3- indazole quinoline ketone compounds, preparation method and its in application pharmaceutically
阅读说明：本技术 3-吲唑啉酮类化合物、其制备方法及其在医药学上的应用 (3- indazole quinoline ketone compounds, preparation method and its in application pharmaceutically ) 是由 不公告发明人 于 2018-05-25 设计创作，主要内容包括：本发明涉及一种新的调控或抑制吲哚胺2,3-双加氧酶(IDO)活性的3-吲唑啉酮类化合物,其制备方法及其在医药学上的应用。具体而言,本发明涉及一种通式(I)所示的化合物及其可药用的盐、含有所述化合物或其可药用的盐的药物组合物、应用所述化合物或其可药用的盐治疗和/或预防IDO介导的相关性病症、特别是肿瘤的方法以及所述化合物或其可药用的盐的制备方法。本发明还涉及所述化合物或其可药用的盐或含有所述化合物或其可药用的盐的药物组合物在制备用于治疗和/或预防IDO介导的相关性病症、特别是肿瘤的药物中的用途。其中通式(I)的各取代基与说明书中的定义相同。<Image he="247" wi="630" file="DDA0001672849270000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to a kind of new regulation or inhibition indoleamine 2,3-dioxygenase (IDO) active 3- indazole quinoline ketone compounds, preparation method and its in application pharmaceutically.Specifically, the present invention relates to a kind of logical formula (I) compound represented and its pharmaceutical salt, the pharmaceutical composition containing the compound or its pharmaceutical salt, using the method for the compound or its pharmaceutical salts for treating and/or prevention IDO the correlation illness, particularly tumour mediated and the preparation method of the compound or its pharmaceutical salt.Pharmaceutical composition the invention further relates to the compound or its pharmaceutical salt or containing the compound or its pharmaceutical salt is in preparation for treating and/or preventing the purposes in the correlation illness of IDO mediation, particularly the drug of tumour.Each substituent group of its formula of (I) is identical as the definition in specification.)
1. logical formula (I) compound represented:
Or its pharmaceutical salt, prodrug, stable isotope derivative, isomers and its form of mixtures, in which:
Z1、Z2、Z3And Z4It is each independently selected from N or CR3, but Z1、Z2、Z3And Z4It is not simultaneously N；
R1And R2The C for being each independently selected from H or optionally replacing1-4Alkyl, C3-6Naphthenic base or 4-7 circle heterocyclic ring base；Alternatively, R1And R2 One is collectively formed optionally containing the heteroatomic 3-7 member ring selected from O, N and S with the carbon atom of connection；
A is N or CR4；
B is N or CR5；
L is key ,-O- or-CR6R7-；
C is 4-7 circle heterocyclic ring base, 6-10 member aryl or the 5-10 unit's heteroaryl optionally replaced；
R3Independently selected from H, halogen, cyano ,-SF5、-OR、-SR、-NR2、-S(O)mR、-S(O)2NR2、-N(R)S(O)2R、-C (O)NR2,-N (R) C (O) R, or the C optionally replaced1-4Alkyl, C3-6Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 member heteroaryl Base；
R4And R5It is each independently selected from H, halogen, OH, or the C optionally replaced1-4Alkyl or-O-C1-4Alkyl；
R6And R7The C for being each independently selected from H or optionally replacing1-4Alkyl；
The C that R replaces independently selected from H or optionally1-4Alkyl, C3-6Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 unit's heteroaryl； The optional nitrogen-atoms in connection of two R on the same nitrogen-atoms is collectively formed one optionally containing another selected from O, N and S Outer heteroatomic 4-7 circle heterocyclic ring；
M is 1 or 2.
2. compound according to claim 1 or its pharmaceutical salt, prodrug, stable isotope derivative, isomers and Its form of mixtures, in which:
Z1、Z2、Z3And Z4It is each independently selected from N or CR3, but Z1、Z2、Z3And Z4In at most one be N；
R1And R2The C for being each independently selected from H or optionally replacing1-4Alkyl；
A is N or CR4；
B is N or CR5；
L is key or-O-；
C is optionally by halogen, cyano, C1-4Alkyl or halogenated C1-4Alkyl-substituted 4-7 circle heterocyclic ring base, 6-10 member aryl or 5-10 Unit's heteroaryl；
R3Independently selected from H, halogen, cyano ,-SF5、-OR、-SR、-NR2、-S(O)mR、-S(O)2NR2、-N(R)S(O)2R、-C (O)NR2,-N (R) C (O) R, or the C optionally replaced1-4Alkyl, C3-6Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 member heteroaryl Base；
R4And R5It is each independently selected from H, halogen, OH, C1-4Alkyl or-O-C1-4Alkyl；
The C that R replaces independently selected from H or optionally1-4Alkyl, C3-6Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 unit's heteroaryl； The optional nitrogen-atoms in connection of two R on the same nitrogen-atoms is collectively formed one optionally containing another selected from O, N and S Outer heteroatomic 4-7 circle heterocyclic ring；
M is 1 or 2.
3. compound according to claim 1 or 2 or its pharmaceutical salt, prodrug, stable isotope derivative, isomers And its form of mixtures, in which:
Z1、Z2、Z3And Z4It is each independently selected from N or CR3, but Z1、Z2、Z3And Z4In at most one be N；
R1And R2It is each independently selected from H or C1-4Alkyl；
A is N or CH；
B is N or CH；
L is key；
C is optionally by halogen, cyano, C1-4Alkyl or halogenated C1-4Alkyl-substituted 5-10 unit's heteroaryl；
R3Independently selected from H, halogen, cyano, or the C optionally replaced1-4Alkyl ,-O-C1-4Alkyl, C3-6Naphthenic base or 4-7 member are miscellaneous Ring group；
The optional substitution refers to and is replaced by substituent group selected from the following: halogen ,-CN ,-OR ' ,-NR ' R ", wherein R ' and R " is each From independently selected from H, C1-4Alkyl or C3-7Naphthenic base.
4. according to the described in any item compounds of preceding claims or its pharmaceutical salt, prodrug, stable isotope derivative, Isomers and its form of mixtures, in which:
Z1And Z4It is each independently selected from N or CH, Z2And Z3It is each independently selected from N or CR3, but Z1、Z2、Z3And Z4In at most one A is N；
R1And R2It is each independently selected from H or C1-4Alkyl；
A is CH；
B is CH；
L is key；
C is optionally by halogen or C1-4Alkyl-substituted 5-10 unit's heteroaryl；
R3For H, halogen or cyano.
5. being the compound of following general formula (IIa)-(IIc) according to the described in any item compounds of preceding claims:
Wherein:
R1For C1-4Alkyl；
Z1、Z2、Z3And Z4Definition as described in claim 1-4.
6. being the compound of following general formula (III) according to the described in any item compounds of preceding claims:
Wherein:
R1For C1-4Alkyl；
Z1、Z2、Z3And Z4Definition as described in claim 1-4.
7. the described in any item compounds of preceding claims or its pharmaceutical salt, prodrug, stable isotope derivative, isomery Body and its form of mixtures, the compound are selected from:
8. pharmaceutical composition, described pharmaceutical composition includes compound according to claim 1-7 or it can medicine Salt, prodrug, stable isotope derivative, isomers and its form of mixtures and pharmaceutically acceptable carrier and figuration Agent.
9. pharmaceutical composition, described pharmaceutical composition includes compound according to claim 1-7 or it can medicine Salt, prodrug, stable isotope derivative, isomers and its form of mixtures and at least one additional drug, wherein institute Stating at least one additional drug is chemotherapeutant, immune and/or inflammation modulators, relevant nerve diseases regulator or anti-sense Stain.
10. pharmaceutical composition according to claim 9, wherein at least one additional drug is the suppression of immunologic test point Preparation.
11. compound according to claim 1-7 or its pharmaceutical salt, prodrug, stable isotope derivative, Isomers and its form of mixtures or according to the described in any item pharmaceutical compositions of claim 8-10 preparation for treat and/ Or prevention IDO mediate diseases related, the purposes especially in the drug of tumour, wherein the tumour be selected from prostate cancer, Colon and rectum carcinoma, film gland cancer, cervix cancer, gastric cancer, carcinoma of endometrium, the cancer of the brain, liver cancer, the dirty cancer of wing, oophoroma, carcinoma of testis, Head cancer, neck cancer, cutaneum carcinoma, mesothelium endometrial carcinomas, lymthoma, leukaemia, cancer of the esophagus, breast cancer, muscle cancer, connective tissue cancer, Lung cancer, adrenal, thyroid cancer, kidney, osteocarcinoma, glioblastoma, celiothelioma, sarcoma, choriocarcinoma, skin base cell Cancer or seminoma of testis.
Technical field
The present invention relates to a kind of new regulation or inhibit that indole amine 2,3-dioxygenase (IDO) is active to contain 3- indazole quinoline Ketone compounds or its pharmaceutical salt, the pharmaceutical composition containing the compound or its pharmaceutical salt, the compound Its pharmaceutical salt preparation method and the compound or its pharmaceutical salt or containing the compound or its can medicine The pharmaceutical composition of salt is in preparation for treating and/or preventing the correlation illness of IDO mediation, particularly the drug of tumour In purposes and its application method.
Background technique
Indoleamine 2,3-dioxygenase (IDO) is a kind of monomeric protein containing ferroheme, is distributed widely in addition to liver Tissue in, be catalyzed tryptophan oxidative degradation at kynurenin, be the rate-limiting enzyme of kynurenine metabolism pathway.Tryptophan is T thin The essential amino acid of born of the same parents' proliferation, while being also the precursor substance of synthesis neurotransmitter.If the tryptophan in cell micro-environment is dense Degree reduces, and the level of kynurenin increases, and will lead to T cell and stagnates in G1 mid-term, thus to the proliferation of T cell, differentiation and Activity has an impact.
IDO is in low expression level in normal cell, but is over-expressed in many tumor tissues, and tumor by local color is caused Propylhomoserin metabolic disorder and regulatory T cells are formed, and then the T cell immune tolerance of mediate tumor part, in the hair of malignant tumour Important function has been played in raw, development and transfer process.If the activity of IDO is suppressed, the tryptophan of near tumor cells Metabolism is effectively prevented, and can promote the growth of T cell, to enhance body immune system to antitumor function.Therefore, The research and development of IDO inhibitor have become the forward position focus of immunotherapy of tumors drug research.Preclinical study shows the selectivity of IDO Inhibitor INCB-024360 single-dose can effectively the activity suppression of blank mice plasma IDO IDO deficient mice water Flat, repeat administration hinders the expansion (Koblish et.al, Mol.Cancer Ther.2010,9,489-98) of CT26 tumour.
IDO inhibitor can also with other anti-tumor small molecular drugs and immunologic test point inhibitor, such as CTLA-4, The antibody such as PD-1 and PD-L1 carry out combination therapy, to reinforce the antitumor curative effect of drug.Small molecule IDO inhibitor and immune inspection The combined immunization treatment of inhibitor is made an inventory of in clinical test, such as indoximod/ipilimumab, epacadostat/ The combination therapy clinical test of pembrolizumab, epacadostat/nivolumab, indoximod/MEDI-4736 etc.. Preliminary clinical results show IDO micromolecular inhibitor and PD-1 drug combination, have additive effect, take in kinds of tumors treatment Good disease control rate, and than PD-1/CTLA-4 Small side effects, show wide immunotherapy of tumors prospect (AACR, 2017；ASCO, 2017).
In addition to cancer, IDO is also related to other many diseases, for example, immunosupress, chronic infection, virus infection, itself Immunity disease or illness (such as rheumatoid arthritis), nerve or neuropsychiatric disease or illness (such as depression) etc..Cause This, IDO inhibitor has huge therapeutic value.
Small molecule IDO inhibitor drug is also in clinical experimental stage at present, in addition to the INCB-024360 of Incyte (epacadostat), there are also the indoximod of NewLink Genetics and the BMS-986205 of Bristol Myers Squibb etc..
Since IDO inhibitor treats the prospect shown in kinds of tumors and Other diseases in independent and combined immunization, It develops the concern for having attracted numerous biopharmaceutical companys, has disclosed the patent application of a series of IDO inhibitor, wherein Including WO2006122150A1, WO2011056652A1, WO2013069765A1, WO2014186035A1, WO2015002918A1、WO2016073738A2、WO2016073770A1、WO2016181348A1、WO2016161960A1、 WO2017079669A1 etc., but still need to develop new compound, it is higher with more preferable druggability and in immunization therapy Response rate.By being continually striving to, the present invention devises the compound with structure shown in logical formula (I), and is found to have such knot The compound of structure shows the excellent active effect of inhibition IDO and effect.
Summary of the invention
The present invention provides a kind of logical formula (I) compound represented as IDO inhibitor:
Or its pharmaceutical salt, prodrug, stable isotope derivative, isomers and its form of mixtures, in which:
Z1、Z2、Z3And Z4It is each independently selected from N or CR3, but Z1、Z2、Z3And Z4It is not simultaneously N；
R1And R2The C for being each independently selected from H or optionally replacing1-4Alkyl, C3-6Naphthenic base or 4-7 circle heterocyclic ring base；Alternatively, R1And R2One is collectively formed optionally containing the heteroatomic 3-7 member ring selected from O, N and S with the carbon atom of connection；
A is N or CR4；
B is N or CR5；
L is key ,-O- or-CR6R7-；
C is 4-7 circle heterocyclic ring base, 6-10 member aryl or the 5-10 unit's heteroaryl optionally replaced；
R3Independently selected from H, halogen, cyano ,-SF5、-OR、-SR、-NR2、-S(O)mR、-S(O)2NR2、-N(R)S(O)2R、-C(O)NR2,-N (R) C (O) R, or the C optionally replaced1-4Alkyl, C3-6Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 member are miscellaneous Aryl；
R4And R5It is each independently selected from H, halogen, OH, or the C optionally replaced1-4Alkyl or-O-C1-4Alkyl；
R6And R7The C for being each independently selected from H or optionally replacing1-4Alkyl；
The C that R replaces independently selected from H or optionally1-4Alkyl, C3-6Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 member heteroaryl Base；The optional nitrogen-atoms in connection of two R on the same nitrogen-atoms is collectively formed one optionally containing selected from O, N and S Other heteroatomic 4-7 circle heterocyclic ring；
M is 1 or 2.
One embodiment of the invention is related to above-mentioned logical formula (I) compound represented or its pharmaceutical salt, prodrug, steady Determine isotope derivatives, isomers and its form of mixtures, in which:
Z1、Z2、Z3And Z4It is each independently selected from N or CR3, but Z1、Z2、Z3And Z4In at most one be N；
R1And R2The C for being each independently selected from H or optionally replacing1-4Alkyl；
A is N or CR4；
B is N or CR5；
L is key or-O-；
C is optionally by halogen, cyano, C1-4Alkyl or halogenated C1-4Alkyl-substituted 4-7 circle heterocyclic ring base, 6-10 member aryl or 5-10 unit's heteroaryl；
R3Independently selected from H, halogen, cyano ,-SF5、-OR、-SR、-NR2、-S(O)mR、-S(O)2NR2、-N(R)S(O)2R、-C(O)NR2,-N (R) C (O) R, or the C optionally replaced1-4Alkyl, C3-6Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 member are miscellaneous Aryl；
R4And R5It is each independently selected from H, halogen, OH, C1-4Alkyl or-O-C1-4Alkyl；
The C that R replaces independently selected from H or optionally1-4Alkyl, C3-6Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 member heteroaryl Base；The optional nitrogen-atoms in connection of two R on the same nitrogen-atoms is collectively formed one optionally containing selected from O, N and S Other heteroatomic 4-7 circle heterocyclic ring；
M is 1 or 2.
Another embodiment of the invention be related to compound described in any of the above-described embodiment or its pharmaceutical salt, Prodrug, stable isotope derivative, isomers and its form of mixtures, in which:
Z1、Z2、Z3And Z4It is each independently selected from N or CR3, but Z1、Z2、Z3And Z4In at most one be N；
R1And R2It is each independently selected from H or C1-4Alkyl；
A is N or CH；
B is N or CH；
L is key；
C is optionally by halogen, cyano, C1-4Alkyl or halogenated C1-4Alkyl-substituted 5-10 unit's heteroaryl；
R3Independently selected from H, halogen, cyano, or the C optionally replaced1-4Alkyl ,-O-C1-4Alkyl, C3-6Naphthenic base or 4-7 Circle heterocyclic ring base；
The optional substitution refers to and is replaced by substituent group selected from the following: halogen ,-CN ,-OR ' ,-NR ' R ", wherein R ' and R " is each independently selected from H, C1-4Alkyl or C3-7Naphthenic base.
Another embodiment of the invention be related to compound described in any of the above-described embodiment or its pharmaceutical salt, Prodrug, stable isotope derivative, isomers and its form of mixtures, in which:
Z1And Z4It is each independently selected from N or CH, Z2And Z3It is each independently selected from N or CR3, but Z1、Z2、Z3And Z4In extremely More one are N；
R1And R2It is each independently selected from H or C1-4Alkyl；
A is CH；
B is CH；
L is key；
C is optionally by halogen or C1-4Alkyl-substituted 5-10 unit's heteroaryl；
R3For H, halogen or cyano.
Another embodiment of the invention is related to compound described in any of the above-described embodiment, and wherein C is optionally quilt Halogen or C1-4Alkyl-substituted quinolyl or pyridyl group, especially fluoroquinolone base.
Another embodiment of the invention is related to compound described in any of the above-described embodiment, wherein R1For C1-4Alkane Base, R2For H, especially R1For methyl, R2For H.
Another embodiment of the invention is related to compound described in any of the above-described embodiment, is following general formula (IIa)-(IIc) compound:
Another embodiment of the invention is related to compound described in any of the above-described embodiment, is following general formula (III) compound:
Another embodiment of the invention is related to above-mentioned logical formula (III) compound represented, wherein R1For methyl.
One embodiment of the invention is related to above-mentioned logical formula (I) compound represented, wherein the compound is selected from:
Or its prodrug, stable isotope derivative, pharmaceutical salt, isomers and its form of mixtures.
The compounds of this invention, which has the activity of IDO in Hela cell, significantly inhibits effect, preferably its IC50Less than 200nM, More preferable IC50Less than 50nM.
Therefore the compounds of this invention can be used for treating or preventing the diseases related of IDO mediation, including but not limited to cancer Disease, immunosupress, chronic infection, virus infection, autoimmune disease or illness (such as rheumatoid arthritis), nerve or mind Through mental disease or illness (such as depression) etc..The compounds of this invention is used to treating or preventing IDO associated tumors, including But it is dirty to be not limited to prostate cancer, colon and rectum carcinoma, film gland cancer, cervix cancer, gastric cancer, carcinoma of endometrium, the cancer of the brain, liver cancer, wing Cancer, oophoroma, carcinoma of testis, head cancer, neck cancer, cutaneum carcinoma (including melanoma and substrate cancer), mesothelium endometrial carcinomas, lymph Tumor, leukaemia, cancer of the esophagus, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including Small Cell Lung Cancer and non-small cell carcinoma), on kidney Gland cancer, thyroid cancer, kidney, osteocarcinoma, glioblastoma, celiothelioma, sarcoma (including Kaposi sarcoma), choriocarcinoma, skin Basal-cell carcinoma or seminoma of testis etc..Therefore, in another aspect, the present invention provide it is a kind for the treatment of or prevention IDO mediate Disease (such as described tumour) method comprising give the compound of the present invention of bacterium in need Or its pharmaceutical salt, prodrug, stable isotope derivative, isomers and its mixture or the drug comprising the compound Composition.
Another aspect of the present invention relates to as drug or for the logical formula (I) compound represented of medical usage or its Pharmaceutical salt, prodrug, stable isotope derivative, isomers and its mixture are used to treat or prevent IDO mediation Disease, such as cancer, immunosupress, chronic infection, virus infection, autoimmune disease or illness (such as rheumatoid arthrosis It is scorching), nerve or neuropsychiatric disease or illness (such as depression) etc..
The invention further relates to a kind of pharmaceutical composition, described pharmaceutical composition include compound of the present invention or its Pharmaceutical salt, prodrug, stable isotope derivative, isomers and its mixture and pharmaceutically acceptable carrier and figuration Agent.
Another aspect of the present invention relates to logical formula (I) compound represented or its pharmaceutical salt, prodrug, stable isotopes The purposes of derivative, isomers and its mixture or described pharmaceutical composition in medicine preparation, wherein the drug is for controlling Treat or prevent the disease that IDO is mediated, such as tumour and immunosupress.
Another aspect of the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes to change shown in logical formula (I) Close object or its pharmaceutical salt, prodrug, stable isotope derivative, isomers and its mixture and at least one additional medicine Object, wherein at least one additional drug is chemotherapeutant, immune and/or inflammation modulators (such as immunologic test point Inhibitor), relevant nerve diseases regulator or anti-infective.
According to the present invention, the drug can be any pharmaceutical dosage form, including but not limited to tablet, capsule, solution, Lyophilized preparation, injection.
Pharmaceutical preparation of the invention can include that the dosage unit form of the active constituent of predetermined amount is given with every dosage unit Medicine.This unit can be according to the illness for the treatment of, medication and the age of patient, weight and situation including, for example, 0.5 milligram to 1 Gram, preferably 1 milligram to 700 milligrams, particularly preferred 5 milligrams to 300 milligrams the compound of the present invention.Preferred dose unit formulation It is comprising those of daily dose or divided dose or the active constituent of its corresponding scores as above instructions.In addition it is possible to use pharmacy Well known method prepares such pharmaceutical preparation in field.
Pharmaceutical preparation of the present invention may be adapted to be administered by any desired appropriate method, such as pass through oral (including oral cavity Or it is sublingual), rectum, intranasal, part (including oral cavity, sublingual or percutaneous), vagina or parenterally it is (including subcutaneous, intramuscular, intravenous Or intradermal) method administration.Known all methods can be used in pharmaceutical field for example, by by active constituent and a kind of or more Kind excipient or one or more adjuvants merge to prepare such preparation.
Specific embodiment
Unless stated to the contrary, otherwise following that there are following meanings with term in the specification and in the claims.
Representation " C used hereinx-y" indicate carbon atom number range, wherein x and y is integer, such as C3-8Cycloalkanes basis representation has the naphthenic base of 3-8 carbon atom, i.e., with the naphthenic base of 3,4,5,6,7 or 8 carbon atoms.Also answer Understand, " C3-8" it also include any sub-range therein, such as C3-7、C3-6、C4-7、C4-6、C5-6Deng.
" alkyl " refers to containing 1 to 20 carbon atom, such as 1 to 8 carbon atom, 1 to 6 carbon atom or 1 to 4 carbon atom Saturation linear chain or branched chain hydrocarbyl group.The non-limiting example of alkyl includes methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propylene Base, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- trimethyl third Base, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl and 2- ethyl-butyl.Institute It states alkyl and can be and optionally replace.
" naphthenic base " refers to the saturation annular hydrocarbyl substituent containing 3 to 14 carboatomic ring atoms.Naphthenic base can be monocyclic carbocyclic ring, Usually contain 3 to 8,3 to 7 or 3 to 6 carboatomic ring atoms.The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl and suberyl.Naphthenic base selectively can be the double or tricyclic being fused to together, such as decahydro naphthalene. The naphthenic base, which can be, optionally to be replaced.
" heterocycle or heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic group comprising 3 to 20 rings Atom, such as can be 3 to 14,3 to 12,3 to 10,3 to 8,3 to 6 or 5 to 6 annular atoms, one of them or Multiple annular atoms are selected from nitrogen, oxygen or S (O)m(wherein m is integer 0 to 2), but do not include the ring portion of-O-O- ,-O-S- or-S-S- Point, remaining annular atom is carbon.Preferably include 3 to 12 annular atoms, more preferable 3 to 10 annular atoms, more preferable 4 to 7 rings original Son, most preferably 5 or 6 annular atoms, wherein 1~4 is hetero atom, more preferable 1~3 is hetero atom, and most preferably 1~2 is Hetero atom.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazinyl, pyranose, morpholinyl, thio Morpholinyl, high piperazine base, oxinane base and azetidinyl.Multiring heterocyclic includes that condensed, bridge joint or spiral shell are polycyclic miscellaneous Ring group, as octahydro cyclopenta [c] pyrroles, octahydro pyrrolo- [1,2-a] pyrazine, 3,8- diazabicylo [3.2.1] octane, 5- azaspiro [2.4] heptane, 2- oxa- -7- azaspiro [3.5] nonane etc..The heterocycle or heterocycle can be optional substitution 's.
" aryl or aromatic ring " refers to aromatic monocyclic or fused polycycle group containing 6 to 14 carbon atoms, preferably 6 to 10 Member, such as phenyl and naphthalene, most preferably phenyl.The aryl rings can be condensed on heteroaryl, heterocycle or cycloalkyl ring, In the ring that links together with precursor structure be aryl rings, non-limiting example includes:
The aryl or aromatic ring, which can be, optionally to be replaced.
" heteroaryl or hetero-aromatic ring " refers to the heteroaromatic system comprising 5 to 14 annular atoms, wherein 1 to 4 annular atom is selected from Hetero atom including oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan.More preferably heteroaryl is 5- or 6-membered, such as furyl, Thienyl, pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyrazolyl, imidazole radicals, tetrazole radical, oxazolyl, Isoxazolyl, thiazolyl, isothiazolyl, quinolyl etc..The heteroaryl ring can be condensed in aryl, heterocycle or cycloalkyl ring On, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting example includes:
The heteroaryl or hetero-aromatic ring, which can be, optionally to be replaced.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" cyano " refers to-CN.
" optional " mean event or environment described later can with but need not occur, which includes the event or ring The occasion that border occurs or do not occur.For example, mean " optionally by alkyl-substituted heterocyclic group " alkyl can with but necessarily deposit , the statement include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" optionally replace " refers to one or more hydrogen atoms in group, preferably 5, more preferably 1~3 hydrogen atom that This is independently replaced by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, ability Field technique personnel can determine in the case where not paying and excessively making great efforts and (pass through experiment or theoretical) possible or impossible substitution. It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key 's.The substituent group includes but is not limited to halogen, cyano, nitro, oxo ,-SF5、C1-4Alkyl, C3-7Naphthenic base, 4-7 circle heterocyclic ring Base, phenyl, 5-6 unit's heteroaryl ,-OR ' ,-NR ' R " ,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' R " ,-C (O) N (R ') OR " ,-OC (O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、-N(R′)S(O)2R″、- S(O)mR ' (m is 1 or 2) ,-S (O)2NR ' R " etc., wherein the alkyl, naphthenic base, heterocycle, phenyl or heteroaryl are optionally by one It is a or multiple selected from halogen, cyano, C1-4Alkyl, C3-7Naphthenic base, 4-7 circle heterocyclic ring base, phenyl, 5-6 unit's heteroaryl ,-OR ' ,- NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N (R′″)C(O)NR′R″、-N(R′)S(O)2R″、-S(O)2R′、-S(O)2Replaced the substituent groups such as NR ' R ".R ', R " and R ' " are respectively Independently selected from H, optionally containing the heteroatomic C selected from N, O and S1-4Alkyl, C3-7Naphthenic base, 4-7 circle heterocyclic ring base, phenyl or 5-6 unit's heteroaryl, wherein the alkyl, naphthenic base, heterocycle, phenyl or heteroaryl optionally by one or more selected from halogen, Cyano, C1-4Alkyl, halogenated C1-4Alkyl ,-O-C1-4Replaced the substituent groups such as alkyl；R ' and R " on the same nitrogen-atoms appoint Nitrogen-atoms in connection is selected to be collectively formed one optionally containing the other heteroatomic 4-7 circle heterocyclic ring selected from O, S and N.
" isomers " refers to the space arrangement for the form or sequence or its atom that with identical molecular formula but its atom combines not Same compound.The different isomers of its steric arrangement is known as " stereoisomer ".Stereoisomer includes optical siomerism Body, geometric isomer and conformer.
The compound of the present invention can exist with enantiomeric form.According to the structure of asymmetric carbon atom peripheral substituents Type, these optical isomers are " R " or " S " configurations.Optical isomer includes enantiomter and diastereoisomer.Preparation and The method of separating optical isomers is as known in the art.
There may also be geometric isomers for the compound of the present invention.The present invention considers by carbon-to-carbon double bond, carbon-to-nitrogen double bond, ring Various geometric isomers caused by the distribution of substituent group around alkyl or heterocyclic group and its mixture.Carbon-to-carbon double bond or Substituent group around carbon-nitrogen bond is appointed as Z or E configuration, and the substituent group around naphthenic base or heterocycle is appointed as cis or trans structure Type.
The compound of the present invention is also possible to display tautomerism, such as ketoenol tautomerization.
It should be understood that the present invention includes any tautomerism or stereoisomeric forms in any ratio and its mixture, and not only limit Any one tautomerism or stereoisomeric forms in any ratio used in the name of compound or chemical structural formula.
" isotope " includes all isotopes of the atom occurred in the compounds of this invention.Isotope includes with identical Those of atomic number but different quality number atom.Be suitble to the isotope in compound incorporated herein example be hydrogen, carbon, Nitrogen, oxygen, phosphorus, fluorine and chlorine, are such as, but not limited to respectively2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F and36Cl.This hair Bright compound isotopically labelled usually can by traditional technology well known by persons skilled in the art or by with appended embodiment Described in those similar methods replace isotope-labeled reagent to prepare using the reagent of isotope labelling appropriate. Such compound has various potential uses, such as the standard specimen and reagent in measurement bioactivity.In stable isotope In the case where, such compound beneficially modifies the potentiality of biology, pharmacology or pharmacokinetic property.
" prodrug " refers to that the compound of the present invention can be given in the form of prodrug.Prodrug refers to physiology item in vivo It is invented under part such as by (each is carried out using enzyme or in the presence of no enzyme) conversion cost oxidation, reduction, hydrolysis Bioactive compound derivative.The example of prodrug is following compounds: the wherein amino quilt in the compound of the present invention Acylated, alkylation or phosphorylation, such as eicosane acyl amino, alanylamino, oxy acid methyl neopentyl amino or in which hydroxyl Base is acylated, is alkylated, phosphorylation or is converted to borate, such as acetoxyl group, palm acyloxy, new pentane acyloxy, amber Acyloxy, fumaroyl oxygroup, alanyl oxygroup or in which carboxyl be esterified or amidation or in which sulfydryl with selectively to The carrier molecule of target and/or cytotropic cytosolic delivery drug, such as peptide form disulfide bridge bond.These compounds can be by The compound of the present invention is prepared according to known method.
" pharmaceutical salt " or " pharmaceutically acceptable salt " refer to by pharmaceutical alkali or acid, including inorganic base or acid With salt made of organic base or acid.In the case where the compound of the present invention contains one or more acid or basic groups, this Invention also includes their corresponding officinal salts.Therefore, the compound of the present invention containing acidic groups can deposit in the form of salts And can be used according to the invention, such as alkali metal salt, alkali salt or as ammonium salt.The more precisely reality of such salt Example include sodium salt, sylvite, calcium salt, magnesium salts or with ammonia or organic amine, such as ethamine, ethanol amine, triethanolamine or amino acid salt. The compound of the present invention containing basic group can in the form of salts exist and can according to the present invention with they with it is inorganic or organic The form of the addition salts of acid uses.The example of suitable acid include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, to first Benzene sulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, Succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, Citric acid, adipic acid and other acid well known by persons skilled in the art.If the compound of the present invention contains simultaneously in the molecule Acid and basic group, the present invention further include inner salt or betaine in addition to the salt form being previously mentioned.Each salt can pass through this field skill Conventional method known to art personnel obtains, such as by contacting these with organic or inorganic acid or alkali in solvent or dispersing agent By exchanged with other salt anionics or cation exchange.
" pharmaceutical composition " refers to containing one or more compounds as described herein or its pharmaceutical salt, prodrug, stabilization The combination of isotope derivatives, isomers and its form of mixtures and other components for example pharmaceutical carrier and excipient Object.The purpose of pharmaceutical composition is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
Therefore, in this application when referring to " compound ", " the compounds of this invention " or " compound of the present invention ", packet Include all compound forms, such as its pharmaceutical salt, prodrug, stable isotope derivative, isomers and its mixture.
Herein, term " tumour " includes benign tumour and malignant tumour (such as cancer).
Herein, term " therapeutically effective amount " refers to function and/or treatment including IDO can be effectively suppressed or prevents institute State the amount of the compounds of this invention of disease.
Synthetic method
The present invention also provides the methods for preparing the compound.The present invention leads to the preparation of compound described in formula (I), can pass through Following exemplary method and embodiment are completed, but these methods and embodiment should not be considered limiting in any way to model of the present invention The limitation enclosed.Compound of the present invention can also be synthesized by synthetic technology known to those skilled in the art, or comprehensive Use means known in the art and the method for the invention.Every step is reacted resulting product and is obtained with isolation technics known in the art It arrives, including but not limited to extraction, filtering, distillation, crystallization, chromatographic isolation etc..Starting material needed for synthesis and chemical reagent can To be conventionally synthesized or buy according to document (can be inquired from SciFinder).
The present invention, which leads to 3- indazole quinoline ketone compounds described in formula (I), to be synthesized according to route described in method A: intermediate amine A1 and o-nitrobenzaldehyde pass through reduction amination or generate A2 by substitution reaction with O-bromo methyl nitrobenzene；The alcoholic solution of A2 exists David-Beruit is carried out under base catalysis to react to obtain the indazole A3 of 2- substitution；Hydrolysis generates target product to A3 in acid solution again 3- indazole quinoline ketone compound A4.
Method A:
Intermediate amine A1 can refer to correlation step in patent application WO2017192844 and synthesize, can also be according to described in method B Route synthesis: starting material ketone B1 generates hydrocarbon alkenyl triflate B2 with trifluoromethanesulfonic acid anhydride reactant under alkaline condition； B2 and borate or boric acid C-B (OR)2B3 is obtained by Suzuki coupling reaction, hydrogenated reduction generates B4；B4 by LAH also Original then uses the oxidizing generation aldehyde B5 of Dai Si-Martin at alcohol；B5 and the reaction of lattice reagent generate B6；B6 prolongs reaction by light Generate B7；Finally deprotection obtains amine A1.
Method B:
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