sigma, Cat. No. C1345-1G and 20 μM L-Trp, purchased from Sigma, catalog number T0254-25G (TDO was 300 μM L-Trp ))stand-by. Add 10 μL of 4* compound to a 384-well plate (Assay plate, purchased from Corning, Cat. No. 3701), then add 20 μL of 2*IDO enzyme (or TDO enzyme), mix by centrifugation, and add 10 μL of 4* substrate mixture. The reaction was initiated (total reaction volume was 40 μL). The 384-well plate was placed in an incubator for 13 minutes at 23 ° C (TDO reaction for 120 minutes), then 4 μL of 6 M TCA was added to each well for 30 min at 55 ° C, centrifuged at 2500 rpm for 10 min, and 40 μL of supernatant was taken per well. 2% 4-dimethylaminobenzaldehyde (available from TCI, Cat. No. D495, dissolved in glacial acetic acid) was added and the absorbance (480 nM light absorption) was read on FlexStation 3 after 5 min. Enzyme activity for each compound respectively, using the data software provided by GraphtPad Prism5.0 IC ₅₀ values of the compounds was determined at a concentration of 5.

Table 2: Results of determination of IDO and TDO enzyme inhibitory activities of the examples

Test Example 2: Pharmacokinetic data

Male Sprague-Dawley rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the rats were divided into groups of 3, and the test sample suspension (5 mg/kg) was administered orally by a single oral administration. Animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with a small animal anesthesia machine, 0.3 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube. The sample was centrifuged at 4 ° C, 4000 rpm for 5 min, and the plasma was transferred to a centrifuge tube and placed in -80. °C is saved until analysis. Samples in plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS/MS.

Table 3: Pharmacokinetic data for the compounds of the examples

Example 51 40 52 Dose (mg/kg) 5 5 5 T _1/2 (hr) 3.28 4.31 3.56 T _max (hr) 0.25 0.58 0.33 C _max (ng/mL) 721 243 507 AUC _0-inf (hr*ng/mL) 1520 1018 2180

Claims (44)

a compound of formula I or a pharmaceutically acceptable salt thereof,

among them, Ring A is absent or ring A is a benzene ring or contains 1, 2 or 3 5-6 membered heteroaryl rings selected from N, O or S atoms; Ring B is a five-membered aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, specifically, i) Y and V are N, Z and W are CH, and X is C; Ii) Y, Z, V and W are N and X is C; Iii) X and V are N, Z and W are CH, and Y is C; Iv) Y, Z and V are N, W is CH and X is C; v) X, Z and V are N, W is CH, and Y is C; Vi) X is N, Z, V and W are CH, and Y is C; Vii) Y is N, Z, V and W are CH, and X is C; Viii) Z is NH, V and W are CH, and X and Y are C; Ix) V is NH, Z and W are CH, and X and Y are C; x) W is NH, V and Z are CH, and X and Y are C; Xi) V and W are N or NH, Z is CH, and X and Y are C; Xii) V and Z are N or NH, W is CH, and X and Y are C; Xiii) Z and W are N or NH, V is CH, and X and Y are C; Xiv) Y and W are N, V and Z are CH, and X is C; Xv) X and W are N, V and Z are CH, and Y is C; Xvi) X and Z are N or NH, V and W are CH, and Y is C; Xvii) Y and Z are N, V and W are CH, and X is C; Xviii) Y, V and W are N, Z is CH, and X is C; Xix) Z, V and W are N or NH, X and Y are C; Xx) X, W and V are N, Z is CH, and Y is C; Xxi) Y, Z and W are N, V is CH, X is C; or Xxii) X, Z, V and W are N and Y is C; P is C(R ⁶ ) or N; Q is O or S; D is selected from NH, O, S or CH ₂ ; E is selected from NH, O or CH ₂ ; L is selected from the group consisting of a single bond, S, SO, SO ₂ , CO, C(O)O, S(O)O or S(O) ₂ O; Each R ^{1 is} independently selected from halogen, amino, hydroxy, cyano, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; R ^{2 is} selected from C _3-12 cycloalkyl, C _3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R ³ ; R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, containing 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, containing 1, 2 or 3 5-6 membered heteroaryl CH ₂ -, -OR ⁴ , -SR ⁴ , -N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N from N, O or S atoms R ⁴ ) ₂ , -C(O)R ⁴ , -S(O)R ⁴ , -S(O)OR ⁴ , -S(O)N(R ⁴ ) ₂ , -S(O) ₂ R ⁴ , -S(O) ₂ OR ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -OC(O)R ⁴ , -OC(O)OR ⁴ , -OC(O)N(R ⁴ ) ₂ , -N(R ⁴ )C(O)R ⁴ , -N(R ⁴ )C(O)OR ⁴ , -N(R ⁴ )C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S (O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , Wherein C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, 5-6 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S atoms, aryl CH ₂ - can be any Optionally substituted with one or more groups independently selected from R ⁵ ; Each R ^{4 is} independently selected from H, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms; R ^{5 is} selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; R ^{6 is} selected from H, halogen, amino, cyano, hydroxy, -COOH or halogenated C _1-3 alkyl; m is 0, 1, or 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is absent or ring A is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, or a hydrazine ring. a azine ring, a pyrazine ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a tetrazole ring or a triazine ring; preferably, ring A is absent or ring A is a benzene ring or a pyridine ring; further preferably, Ring A does not exist or ring A is

The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, each R ^{1 is} independently selected from halogen, halogenated C _1-3 alkyl or C _1-6 alkyl; preferably, each R ¹ Independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, Fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or trichloromethyl; further preferably, each R ^{1 is} independently selected from Fluorine, chlorine or trifluoromethyl. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring B is an aromatic ring, wherein i) Y and V are N, Z and W are CH, and X is C; ii) Y, Z, V and W are N, X is C; iii) X and V are N, Z and W are CH, Y is C; iv) Y, Z and V are N, W is CH, and X is C; v) X, Z and V are N, W is CH and Y is C. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, structural unit

Selected from

The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, structural unit

Selected from

A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, D is selected from NH, O or CH ₂ ; and E is selected from NH, O, or CH ₂ . The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, -DC(Q)-E- is selected from the group consisting of -NHC(O)NH-, -NHC(S)NH-, -OC (O) NH-, -NHC(O)CH ₂ - or -CH ₂ C(O)NH-. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a single bond or SO ₂ . The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms, which may be optionally substituted by one or more groups independently selected from R ³ ; preferably, R ^{2 is} selected from cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, losing a hydrogen atom at any position

Phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetra An oxazolyl, triazinyl group, which may be optionally substituted by one or more groups independently selected from R ³ ; further preferably, R ^{2 is} selected from cyclohexyl, which loses a hydrogen atom at any position.

a phenyl, pyridyl or pyrimidinyl group, which may be optionally substituted by one or more groups independently selected from R ³ ; more preferably, R ^{2 is} selected from cyclohexyl, which loses a hydrogen atom at any position.

a phenyl, pyridyl or pyrimidinyl group, which may be optionally substituted by one or more groups independently selected from R ³ ; more preferably, R ^{2 is} selected from

A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halogenated C _1-3 alkyl, C _1-6 alkyl, C _3-6 heterocycloalkyl, 5-6 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms, C _3-6 heterocycloalkyl CH ₂ -, -OR ⁴ , - SR ⁴ , -S(O) ₂ R ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , wherein C _1-6 alkyl, C _3-6 heterocycloalkane a 5-6 membered heteroaryl or C _3-6 heterocycloalkyl CH ₂ - containing 1, 2 or 3 selected from N, O or S atoms may be optionally independently selected from one or more Substituting for a group of R ⁵ ; preferably, R ^{3 is} selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, Trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, -OR ⁴ , -SR ⁴ , -S(O) ₂ R ⁴ , -S ( O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P (O)(R ⁴ ) ₂ , -P(O)(OR ⁴ ) ₂ , methyl, ethyl, propyl, isopropyl, butyl Base, isobutyl, tert-butyl, losing a H atom at any position

Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, Triazinyl,

Among them, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, which loses a H atom at any position

Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, Triazinyl,

Optionally substituted with one or more groups independently selected from R ⁵ ; further preferably, R ^{3 is} selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, -OR ⁴ , -SR ⁴ , -S(O) ₂ R ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ ) S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ , -P(O)(OR ⁴ ) ₂ , methyl, losing a hydrogen atom at any position

Tetrazolyl or

Where the methyl group, at any position, loses a hydrogen atom

Tetrazolyl or

Optionally substituted with one or more groups independently selected from R ⁵ ; more preferably, R ^{3 is} selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, -OCF ₃ , SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₂ NH ₂ , -C(O)OCH ₃ , -COOH, -C(O)NHCH ₃ , -C(O)NH ₂ , -NHS (O) ₂ NH ₂ , -P(O)(CH ₃ ) ₂ , -P(O)(OCH ₂ CH ₃ ) ₂ , -C(OH)(CF ₃ ) ₂ ,

The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, each R ^{4 is} independently selected from H, halo C _1-3 alkyl or C _1-6 alkyl; preferably, Each R ^{4 is} independently selected from the group consisting of H, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, Monochloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; further preferably, each R ^{4 is} independently selected from H, trifluoromethyl, methyl or ethyl. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R ^{5 is} selected from the group consisting of hydroxyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoro. ethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, a chloromethyl, dichloromethyl or trichloromethyl; preferably, R ⁵ is selected from hydroxy or trifluoromethyl. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R ^{6 is} selected from H or halogen, preferably R ^{6 is} selected from H or chlorine. a compound of formula II or a pharmaceutically acceptable salt thereof,

among them, Ring A is a benzene ring or contains 1, 2 or 3 5-6 membered heteroaryl rings selected from N, O or S atoms; Ring B is an aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, in particular, i) Y and V are N, Z and W are CH, and X is C; Ii) Y, Z, V and W are N and X is C; Iii) X and V are N, Z and W are CH, and Y is C; Iv) Y, Z and V are N, W is CH and X is C; v) X, Z and V are N, W is CH, and Y is C; Vi) X is N, Z, V and W are CH, and Y is C; Vii) Y is N, Z, V and W are CH, and X is C; Viii) Z is NH, V and W are CH, and X and Y are C; Ix) V is NH, Z and W are CH, and X and Y are C; x) W is NH, V and Z are CH, and X and Y are C; Xi) V and W are N or NH, Z is CH, and X and Y are C; Xii) V and Z are N or NH, W is CH, and X and Y are C; Xiii) Z and W are N or NH, V is CH, and X and Y are C; Xiv) Y and W are N, V and Z are CH, and X is C; Xv) X and W are N, V and Z are CH, and Y is C; Xvi) X and Z are N or NH, V and W are CH, and Y is C; Xvii) Y and Z are N, V and W are CH, and X is C; Xviii) Y, V and W are N, Z is CH, and X is C; Xix) Z, V and W are N or NH, X and Y are C; Xx) X, W and V are N, Z is CH, and Y is C; Xxi) Y, Z and W are N, V is CH, X is C; or Xxii) X, Z, V and W are N and Y is C; P is C(R ⁶ ) or N; Q is O or S; L is selected from the group consisting of a single bond, S, SO, SO ₂ , CO, C(O)O, S(O)O or S(O) ₂ O; Each R ^{1 is} independently selected from halogen, amino, hydroxy, cyano, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; R ^{2 is} selected from C _3-12 cycloalkyl, C _3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R ³ ; R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, containing 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, containing 1, 2 or 3 5-6 membered heteroaryl CH ₂ -, -OR ⁴ , -SR ⁴ , -N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N from N, O or S atoms R ⁴ ) ₂ , -C(O)R ⁴ , -S(O)R ⁴ , -S(O)OR ⁴ , -S(O)N(R ⁴ ) ₂ , -S(O) ₂ R ⁴ , -S(O) ₂ OR ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -OC(O)R ⁴ , -OC(O)OR ⁴ , -OC(O)N(R ⁴ ) ₂ , -N(R ⁴ )C(O)R ⁴ , -N(R ⁴ )C(O)OR ⁴ , -N(R ⁴ )C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S (O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , Wherein C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, 5-6 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S atoms, aryl CH ₂ - can be any Optionally substituted with one or more groups independently selected from R ⁵ ; Each R ^{4 is} independently selected from H, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms; R ^{5 is} selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; R ^{6 is} selected from H, halogen, amino, cyano, hydroxy, -COOH or halogenated C _1-3 alkyl; m is 0, 1, or 2. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein ring A is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, or a pyrazine. a ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a tetrazole ring or a triazine ring; preferably, the ring A is a benzene ring or a pyridine ring; further preferably, the ring A is absent or the ring A is

The compound of claim 16 or 17, or a pharmaceutically acceptable salt thereof, each R ^{1 is} independently selected from halogen, halo C _1-3 alkyl or C _1-6 alkyl; preferably, each R ¹ Independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, Fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or trichloromethyl; further preferably, each R ^{1 is} independently selected from Fluorine, chlorine or trifluoromethyl. The compound of any one of claims 16-18, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein ring B is an aromatic ring, wherein i) Y and V are N, Z and W are CH, and X is C; ii) Y, Z, V and W are N, X is C; iii) X and V are N, Z and W are CH, Y is C; iv) Y, Z and V are N, W is CH, and X is C; v) X, Z and V are N, W is CH and Y is C. A compound according to any one of claims 16 to 20, or a pharmaceutically acceptable salt thereof, structural unit

Selected from

The compound of any one of claims 16-21, or a pharmaceutically acceptable salt thereof, structural unit

Selected from

The compound of any one of claims 16-22, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a single bond or SO ₂ . A compound according to any one of claims 16 to 23, or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms, which may be optionally substituted by one or more groups independently selected from R ³ ; preferably, R ^{2 is} selected from cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, losing a hydrogen atom at any position

Phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetra An oxazolyl, triazinyl group, which may be optionally substituted by one or more groups independently selected from R ³ ; further preferably, R ^{2 is} selected from cyclohexyl, which loses a hydrogen atom at any position.

a phenyl, pyridyl or pyrimidinyl group, which may be optionally substituted by one or more groups independently selected from R ³ ; more preferably, R ^{2 is} selected from

It may be optionally substituted by one or more groups independently selected from R ³ ; more preferably, R ^{2 is} selected from

A compound according to any one of claims 16 to 24, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 heterocycloalkyl, 5-6 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms, C _3-6 heterocycloalkyl CH ₂ -, -OR ⁴ , - SR ⁴ , -S(O) ₂ R ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , wherein C _1-6 alkyl, C _3-6 heterocycloalkane a 5-6 membered heteroaryl or C _3-6 heterocycloalkyl CH ₂ - containing 1, 2 or 3 selected from N, O or S atoms may be optionally independently selected from one or more Substituting for a group of R ⁵ ; preferably, R ^{3 is} selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, Trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, -OR ⁴ , -SR ⁴ , -S(O) ₂ R ⁴ , -S ( O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P _{^{(O) (R 4) 2}} , -P (O) (OR 4) 2, methyl, ethyl, propyl, isopropyl, , Isobutyl, tert-butyl group, a H atom at any position of losing

Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, Triazinyl,

Among them, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, which loses a H atom at any position

Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, Triazinyl,

Optionally substituted with one or more groups independently selected from R ⁵ ; further preferably, R ^{3 is} selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, -OR ⁴ , -SR ⁴ , -S(O) ₂ R ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N(R ⁴ ) ₂ , -N(R ⁴ ) S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ , -P(O)(OR ⁴ ) ₂ , methyl, losing a hydrogen atom at any position

Tetrazolyl or

Where the methyl group, at any position, loses a hydrogen atom

Tetrazolyl or

Optionally substituted with one or more groups independently selected from R ⁵ ; more preferably, R ^{3 is} selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, -OCF ₃ , SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₂ NH ₂ , -C(O)OCH ₃ , -COOH, -C(O)NHCH ₃ , -C(O)NH ₂ , -NHS (O) ₂ NH ₂ , -P(O)(CH ₃ ) ₂ , -P(O)(OCH ₂ CH ₃ ) ₂ , -C(OH)(CF ₃ ) ₂ ,

The compound of any one of claims 16-25, or a pharmaceutically acceptable salt thereof, each R ^{4 is} independently selected from H, halo C _1-3 alkyl or C _1-6 alkyl; preferably, Each R ^{4 is} independently selected from the group consisting of H, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, Monochloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; further preferably, each R ^{4 is} independently selected from H, trifluoromethyl, methyl or ethyl. A compound according to any one of claims 16 to 26, or a pharmaceutically acceptable salt thereof, wherein R ^{5 is} selected from the group consisting of hydroxyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoro. ethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, a chloromethyl, dichloromethyl or trichloromethyl; preferably, R ⁵ is selected from hydroxy or trifluoromethyl. The compound of any one of claims 16 to 27, or a pharmaceutically acceptable salt thereof, wherein R ^{6 is} selected from H or halogen; preferably, R ^{6 is} selected from H or chlorine. a compound of formula III or a pharmaceutically acceptable salt thereof,

among them, Ring B is an aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, in particular, i) Y and V are N, Z and W are CH, and X is C; Ii) Y, Z, V and W are N and X is C; Iii) X and V are N, Z and W are CH, and Y is C; Iv) Y, Z and V are N, W is CH and X is C; v) X, Z and V are N, W is CH, and Y is C; Vi) X is N, Z, V and W are CH, and Y is C; Vii) Y is N, Z, V and W are CH, and X is C; Viii) Z is NH, V and W are CH, and X and Y are C; Ix) V is NH, Z and W are CH, and X and Y are C; x) W is NH, V and Z are CH, and X and Y are C; Xi) V and W are N or NH, Z is CH, and X and Y are C; Xii) V and Z are N or NH, W is CH, and X and Y are C; Xiii) Z and W are N or NH, V is CH, and X and Y are C; Xiv) Y and W are N, V and Z are CH, and X is C; Xv) X and W are N, V and Z are CH, and Y is C; Xvi) X and Z are N or NH, V and W are CH, and Y is C; Xvii) Y and Z are N, V and W are CH, and X is C; Xviii) Y, V and W are N, Z is CH, and X is C; Xix) Z, V and W are N or NH, X and Y are C; Xx) X, W and V are N, Z is CH, and Y is C; Xxi) Y, Z and W are N, V is CH, X is C; or Xxii) X, Z, V and W are N and Y is C; Q is O or S; D is selected from NH, O, S or CH ₂ ; E is selected from NH, O or CH ₂ ; L is selected from the group consisting of a single bond, S, SO, SO ₂ , CO, C(O)O, S(O)O or S(O) ₂ O; Each R ^{1 is} independently selected from halogen, amino, hydroxy, cyano, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; R ^{2 is} selected from C _3-12 cycloalkyl, C _3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R ³ ; R ^{3 is} selected from the group consisting of halogen, cyano, nitro, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, containing 1, 2 or 3 heteroatoms selected from N, 5-6 membered O or S atoms hetero aryl group, C _3-6 cycloalkyl, CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, 1, 2 or 3 selected from the group comprising 5-6 membered heteroaryl CH ₂ -, -OR ⁴ , -SR ⁴ , -N(R ⁴ ) ₂ , -C(O)OR ⁴ , -C(O)N from N, O or S atoms R ⁴ ) ₂ , -C(O)R ⁴ , -S(O)R ⁴ , -S(O)OR ⁴ , -S(O)N(R ⁴ ) ₂ , -S(O) ₂ R ⁴ , -S(O) ₂ OR ⁴ , -S(O) ₂ N(R ⁴ ) ₂ , -OC(O)R ⁴ , -OC(O)OR ⁴ , -OC(O)N(R ⁴ ) ₂ , -N(R ⁴ )C(O)R ⁴ , -N(R ⁴ )C(O)OR ⁴ , -N(R ⁴ )C(O)N(R ⁴ ) ₂ , -N(R ⁴ )S (O)N(R ⁴ ) ₂ , -N(R ⁴ )S(O) ₂ N(R ⁴ ) ₂ , -P(O)(R ⁴ ) ₂ or -P(O)(OR ⁴ ) ₂ , Wherein C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, 5-6 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms, C _3-6 cycloalkyl CH ₂ -, C _3-6 heterocycloalkyl CH ₂ -, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S atoms, aryl CH ₂ - can be any Optionally substituted with one or more groups independently selected from R ⁵ ; Each R ^{4 is} independently selected from H, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms; R ^{5 is} selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C _1-3 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; m is 0, 1, or 2. The compound of claim 29, or a pharmaceutically acceptable salt thereof, each R ^{1 is} independently selected from halogen, halo C _1-3 alkyl or C _1-6 alkyl; preferably, each R ¹ independently Selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl Further, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or trichloromethyl; further preferably, each R ^{1 is} independently selected from chlorine or Trifluoromethyl. The compound of claim 29 or 30, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1. The compound of any one of claims 29-31, or a pharmaceutically acceptable salt thereof, wherein Ring B is an aromatic ring wherein i) Y and V are N, Z and W are CH, and X is C; ii) X and V are N, Z and W are CH, and Y is C. The compound of any one of claims 29-32, or a pharmaceutically acceptable salt thereof, structural unit

Selected from

The compound of any one of claims 29-33, or a pharmaceutically acceptable salt thereof, structural unit

Selected from

The compound of any one of claims 29-34, or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of NH, O or CH ₂ ; and E is selected from the group consisting of NH, O or CH ₂ . The compound of any one of claims 29-35, or a pharmaceutically acceptable salt thereof, -DC(Q)-E- is selected from the group consisting of -NHC(O)NH-, -NHC(S)NH-, -OC (O) NH-, -NHC(O)CH ₂ - or -CH ₂ C(O)NH-. The compound of any one of claims 29-36, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a single bond. The compound or a pharmaceutically acceptable salt thereof according to any of claims 29-37, R ² is selected from phenyl, or containing 1, 2 or 3 heteroatoms selected from N, O or S atoms, 5-6 membered heteroaryl An aryl group which may be optionally substituted by one or more groups independently selected from R ³ ; preferably, R ^{2 is} selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridine , pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazinyl, which may optionally be independently selected by one or more Substituted from a group of R ³ ; further preferably, R ^{2 is} selected from phenyl, pyridyl or pyrimidinyl, which may be optionally substituted by one or more groups independently selected from R ³ ; more preferably, R ² selected from

It may be optionally substituted by one or more groups independently selected from R ³ ; more preferably, R ^{2 is} selected from

The compound of any one of claims 29-38, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is} selected from halogen or halo C _1-3 alkyl; preferably, R ^{3 is} selected from fluoro, chloro, bromo or tri Fluoromethyl. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein the compound is preferably:

A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, is treated with guanamine 2,3-dioxygenase (IDO) and tryptophan 2,3-oxygenase (TDO) A method of mediated immunosuppressive disease comprising administering to a mammal, preferably a human in need of such treatment, a therapeutically effective amount of a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt thereof, or Claim 41 Pharmaceutical composition. The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 41, for the preparation or prevention of guanamine 2,3-dioxygenase (IDO) And the use of tryptophan 2,3-oxygenase (TDO) mediated drugs for immunosuppressive diseases. The use according to claim 43, wherein the immunosuppressive disease is associated with an infectious disease or cancer selected from the group consisting of influenza, hepatitis C virus (HCV), human papillomavirus (HPV) , cytomegalovirus (CMV), poliovirus, herpes zoster virus, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV) or Coxsackie virus; said cancer is selected from colon cancer , pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, lymphoma, leukemia or melanoma.