WO2020147582A1 - 环烷基取代的酰胺类衍生物、其制法与医药上的用途 - Google Patents

环烷基取代的酰胺类衍生物、其制法与医药上的用途 Download PDF

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WO2020147582A1
WO2020147582A1 PCT/CN2019/130744 CN2019130744W WO2020147582A1 WO 2020147582 A1 WO2020147582 A1 WO 2020147582A1 CN 2019130744 W CN2019130744 W CN 2019130744W WO 2020147582 A1 WO2020147582 A1 WO 2020147582A1
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alkyl
formula
compound
substituted
ring
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French (fr)
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关慧平
蒋涛
许峰
王海龙
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN201980042108.8A priority Critical patent/CN112384502B/zh
Publication of WO2020147582A1 publication Critical patent/WO2020147582A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the technical field of medicine, in particular to a cycloalkyl substituted amide derivative, a preparation method thereof, and application as an IDO inhibitor, as well as pharmaceutical compositions and pharmaceutical compositions prepared therefrom.
  • IDO Indoleamine 2,3-dioxygenase
  • Tryptophan is one of the eight essential amino acids. Tryptophan can be used to synthesize proteins in the body. Tryptophan can also be used as a precursor substrate to synthesize serotonin and melatonin (N- Acetyl-5-methoxytryptamine). Serotonin and melatonin are neurotransmitters and neuroendocrine hormones, which are involved in the regulation of various nerve and physiological processes in the body. In addition, tryptophan can also produce kynurenine and other metabolites through the kynurenine metabolic pathway.
  • the first step of the kynurenine metabolic pathway is the catalysis of indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase (TDO), tryptophan L-tryptophan Acid degrades to N-formyl-kynurenine, N-formyl-kynurenine is catalyzed by kynurenine carboxamidase to form kynurenine, which can be further metabolized to form kynurenine 3-hydroxyanthranilic acid, quinolinic acid, picolinic acid. Quinolinic acid has neurotoxicity, while picolinic acid has neuroprotective effect. Kynurenine and 3-hydroxyanthranilic acid participate in the regulation of lymphocyte activity and cause the immune system to be suppressed.
  • TDO tryptophan 2,3-dioxygenase
  • indoleamine 2,3-dioxygenase is not expressed in most tissue cells under normal health conditions. In areas where inflammation occurs, inflammatory cytokines such as interferon gamma can induce indoleamine 2,3-dioxygenase expression to increase.
  • inflammatory cytokines such as interferon gamma
  • Various experimental results have proved that the high expression of indoleamine 2,3-dioxygenase in tissue cells can cause the immune system of the tissue microenvironment to be suppressed, or immune suppression or immune checkpoint (immune checkpoint) .
  • the high expression of indoleamine 2,3-dioxygenase in placenta tissue can prevent immune rejection to the fetus.
  • indoleamine 2,3-dioxygenase in the inflammation area can prevent excessive immune response and prevent excessive damage to cell tissues.
  • One of the mechanisms leading to immune suppression is that high expression of indoleamine 2,3-dioxygenase causes local L-tryptophan depletion, which is sensed by surrounding lymphocytes through GCN2 and other mechanisms, causing CD8+ cytotoxic T cells Cell cycle arrest or apoptosis occurs.
  • Another mechanism that leads to immune suppression is that high expression of indoleamine 2,3-dioxygenase causes an increase in kynurenine. After kynurenine is formed, it can leave the cell and enter the extracellular matrix, and then enter the nearby lymph. Cells regulate CD8+T cells and regulatory TR32g cells by combining with AHR transcription factors. The activity of CD8+ cytotoxic T cells is inhibited, while the number of regulatory TR32g cells increases and is activated, which leads to immune suppression.
  • Indoleamine 2,3-dioxygenase has abnormally high expression in many different types of tumors, including hematological tumors and solid tumors such as colorectal cancer, liver cancer, lung cancer, pancreatic cancer, and throat cancer. Abnormally high expression of indoleamine 2,3-dioxygenase is positively correlated with poor tumor prognosis. The escape of tumor cells from immune monitoring is a key step for canceration and the further development of cancer. The abnormally high expression of indoleamine 2,3-dioxygenase in tumors may be the escape of tumor cells.
  • indoleamine 2,3-dioxygenase Inhibitors as an immune checkpoint inhibitor (immune checkpoint inhibitor) have aroused great interest in the medical field.
  • IDO indoleamine 2,3-dioxygenase
  • IDO-1 IDO-1
  • IDO-2 IDO-2
  • the main part of the above-mentioned immune suppression is IDO-1.
  • the role of IDO-2 in immune suppression is not yet very clear.
  • Tryptophan 2,3-dioxygenase (TDO) also has abnormally high expression in many types of tumors.
  • TDO tumors are also positive for IDO and TDO, so some people think that it can also be achieved by inhibiting TDO immune checkpoints.
  • the purpose of tumor treatment Because normal liver cells express TDO, it is not clear whether TDO inhibitors will affect liver function and normal tryptophan metabolism, but the mouse model of TDO knockout shows no abnormalities, indicating that TDO inhibitors may not affect liver function and normal Metabolism of Tryptophan.
  • IDO and TDO cause immune suppression in basically the same mechanism, so IDO/TDO bispecific inhibitors have also attracted the interest of the medical community. IDO/TDO bispecific inhibitors will be applicable to IDO positive, TDO positive, IDO/TDO double positive Patient.
  • kynurenine metabolic pathway of tryptophan Many metabolites of the kynurenine metabolic pathway of tryptophan are related to schizophrenia, depression, and neuronal degeneration. Indoleamine 2,3-dioxygenase inhibitors may also be used in the treatment of these diseases.
  • Kynurenine can be converted to kynurenic acid under the catalysis of kynurenine aminotransferase.
  • Kynurenic acid is an NMDA antagonist, which is common in the central nervous system of patients with schizophrenia. The level of kynurenic acid.
  • Quinolinic acid is neurotoxic and can cause nerve cell apoptosis and neurodegeneration.
  • Indoleamine 2,3-dioxygenase not only participates in the metabolism of tryptophan, but also participates in the metabolism of tryptophan, etc.
  • 5-hydroxytryptamine can be converted into 5-hydroxytryptamine under the catalysis of indoleamine 2,3-dioxygenase. Ox
  • indoleamine 2,3-dioxygenase inhibitors are still in the early stage of research and development, and the development of IDO inhibitors with better activity and lower toxicity on the existing basis has important clinical significance.
  • the purpose of the present invention is to provide a class of IDO inhibitors with novel structures and their preparation methods and uses.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:
  • A is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl group, or a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl group;
  • Ring B is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl ring;
  • L 1 is a key or NR 1 ;
  • L 2 is a key or NR 2 ;
  • L 1 and L 2 are not a bond at the same time, and L 1 and L 2 do not contain N at the same time;
  • E 1 and E 4 are each independently CR 3 or N;
  • E 2 is (CR 21 R 22 ) m , (CR 21 R 22 ) t -O or (CR 21 R 22 ) t -NR 23 ;
  • E 3 is CR 31 R 32 , O or NR 33 , and E 2 and E 3 do not contain O or N at the same time;
  • R 1 and R 2 are each independently hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R 3 is hydrogen, cyano, hydroxy, carboxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1 -3 alkyl);
  • R 21 , R 22 , R 31 , and R 32 are each independently -(CH 2 ) r -R 0 ;
  • R 0 is hydrogen, halogen, cyano, hydroxyl, C 1-10 alkyl (preferably C 1-6 alkane Group, more preferably C 1-3 alkyl), -C(O)C 1-10 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 Alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy);
  • R 23 and R 33 are each independently hydrogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C (O) C 1-10 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl);
  • n 0, 1 or 2;
  • t is 0 or 1;
  • r 0, 1, 2 or 3;
  • R a , R b , R c and R d are one selected from the following group:
  • R a and R b are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl) or substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy base);
  • R c and R d together with the carbon atoms to which they are attached form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
  • R b and R d are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl) or substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy base);
  • R a, R c forming a carbon atom to which they are attached form a substituted or unsubstituted 3- to 6-membered saturated or unsaturated monocyclic or unsubstituted or substituted 3- to 6-membered saturated or unsaturated monocyclic heterocycle;
  • Z 1 is N or CR 01 ;
  • Z 2 is N or CR 02 ;
  • Z 3 is N or CR 03 ;
  • Z 4 is N or C;
  • R 01 , R 02 , R 03 are each independently hydrogen, halogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl Group), C 3-10 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), NR a0 R b0 or -C(O)C 1-10 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1- 3 alkyl);
  • substitution means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A1;
  • the alkoxy group in R 03 is unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from Group A1;
  • the A1 group substituent is selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably Halo (C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6-10 aryl (preferably phenyl), 5 or 6-membered monocyclic heteroaryl, C 1-10 alkyl (Preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl,
  • the compound of formula (I) has a structure represented by formula (I-1) or formula (I-2):
  • the compound of formula (I) has a structure represented by formula (I-a):
  • the C ring is a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring; the other groups are as defined in the specification.
  • the compound of formula (I-a) has a structure represented by formula (I-a-1) or formula (I-a-2):
  • R b and R d are each independently hydrogen, halogen, C 1-3 alkyl or C 1- alkoxy.
  • R b and R d are each independently hydrogen, fluorine, chlorine, methyl, ethyl, methoxy ⁇ or ethoxy.
  • R b and R d are each independently hydrogen.
  • the C ring is a 3- to 6-membered saturated monocyclic ring.
  • the C ring is a 3-membered saturated monocyclic ring.
  • the C ring is a cyclopropyl ring.
  • formula (Ia), formula (Ia-1) and formula (Ia-2) (a) L 1 is NH, and L 2 is a bond; or (b) L 1 is a Bond; L 2 is NH.
  • the compound of formula (I) has a structure represented by formula (I-b):
  • Ring D is a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring; other groups are as defined in the specification.
  • the compound of formula (I-b) has a structure represented by formula (I-b-1) or formula (I-b-2):
  • formula (Ib), the formula (Ib-1) and formula (Ib-2), R a , R b are each independently hydrogen, halo, C 1-3 alkyl or C 1- alkoxy.
  • formula (Ib), formula (Ib-1) and formula (Ib-2) in a, R a, R b are each independently hydrogen, fluoro, chloro, methyl, ethyl, methoxy ⁇ or ethoxy.
  • formula (Ib), formula (Ib-1) and formula (Ib-2) in a, R a, R b are each independently hydrogen.
  • the D ring is a 3- to 6-membered saturated monocyclic ring.
  • the D ring is a 3-membered saturated monocyclic ring.
  • the D ring is a cyclopropyl ring.
  • L 1 is NH and L 2 is a bond.
  • the A1 group substituent is selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogenated C 1-3 alkyl, halogen (preferably F or Cl ), nitro, phenyl, 5- or 6-membered monocyclic heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -CONR a0 R b0 , -C(O)OC 1-3 alkyl, -CHO, -OC(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 -phenyl, -CO-phenyl, 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring or 4 to 6-membered saturated or unsaturated monocyclic ring, wherein R a0 , R b
  • Z 1 , Z 2 , Z 3 and Z 4 are not N at the same time.
  • At least one of Z 1 , Z 2 and Z 3 is not N.
  • two of Z 1 , Z 2 and Z 3 are not N.
  • Z 1 is N;
  • Z 2 is CR 02 ;
  • Z 3 is CR 03 ;
  • R 02 and R 03 are as defined above.
  • Z 1 is CR 01 ;
  • Z 2 is N;
  • Z 3 is CR 03 ;
  • R 01 and R 03 are as defined above.
  • Z 1 is CR 01 ;
  • Z 2 is CR 02 ;
  • Z 3 is N;
  • R 01 and R 02 are as defined above.
  • R 02 and R 03 are hydrogen.
  • ring B is a benzene ring, a pyridine ring, a pyrazole ring, an imidazole ring or a pyrrole ring, and Z 4 is N or C; It is a single bond or a double bond.
  • the 5- to 6-membered monocyclic heteroaryl group in A is selected from: thiophene, N-alkane pyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1, 2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3 -Oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine.
  • the 8- to 10-membered bicyclic heteroaryl group in A is selected from: benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole , Benzimidazole, quinazoline, quinoxaline, cinnoline, phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d] Pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine.
  • A is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl group, and the "substituted” refers to 1, 2, or 3 of the group
  • the hydrogen atoms are replaced by substituents each independently selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogenated C 1-3 alkyl, halogen, nitro, C 1 -3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -CONR a0 R b0 , -C(O)OC 1-3 alkyl, -CHO, -OC(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 -phenyl and -CO-phen
  • A is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted pyridyl group, and the "substituted" means that 1, 2, or 3 hydrogen atoms in the group are independently selected Substitution from the following group of substituents: cyano, acetyl, hydroxyl, hydroxymethyl, hydroxyethyl, carboxyl, trifluoromethyl, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, Methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclopropyloxy, vinyl, ethynyl, -CONR a0 R b0 , -C(O)OC 1-3 alkane Group, -OC(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, wherein R a0 and R b0 are each independently hydrogen or
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring in the substituent group A1 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole , Piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2- Dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4 -Dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
  • the 4- to 6-membered saturated or unsaturated monocyclic ring in the substituent group A1 is selected from: cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl Ring, cyclohexadienyl ring.
  • the 5- or 6-membered monocyclic heteroaryl group described in the A1 group of substituents is selected from: thiophene, N-alkyl pyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, three Azole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1 , 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or Pyrazine.
  • the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R c and R d together with the carbon atoms to which they are connected is selected from: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentene Base ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R c and R d together with the carbon atoms to which they are connected is selected from: aziridine, ethylene oxide, azetidine, Oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1, 2-Dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran , 2,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran,
  • the 3 to 6-membered saturated or unsaturated monocyclic ring formed by Ra , Rc and the carbon atoms to which they are connected is selected from: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentene Base ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by Ra , Rc and the carbon atoms to which they are connected is selected from: aziridine, ethylene oxide, azetidine, Oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1, 2-Dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran , 2,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,
  • R 3 is hydrogen, cyano, hydroxy, carboxy, halogen, substituted or unsubstituted C 1-3 alkyl, and the "substituted” refers to 1, 2, or 3 of the groups
  • the hydrogen atoms are substituted with substituents each independently selected from the group consisting of cyano, acetyl, hydroxy, carboxy, halogen, C 3-6 cycloalkyl.
  • L 1 is NR 1 ; L 2 is a bond.
  • L 1 is a bond
  • L 2 is NR 2 .
  • Z 5 is N or CR 7 ;
  • Z 1 , Z 2 , Z 3 are as defined in the specification;
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen and halogen , C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkyl, C 3-10 cycloalkyl, halogenated C 1-10 alkoxy, NR a0 R b0 or -C (O) C 1-10 alkyl; wherein the C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkyl, C 3-10 cycloalkyl, halogenated C 1-
  • the alkyl group and the alkoxy group in the 10 alkoxy group and the -C(O)C 1-10 alkyl group are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from Group A1.
  • R 4 , R 5 , and R 6 are each independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, C 3- 6 cycloalkyl, halogenated C 1-3 alkoxy, NR a0 R b0 or -C(O)C 1-3 alkyl, wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl .
  • R 7 is hydrogen
  • R 4 and R 6 are hydrogen.
  • R 5 is halogen, preferably fluorine.
  • Z 1 is N;
  • Z 2 is CR 02 ;
  • Z 3 is CR 03 ;
  • Z 5 is N;
  • R 02 and R 03 are as defined above.
  • Z 1 is N;
  • Z 2 is CR 02 ;
  • Z 3 is CR 03 ;
  • Z 5 is CR 7 ;
  • R 02 , R 03 , and R 7 are as defined above.
  • Z 1 is CR 01 ;
  • Z 2 is CR 02 ;
  • Z 3 is CR 03 ;
  • Z 5 is N;
  • R 01 , R 02 and R 03 are as defined above.
  • Z 1 is N;
  • Z 2 is CR 02 ;
  • Z 3 is CR 03 ;
  • R 02 and R 03 are as defined above.
  • R 02 is hydrogen; R 03 is hydrogen.
  • Z 1 is N; Z 2 and Z 3 are CH; R 8 and R 9 are hydrogen.
  • Z 1 is N; Z 2 and Z 3 are CH; R 9 is hydrogen; R 10 is hydrogen, halogen, C 1-10 alkyl, C 1-10 alkane Oxy, halogenated C 1-10 alkyl, C 3-10 cycloalkyl, halogenated C 1-10 alkoxy, NR a0 R b0 or -C(O)C 1-10 alkyl.
  • E 1 and E 4 are CH; E 3 is CR 31 R 32 , O or NR 33 ; E 2 is (CR 21 R 22 ) m ; m is 0, 1 or 2; R 21 , R 22 , R 31 , R 32 and R 33 are as defined in the specification.
  • E 1 and E 4 are CH; E 3 is CR 31 R 32 ; E 2 is (CR 21 R 22 ) t -O or (CR 21 R 22 ) t -NR 23 ; t is 0 Or 1; R 21 , R 22 , R 23 , R 31 , and R 32 are as defined in the specification.
  • E 1 and E 4 are each independently CH or N; E 2 is (CR 21 R 22 ) m ; m is 0, 1 or 2; E 3 is CR 31 R 32 ; R 21 , R 22 , R 31 and R 32 are as defined in the specification.
  • E 1 is CH, E 4 is CH or N; E 2 is (CR 21 R 22 ) m ; m is 0, 1 or 2; E 3 is CR 31 R 32 ; R 21 , R 22 , R 31 and R 32 are as defined in the specification.
  • E 1 is CH, E 4 is CH or N; E 2 is CH; E 3 is CH.
  • R 23 and R 33 are as defined in the specification.
  • E 1 and E 4 are CH; E 3 is CR 31 R 32 , O or NR 33 ; E 2 is (CR 21 R 22 ) m ; m is 0, 1 or 2; It is the structure shown in formula (IA).
  • E 1 and E 4 are CH; E 3 is CR 31 R 32 ; E 2 is CR 21 R 22 ; It is the structure shown in formula (IA).
  • E 1 and E 4 are CH; E 3 is CR 31 R 32 ; E 2 is (CR 21 R 22 ) t -O or (CR 21 R 22 ) t -NR 23 ; t is 0 Or 1; It is the structure shown in formula (IA).
  • E 1 and E 4 are each independently CH or N; E 2 is (CR 21 R 22 ) m ; m is 0, 1, or 2; E 3 is CR 31 R 32 ; It is the structure shown in formula (IA).
  • E 1 is CH; E 4 is N; E 2 is (CR 21 R 22 ) m ; m is 0, 1 or 2; E 3 is CR 31 R 32 ; It is the structure shown in formula (IA).
  • formula (IA) is the following structure:
  • the 3- to 6-membered saturated monocyclic heterocyclic ring is selected from the following structures:
  • the aforementioned 3- to 6-membered saturated monocyclic heterocyclic ring is optionally substituted with 1, 2 or 3 substituents each independently selected from Group A1.
  • the 5- to 6-membered monocyclic heteroaryl ring or heteroaryl group is selected from: thiophene ring, N-alkane pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole Ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, Tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3 , 4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring.
  • the 5- to 6-membered monocyclic heteroaryl ring or heteroaryl group is selected from the following structures:
  • the above 5- to 6-membered monocyclic heteroaryl ring or heteroaryl group is optionally substituted with 1, 2, or 3 substituents each independently selected from Group A1.
  • the compound is selected from Table A or Table B.
  • the compound of Table A is selected from the following group:
  • the compound of Table B is selected from the following group:
  • the compound of formula (I) has a structure selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof; and a pharmaceutically acceptable carrier .
  • the third aspect of the present invention provides a compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition as described in the second aspect of the present invention in preparing a medicine Application, the drug is used to inhibit the activity of indoleamine 2,3-dioxygenase or to inhibit immunosuppression of patients.
  • the drug is used to treat or prevent cancer or tumors, viral infections, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplant rejection or autoimmune diseases in patients; preferably, wherein
  • the cancer or tumor is selected from lung cancer, bone cancer, gastric cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, Vulvar cancer, rectal cancer, colon cancer, anal cancer, breast cancer, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, urethral cancer, penile cancer, prostate cancer, pancreatic cancer, brain Cancer, testicular cancer, lymphoma, transitional cell cancer, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvis cancer, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma
  • the application refers to combining a therapeutically effective dose of the aforementioned compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition with an anti-CTLA-4 antibody , Anti-PD-1 antibody, anti-PD-L1 antibody, antiviral agent, chemotherapeutic agent, immunosuppressive agent, radiation, anti-tumor vaccine, antiviral vaccine, cytokine therapy or tyrosine kinase inhibitor for combined use; preferred
  • the cytokine is preferably IL-2, IL-3, IL-4 or IL-5
  • the chemotherapeutic agent is preferably a cytotoxic agent
  • the anti-PD-1 antibody is preferably a Keytruda antibody.
  • the fourth aspect of the present invention provides a method for regulating the activity of indoleamine 2,3-dioxygenase, which comprises adding a therapeutically effective dose of the aforementioned compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof Or contacting the aforementioned pharmaceutical composition with indoleamine 2,3-dioxygenase.
  • the adjustment is preferably an inhibitory effect.
  • the fifth aspect of the present invention provides a method for inhibiting immunosuppression in a patient, the method comprising combining a therapeutically effective dose of the aforementioned compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned drug Give the patient.
  • the sixth aspect of the present invention provides a method for the treatment of cancer, the method comprising administering to a patient a therapeutically effective dose of the compound of the general formula (I) of the present invention or its tautomers, mesosomes, exogenous Rotary form, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the cancer or tumor is selected from lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, Cervical cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, anal cancer, breast cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, urethral cancer, penile cancer, Prostate cancer, pancreatic cancer, brain cancer, testicular cancer, lymphoma, transitional cell cancer, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, Childhood solid tumors, lymphocytic lymphoma, central nervous system (CNS) tumors, primary central nervous system lymphoma, tumor angiogenesis, spinal tumors,
  • CNS
  • the inventors unexpectedly discovered a class of cycloalkyl-substituted amide derivatives, which have better inhibitory activity and lower toxicity against IDO inhibitors.
  • the compounds of the present invention have excellent pharmacokinetic properties. Therefore, the series of compounds are expected to be developed into drugs for the treatment and prevention of cancer and other diseases. On this basis, the inventor completed the present invention.
  • alkyl refers to linear and branched saturated aliphatic hydrocarbon groups
  • C 1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C 1-6 alkyl, more preferably It is a C 1-3 alkyl group with similar definitions; non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , N-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl
  • alkenyl refers to an aliphatic group containing at least one double bond.
  • C 2-10 alkenyl is an alkenyl group containing 2 to 10 carbon atoms, preferably a C 2-6 alkenyl group, more preferably a C 2-4 alkenyl group, the definition is similar; the alkenyl group is not limiting Examples include: vinyl, 1-propenyl, 2-propenyl, 1-butenyl or 2-butenyl and various branched isomers thereof. More preferred.
  • alkynyl refers to an aliphatic group containing at least one triple bond
  • C 2-10 alkynyl is an alkynyl containing 2 to 10 carbon atoms, preferably C 2-6 alkynyl, and more It is preferably C 2-4 alkynyl, with similar definitions; non-limiting examples of alkynyl include: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl or 2-butynyl and Various branched isomers and the like are more preferable.
  • cycloalkyl and “cycloalkyl ring” are used interchangeably and both refer to a saturated or unsaturated monocyclic cyclic hydrocarbon group.
  • C 3-8 cycloalkyl refers to a group containing 3 to 8 carbons.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl , Cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, and cyclohexenyl.
  • C 1-10 alkoxy refers to -O-(C 1-10 alkyl), where the definition of alkyl is as described above.
  • C 1-6 alkoxy is preferable, and C 1-3 alkoxy is more preferable.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, pentoxy and the like.
  • C 3-8 cycloalkoxy refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is defined as described above. Preferred is C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • C 6-10 aryl and C 6-10 aryl ring are used interchangeably, and both refer to all-carbon monocyclic or fused polycyclic rings with a conjugated ⁇ -electron system (that is, sharing adjacent A ring) group with a pair of carbon atoms refers to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
  • a bond means that two groups connected by it are connected by a covalent bond.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo refers to the replacement of one or more (such as 1, 2, 3, 4, or 5) hydrogens in a group with halogen.
  • halo C 1-10 alkyl means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-10 alkyl groups include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • halogenated C 1-10 alkoxy means that the alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above. It is preferably a halogenated C 1-6 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
  • amino refers to NH 2
  • cyano refers to the CN
  • Niro refers to NO 2
  • benzyl refers to -CH 2 - phenyl
  • carboxy refers to -C (O) OH
  • acetyl refers to -C (O) CH 3
  • hydroxymethyl group refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • hydroxy refer to -OH.
  • heteroaryl ring and “heteroaryl” are used interchangeably and refer to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl ;
  • the ring array shares 6, 10 or 14 ⁇ electrons; and in addition to carbon atoms, there are groups with 1 to 5 heteroatoms.
  • Heteroatom refers to nitrogen, oxygen, or sulfur.
  • 3 to 6 membered (4 to 6 membered) saturated or unsaturated monocyclic ring refers to a saturated or partially unsaturated all-carbon monocyclic ring containing 3 to 6 ring atoms.
  • 3 to 6-membered saturated or unsaturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexyl ring Dienyl ring and so on.
  • 3- to 6-membered (4 to 6-membered) saturated or unsaturated monocyclic heterocyclic ring means that 1, 2, or 3 carbon atoms in a 3- to 6-membered monocyclic ring are selected from nitrogen, oxygen or S( O) t (where t is an integer of 0 to 2) substituted by heteroatoms, but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 yuan.
  • Examples of 3 to 6-membered saturated or partially unsaturated monocyclic heterocycles include (but are not limited to) propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrrole Morpholine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-di Hydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2, 3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H
  • 5- to 6-membered monocyclic heteroaryl ring and “5- to 6-membered monocyclic heteroaryl” are used interchangeably, and both refer to a mono-heteroaryl ring containing 5 to 6 ring atoms
  • Examples include (but are not limited to): thiophene ring, N-alkane pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole
  • 8 to 10 membered bicyclic heteroaryl ring and “8 to 10 membered bicyclic heteroaryl ring” are used interchangeably, and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, for example including (But not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, Phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8 -Naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphth
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently substituted with each other Ground is substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • substituted by a substituent means that when more than one hydrogen on the group is substituted by a substituent, the types of the substituents may be the same or different, so The selected substituents are of independent types.
  • L is (CR 01 R 02 ) s , when s is 2, that is, L is (CR 01 R 02 )-(CR 01 R 02 ), and the two R 01 or R 02 can be the same or different.
  • Independent type for example L can be C(CH 3 )(CN)-C(CH 2 CH 3 )(OH), C(CH 3 )(CN)-C(CH 3 )(OH) or C(CN) (CH 2 CH 3 )-C(OH)(CH 2 CH 3 ).
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 (more preferably 1, 2 or 3) or less groups, independently selected from CN, halogen, C 1-10 alkyl (preferably C 1-6 alkane Group, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkane Group (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1- 8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, amino, halogenated C 1- 8 Alkyl-substituted amino, acetyl, hydroxy, hydroxymethyl, hydroxye
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like.
  • solvate refers to a complex formed by the compound of the present invention and a solvent. They either react in the solvent or precipitate or crystallize out of the solvent. For example, a complex formed with water is called a "hydrate”. Solvates of compounds of formula (I) fall within the scope of the present invention.
  • the two carbon atoms on the cyclohexyl group connected by a group of substituents substituted in the para position on the ring are not chiral centers
  • the chemical bond notation of is only meant to indicate that the two chemical bonds connected to a group of substituents substituted in the para position are in trans or cis structure relative to the cyclohexyl group, so these two chemical bonds
  • the compounds expressed in exchange for each other also fall within the protection scope of the present invention.
  • the compounds represented by formula (I), formula (Ia) and formula (Ib) of the present invention may exist in the form of a mixture of trans and cis structures, or exist in the form of cis structure, or exist in the form of trans structure. It preferably exists in the form of a cis structure.
  • a group of substituents substituted in the para position on the cyclohexyl group are connected to the two carbon atoms on the cyclohexyl group through
  • the protection scope of the structure represented by the bond includes trans or cis structure.
  • the pair of chemical bonds connected to the cyclohexyl position in the compound structure are both Or both , Mean the same meaning, and both mean cis structure.
  • the pair of chemical bonds connected in the para position of the cyclohexyl group are Or respectively , Mean the same meaning, and both mean trans structure.
  • the compound represented by formula (I) of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • a compound contains a chiral center
  • the compound contains enantiomers.
  • the present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • diastereomers may exist.
  • the present invention includes the resolved optically pure specific isomers and mixtures of diastereomers. Diastereoisomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the compounds of the present invention also include cis isomers, trans isomers, and mixtures of cis and trans isomers.
  • cis isomers when the compound of the present invention has a cycloalkyl structure, different substituents on the cycloalkyl ring can form Cis isomer or trans isomer.
  • the present invention includes prodrugs of the aforementioned compounds.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released through enzymatic reactions to obtain the parent compound.
  • Specific preparation methods of prodrugs please refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMBioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • the compound of the present invention or a pharmaceutically acceptable salt, a solvate, a stereoisomer, or a prodrug of the present invention can be administered in a suitable dosage form with one or more pharmaceutical carriers.
  • dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (for example, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
  • the above-mentioned dosage forms can be prepared from the active compound and one or more carriers or excipients through general pharmaceutical methods.
  • the aforementioned carrier needs to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or a suspension with the aforementioned carriers.
  • composition of the present invention is formulated, quantified and administered in a manner conforming to medical practice standards.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual to be treated, the cause of the condition, the target of the drug, and the mode of administration.
  • therapeutically effective amount refers to the amount of the compound of the present invention that will cause an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc. the amount.
  • the therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).
  • pharmaceutically acceptable carrier refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient, which is compatible with the patient and most It is preferably a mammal, more preferably a human, which is suitable for delivering the active agent to the target target without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded spinal mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.
  • the compound represented by formula (I) of the present invention can be prepared by a known method, for example, by the following method, a method equivalent thereto, or the method described in the examples.
  • the raw material compound may be in the form of a salt
  • the salt may be any pharmaceutically acceptable salt exemplified by the compound represented by formula (I) of the present invention.
  • E 1, E 4 are each independently CH, E 2, E 3 are each independently CH 2, R a, R b are each independently hydrogen, D ring 3-membered saturated monocyclic ring, L 1 is NH, L
  • the compound represented by formula (Ib) in which 2 is a bond (such as the compound represented by formula (I-8)) can be prepared by the method represented by reaction scheme (I).
  • E 1 is CH
  • E 4 is N
  • E 2 are each independently CH
  • R a, R b are each independently hydrogen
  • L 1 is NH
  • L 2 The compound represented by the formula (Ib) which is a bond (such as the compound represented by the formula (II-7)) can be prepared by the method represented by the reaction scheme (II).
  • E 1 and E 4 are each independently CH, E 2 and E 3 are each independently CH 2 , R b and Rd are each independently hydrogen, ring C is a 3-membered saturated monocyclic ring, and L 1 is a bond
  • the compound represented by formula (Ia) in which L 2 is NH (such as the compound represented by formula (III-8)) can be prepared by the method represented by reaction scheme (III).
  • E 1 and E 4 are each independently CH, E 2 and E 3 are each independently CH 2 , R b and Rd are each independently hydrogen, C ring is a 3-membered saturated monocyclic ring, L 1 is NH, L
  • the compound represented by formula (Ia) in which 2 is a bond (such as the compound represented by formula (IV-3)) can be prepared by the method represented by reaction scheme (IV).
  • Step 1 Suzuki coupling reaction between the corresponding compound represented by formula (I-1) and 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester A compound represented by formula (I-2).
  • Step 2 The compound represented by the formula (I-2) undergoes a carbon-carbon double bond reduction reaction to obtain the compound represented by the formula (I-3).
  • Step 3 The carbonyl group of the compound represented by the formula (I-3) is deprotected to obtain the compound represented by the formula (I-4).
  • Step 4 Wittig reaction between the compound represented by formula (I-4) and the phosphorous ylide reagent to prepare the compound represented by formula (I-5).
  • Step 5 The compound represented by formula (I-5) undergoes a carbon-carbon double bond reduction reaction to prepare a compound represented by formula (I-6).
  • Step 6 The compound represented by the formula (I-6) is reacted with a Grignard reagent to prepare the compound represented by the formula (I-7).
  • Step 7 The compound represented by the formula (I-7) and the compound represented by the formula A-COOH, or the compound represented by the formula (I-7) and the compound represented by the formula A-COCl undergo an amidation reaction to obtain the formula (I-8) ) Represents the compound.
  • Step 1 Miyaura boronization of the compound represented by the corresponding formula (I-1) and pinacol diborate to prepare the compound represented by the formula (II-1).
  • Step 2 Suzuki coupling between the compound represented by formula (II-1) and the compound 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1a The reaction produces the compound represented by formula (II-2).
  • Step 3 The compound represented by the formula (II-2) undergoes a carbon-carbon double bond reduction reaction to obtain the compound represented by the formula (II-3).
  • Step 4 The compound represented by formula (II-3) is deaminated to obtain a compound represented by formula (II-4).
  • Step 5 The compound represented by the formula (II-4) and the compound 1-formylcyclopropyl carbamate 2a undergo reductive amination reaction to obtain the compound represented by the formula (II-5).
  • Step 6 The protective group of the compound represented by the formula (II-5) is removed to obtain the compound represented by the formula (II-6).
  • Step 7 The compound represented by the formula (II-6) and the compound represented by the formula A-COOH, or the compound represented by the formula (II-6) and the compound represented by the formula A-COCl undergo amidation reaction to obtain the formula (II-7) ) Represents the compound.
  • Step 1 Suzuki coupling reaction between the corresponding compound represented by formula (I-1) and 1-ethoxycarbonyl cyclohex-3-ene-4-boronic acid pinacol ester to prepare formula (III-1) compound of.
  • Step 2 The compound represented by the formula (III-1) undergoes a carbon-carbon double bond reduction reaction to prepare the compound represented by the formula (III-2).
  • Step 3 The compound represented by the formula (III-2) undergoes an ester reduction reaction to obtain the compound represented by the formula (III-3).
  • Step 4 The compound represented by formula (III-3) undergoes oxidation reaction to prepare the compound represented by formula (III-4).
  • Step 5 Wittig reaction between the compound represented by formula (III-4) and the phosphorous ylide reagent to prepare the compound represented by formula (III-5).
  • Step 6 The compound represented by formula (III-5) undergoes the Corey-Chaykovsky reaction to prepare the compound represented by formula (III-6).
  • Step 7 The compound represented by formula (III-6) undergoes an ester hydrolysis reaction to obtain the compound represented by formula (III-7).
  • Step 8 The compound represented by formula (III-7) and the compound represented by formula A-NH 2 undergo an amidation reaction to prepare a compound represented by formula (III-8).
  • Step 1 The compound represented by formula (III-4) undergoes Curtius rearrangement reaction to prepare the compound represented by formula (IV-1).
  • Step 2 The compound represented by the formula (IV-1) undergoes an amino deprotection reaction to obtain the compound represented by the formula (IV-2).
  • Step 3 The compound represented by the formula (IV-2) and the compound represented by the formula A-COOH, or the compound represented by the formula (IV-2) and the compound represented by the formula A-COCl undergo amidation reaction to obtain the formula (IV-3) ) Represents the compound.
  • the Suzuki coupling reaction is known and can be.
  • a solvent such as 1,4-dioxane, THF or a mixed solvent of 1,4-dioxane and water, etc.
  • a base such as sodium carbonate, potassium carbonate or cesium carbonate, etc.
  • palladium catalyst Pd(OAc) 2 , Pd(Ph 3 P) 4 , Pd(Ph 3 P) 2 Cl 2 or Pd(dppf)Cl 2 etc.
  • 1,4-dioxa-spiro[4, 5] Dec-7-ene-8-boronic acid pinacol ester is cross-coupled with halogenated aromatic hydrocarbons.
  • the amidation reaction is known and can be. For example, at about 0°C to reflux temperature, in an organic solvent (such as DMSO, DCM, DMF or THF, etc.) or in the absence of a solvent, in the presence of a base (such as DIEA, TEA, dimethylaniline or dimethylamino)
  • a condensing agent such as HATU, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide Imine (EDC), N,N'-carbonyldiimidazole (CDI) or 1-propyl phosphoric anhydride (T 3 P), etc.
  • HOBT 1-hydroxybenzotriazole
  • the carboxylic acid or acid chloride reacts with the amine.
  • the double bond reduction is known and can be.
  • a catalyst such as Pd/C
  • a reducing agent such as hydrogen
  • the carbonyl deprotection reaction is known and can be.
  • a solvent such as a mixed solvent of DCM, THF and water, THF, or a mixed solvent of ethanol and water, etc.
  • an acid catalyst such as TFA, acetic acid, hydrochloric acid, or p-toluenesulfonic acid, etc.
  • the amino deprotection reaction is known and can be.
  • an organic solvent such as DCM, EA or 1,4-dioxane, etc.
  • an acid catalyst such as TFA is used to decarbonyl the protecting group to convert the ketal into the corresponding carbonyl compound.
  • the ester hydrolysis reaction is known and can be.
  • an organic solvent such as DCM, THF, EA or 1,4-dioxane, etc.
  • an acid catalyst such as TFA or hydrochloric acid
  • TFA or hydrochloric acid
  • the Wittig reaction is known and can be.
  • an organic solvent such as THF or 1,4-dioxane, etc.
  • a catalyst such as sodium hydride, etc.
  • carbonyl and phosphorus ylide reagents such as tert-butyl dimethoxyphosphonoacetate or cyanomethyl Diethyl phosphonate, etc.
  • the Miyaura boronation reaction is known and can be.
  • an organic solvent such as 1,4-dioxane, etc.
  • a base such as potassium acetate, etc.
  • a palladium catalyst Pd(dppf)Cl 2 etc.
  • halogenated aromatic hydrocarbons and diboronic acid
  • the ester reduction reaction is known and can be.
  • an organic solvent such as THF, etc.
  • a reducing agent such as lithium aluminum hydride
  • the oxidation reaction is known and can be.
  • an organic solvent such as EA, etc.
  • an oxidizing agent such as 2-iodoylbenzoic acid
  • the Corey-Chaykovsky reaction is known and can be.
  • an organic solvent such as DMSO, etc.
  • a catalyst such as Pd(OAc) 2 , ethyl zinc iodide or sodium hydride, etc.
  • a methylation reagent diazomethane, trimethylsulfoxide iodide or diiodide
  • Methane reacts with olefins to form a cyclopropane ring.
  • the Curtius rearrangement reaction is known and can be.
  • an organic solvent such as toluene, etc.
  • a base such as triethylamine, etc.
  • the carboxyl group and diphenyl azide phosphate react and rearrange to a primary amine, and the primary amine reacts with tert-butanol to form Boc (Tert-Butyloxycarbonyl) group protected amine.
  • the Grignard reaction is known and can be.
  • an organic solvent such as THF, diethyl ether, etc.
  • a catalyst such as tetraisopropyl titanate
  • Lewis acid such as boron trifluoride ethyl ether
  • cyano and Grignard reagent such as Ethyl magnesium bromide
  • the reductive amination is known and can be.
  • organic solvents such as DCM, EA or THF, etc.
  • catalysts such as Pd/C
  • reducing agents such as hydrogen, NaBH(OAc) 3
  • secondary amines and compounds Tert-butyl 1-formylcyclopropylcarbamate 2a undergoes reductive amination to form a CN bond.
  • the compound having an amino group, a carboxyl group, or a hydroxyl group used in the present invention can be prepared using a compound that has been protected by a protective group commonly used for this group as required. After passing through the reaction process of the above-mentioned reaction scheme, a known desorption can be carried out. Protection response.
  • the main advantage of the present invention is that it has better IDO inhibitory activity and lower toxicity.
  • THF is tetrahydrofuran
  • EA is ethyl acetate
  • PE is petroleum ether
  • DCM dichloromethane
  • Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphorus)ferrocene]dichloride Palladium
  • Pd/C palladium-carbon catalyst
  • LiHMDS is lithium bis(trimethylsilyl)amide
  • Dess-Martin reagent is (1,1,1-triacetoxy)-1,1-dihydro-1 ,2-phenyliodoyl-3(1H)-one
  • HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DMF is dimethylformamide
  • CDCl 3 is deuterated chloroform
  • DMSO is dimethyl sulfoxide
  • DMSO-d 6 is deuterated di
  • reaction solution was poured into a mixture of ice and water, extracted with ethyl acetate (100ml*2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and separated and purified by a silica gel column to obtain compound 1a (1.60g, yield 51.12%).
  • Example 1 Two of 4-cyano-N-(1-((4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide (J-1) Preparation of isomers (J-1-1 and J-1-2)
  • Step 1 4-chloro-6-fluoroquinoline 1-1 (1.0g, 5.51mmol), 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester (1.47g, 5.51mmol), K 2 CO 3 (1.52g, 11.01mmol) in a mixed solvent of 1,4-dioxane 30ml and water 3.0ml, under the protection of argon, add Pd(dppf)Cl 2 (403mg, 0.551mmol), stirred and heated to 110°C for 5 hours. LC-MS detected that the reaction was complete. The reaction solution was filtered and spin-dried, and separated and purified with a silica gel column to obtain compound 1-2 (1.3 g, purity: 100%, yield 83.33%). MS (ESI) 286.1 [M+H] + .
  • Step 2 Compound 1-2 (1.3g, 4.56mmol) was added to 30ml of ethyl acetate, 150mg of Pd/C was added, and the reaction solution was stirred at room temperature overnight under the protection of hydrogen. LC-MS detected that the reaction was complete. The reaction solution was filtered, concentrated and dried under reduced pressure to obtain compound 1-3 (1.0 g, purity: 95.17%, yield 76.92%). MS (ESI) 288.1 [M+H] + .
  • Step 3 Compound 1-3 (1.0 g, 3.48 mmol) was added to 3.0 ml of trifluoroacetic acid in 20 ml of dichloromethane while stirring at room temperature. The reaction solution was stirred at room temperature overnight. LC-MS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, then 100ml of saturated sodium bicarbonate was added, extracted with ethyl acetate (50ml*2), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to dryness to obtain compound 1-4 (0.7g, purity: 97.01%) , The yield is 82.68%). MS (ESI) 244.1 [M+H] + .
  • Step 4 Add diethyl cyanomethylphosphonate (1.09g, 6.17mmol) to 20ml of tetrahydrofuran, reduce the temperature to 0°C under argon protection, and slowly add sodium hydrogen (247mg, 6.17mmol). After stirring for 20 minutes at °C, compound 1-4 (1.0 g, 4.11 mmol) was slowly added dropwise (compound 1-4 was dissolved in 3 ml of tetrahydrofuran solution). The reaction solution was stirred at 0°C for 30 minutes, and then slowly warmed to room temperature to continue stirring for 3 hours. LC-MS detected that the reaction was complete.
  • Step 5 Compound 1-5 (2.5 g, 2.71 mmol) was dissolved in 20 ml of ethyl acetate, palladium carbon (200 mg) was added, and the reaction solution was stirred overnight at room temperature under hydrogen protection. LC-MS detected that the reaction was complete. The reaction solution was filtered and concentrated to dryness under reduced pressure to obtain compound 1-6. (700mg, purity: 100%, yield 96.50%). MS (ESI) 269.1 [M+H] + .
  • Step 6 Compound 1-6 (1.67g, 6.22mmol) was dissolved in 40ml of tetrahydrofuran, the temperature was reduced to -78°C under argon atmosphere, tetraisopropyl titanate (1.95g, 6.85mmol) was added dropwise, followed by ethyl Magnesium bromide (4.56ml, 13.69mmol), the reaction solution was stirred at -78°C for 1 hour, slowly warmed to room temperature, and stirred at room temperature for 2 hours. The reaction solution was cooled to 0°C again, and boron trifluoride ether (1.94 g, 13.69 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour.
  • Step 7 Compound 1-7 (640mg, 2.14mmol), 4-cyanobenzoic acid (631mg, 4.29mmol) was dissolved in 20ml DMF, HATU (1.63g, 4.29mmol) was added with stirring at room temperature, followed by diisopropyl Ethylethylamine (0.832g, 6.43mmol), the reaction solution was stirred at room temperature for 2 hours, and the reaction was complete as determined by LC-MS.
  • reaction solution was added to 100ml water, extracted with ethyl acetate (50ml*2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was subjected to high performance liquid phase separation (Waters-SunFire Prep 19*250mm, mobile phase: A: acetonitrile, B: water + 0.045% formic acid, wavelength: 214/254nm, gradient: 10-22, needle number: 29) Purification to obtain 4-cyano-N-(1-(((1s, 4s)-4-(6- Fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide J-1-1 (125 mg, purity: 100%, yield 13.63%).
  • Step 1 Dissolve ethyl 4-cyclohexanonecarboxylate 2-1 (40g, 240mmol) and 2,6-di-tert-butyl-4-methylpyridine (50g, 260mmol) in dichloromethane (700mL), Then the inner temperature of the reaction solution was reduced to 0°C, and trifluoromethanesulfonic anhydride (73g, 260mmol) in dichloromethane (100mL) was added dropwise.
  • Step 2 Combine compound 2-2 (51g, 170mmol), potassium acetate (50g, 510mmol), pinacol diborate (48g, 190mmol) and [1,1'-bis(diphenylphosphine)ferrocene ] Palladium dichloride dichloromethane complex (5 g, 6 mmol) was added to dimethyl sulfoxide (300 mL), and then under nitrogen, the reaction was heated to 90° C. and stirred for 6 hours.
  • Step 3 Combine compound 2-3 (15.0g, 54mmol), 4-chloro-6-fluoroquinoline (9.7g, 54mmol), anhydrous sodium carbonate (17.0g, 161mmol), and [1,1'-bis (Diphenylphosphine)ferrocene]palladium dichloride (2.3g, 3mmol) was added to the mixture solution of dioxane (200mL) and water (40mL), and then under nitrogen, the reaction was heated to 110°C And stirred for 6 hours.
  • Step 4 Combine 4-(6-fluoroquinolin-4-yl)cyclohexyl-3-ene-1-carboxylic acid ethyl ester 2-4 (21.0g, 70mmol) and palladium on carbon (10%, 50% w/w , 4.2g) was added to anhydrous tetrahydrofuran (300mL), and stirred under hydrogen for 16 hours, the raw material reaction was complete, the reaction solution was filtered, the filtrate was evaporated under reduced pressure to obtain the crude product 4-(6-fluoroquinoline-4- Yl) ethyl cyclohexyl-1-carboxylate 2-5 (19.7 g). MS (ESI) 302.2 [M+H] + .
  • Step 5 Add lithium aluminum hydride (2.9g, 76mmol) to -30°C tetrahydrofuran (300mL), and then add 4-(6-fluoroquinolin-4-yl)cyclohexyl-1-carboxylic acid ethyl ester 2- 5 (11.5g, 70mmol) of tetrahydrofuran (50mL) solution was dropped into the reaction solution, and the reaction temperature was controlled not to exceed -20°C and stirred for 2 hours. The raw material reaction was complete, and then sodium sulfate decahydrate was added in batches until no obvious bubbles were generated.
  • Step 6 Combine (4-(6-fluoroquinolin-4-yl)cyclohexyl)methanol 2-6 (7.9g, 31mmol) and 2-iodoylbenzoic acid (25.6g, 92mmol) in ethyl acetate (300mL ) The solution was heated to reflux for 16 hours, then the reaction solution was filtered, the filtrate was evaporated to dryness under reduced pressure, and the oily product 4-(6-fluoroquinolin-4-yl)cyclohexyl-1-carbaldehyde 2-7(6.7 g, yield 85%). MS (ESI) 258.1 [M+H] + .
  • Step 7 Add sodium hydride (60%, 480mg, 12mmol) to tetrahydrofuran (70mL), then dropwise add tert-butyl dimethoxyphosphonoacetate (2.69g, 12mmol) in tetrahydrofuran (10mL) and react at room temperature After 10 minutes, 4-(6-fluoroquinolin-4-yl)cyclohexyl-1-carbaldehyde 2-7 (2.57g, 10mmol) in tetrahydrofuran (10mL) was dropped into the reaction solution, and the reaction was stirred overnight.
  • Step 8 Add sodium hydride (60%, 563 mg, 14 mmol) to dimethyl sulfoxide (100 mL), add trimethyl sulfoxide iodide (3.10 g, 14 mmol) at room temperature and stir for 1 hour, then add 3 -(4-(6-Fluoroquinolin-4-yl)cyclohexyl)tert-butyl acrylate 2-8 (2.50g, 7mmol) in dimethyl sulfoxide (40mL) was dropped into the reaction solution and stirred at room temperature for 16 hours .
  • Step 9 Add tert-butyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)cyclopropane-1-carboxylate 2-9 (457 mg, 1.24 mmol) to dichloromethane (5 mL) Add trifluoroacetic acid (4mL) slowly at room temperature and stir for 1 hour. After the reaction of the raw materials is complete, the reaction solution is concentrated to dryness under reduced pressure to obtain the solid crude product 2-(4-(6-fluoroquinolin-4-yl) Cyclohexyl) cyclopropane-1-carboxylic acid 2-10 (612 mg), the product was used directly in the next reaction without purification. MS (ESI) 314.2 [M+H] + .
  • Step 10 Combine 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)cyclopropane-1-carboxylic acid 2-10 (100mg, 0.32mmol), 4-chloroaniline (81mg, 0.64mmol) and Diisopropylethylamine (295mg, 2.29mmol) was added to dimethyl sulfoxide (6mL), then HATU (182mg, 0.48mmol) was added at room temperature and stirred for 1 hour.
  • reaction solution was poured into saturated In sodium bicarbonate aqueous solution, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter the filtrate and evaporate to dryness under reduced pressure, pass through high performance liquid phase (Waters-SunFire Prep 19*250mm, mobile phase: A: acetonitrile, B : Water + 0.045% formic acid, wavelength: 214/254nm, gradient: 48-68)
  • Preparation of the solid product N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl) Diastereomer 1 of cyclohexyl)cyclopropane-1-carboxamide (J-2, containing cis and trans configurations) (2.78 mg, yield 2%).
  • Step 1 Combine 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)cyclopropane-1-carboxylic acid 2-10 (370mg, 1.18mmol), diphenyl azide phosphate (650mg, 2.36mmol) ), and triethylamine (716 mg, 7.09 mmol) were added to the mixed solution of tert-butanol (7 mL) and toluene (10 mL) and heated to reflux for 48 hours.
  • Step 2 Add (2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)cyclopropane) tert-butyl carbamate 4-1 (120mg, 0.31mmol) to dichloromethane (5mL) Add trifluoroacetic acid (3mL) slowly at room temperature and stir for 2 hours. After the reaction of the raw materials is complete, the reaction solution is concentrated to dryness under reduced pressure to obtain a solid crude product 2-(4-(6-fluoroquinolin-4-yl) Cyclohexyl)cyclopropane-1-amine 4-2 (139mg), the product was directly used in the next reaction without purification. MS (ESI) 285.2 [M+H] + .
  • Step 3 Mix 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)cyclopropane-1-amine 4-2 (50mg, 0.18mmol), 4-chlorobenzoic acid (41mg, 0.26mmol) , And diisopropylethylamine (114mg, 0.88mmol) were added to N,N-dimethylformamide (5mL), then HATU (100mg, 0.26mmol) was added at room temperature and stirred for 2 hours, the reaction was complete, The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the filtrate was filtered and evaporated to dryness under reduced pressure, and a white solid product isomer mixture J was prepared by HPLC -4 (22mg, yield 30%).
  • Step 1 Combine 4-chloro-6-fluoroquinoline 5-1 (5.0g, 27.53mmol), pinacol diborate (14.0g, 55.07mmol), AcOK (5.4g, 55.07mmol) in dioxane Pd(dppf)Cl 2 (1.0 g, 1.38 mmol) was added to the ring of 200 ml under the protection of argon, and the reaction solution was heated to 90° C. for 4 hours. LC-MS detected that the reaction was complete.
  • reaction solution was poured into a large amount of water, extracted with ethyl acetate (150ml*2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and separated and purified by a silica gel column to obtain 6-fluoro-4-(4,4,5,5) -Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline 5-2 (7.0 g, purity: 100%, yield: 93.09%).
  • Step 2 6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline 5-2 (500mg, 1.83mmol ), compound 1a (607mg, 1.83mmol) in a mixed solution of 1,4-dioxane 15ml and water 2.0ml, under the protection of argon, add Pd(dppf)Cl 2 (134mg, 0.183mmol), K 2 CO 3 (649 mg, 3.66 mmol). The reaction solution was heated to 95°C for 4 hours, and the reaction was completed by LC-MS.
  • Step 3 4-(6-Fluoroquinolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 5-3 (380mg, 0.854mmol) was dissolved in 20ml of ethyl acetate In the ester, palladium on carbon (200 mg) was added, and the reaction solution was stirred at room temperature under hydrogen protection for 6 hours. LC-MS detected that the reaction was complete. The reaction solution was filtered and concentrated to dryness under pressure to obtain tert-butyl 4-(6-fluoroquinolin-4-yl)piperidine-1-carboxylate 5-4 (400 mg, purity: 81.61%, yield: 100%). MS (ESI) 231.0 [M+H-56] + .
  • Step 4 4-(6-fluoroquinolin-4-yl)piperidine-1-carboxylic acid tert-butyl ester 5-4 (400mg, 1.21mmol) was dissolved in 2.5ml of dichloromethane, and 4M hydrochloric acid was added/ 2.5 ml of dioxane, stirred at room temperature for 1 hour, LC-MS detected that the raw material was left, 2.0 ml of methanol was added to the reaction solution, and stirring was continued for 1 hour. LC-MS detected that the reaction was complete.
  • Step 5 6-Fluoro-4-(piperidin-4-yl)quinoline 5-5 (240mg, 1.04mmol), compound 2a (386mg, 2.08mmol) was dissolved in 10ml of dichloromethane, and NaBH was added with stirring at room temperature (OAc) 3 (663 mg, 3.13 mmol), followed by the addition of AcOH (0.5 ml), the reaction solution was stirred at room temperature overnight, and LC-MS detected that the reaction was complete. The reaction solution was added to saturated NaHCO 3 solution, extracted with ethyl acetate (50ml*2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • OAc room temperature
  • AcOH 0.5 ml
  • Step 6 1-((4-(6-Fluoroquinolin-4-yl)piperidin-1-yl)methyl)tert-butyl cyclopropylcarbamate 5-6 (200mg, 0.501mmol) was dissolved in 2.0 Add 2.5 ml of 4M hydrochloric acid/dioxane to a mixed solvent of ml of dichloromethane and 2.0 ml of methanol, and stir overnight at room temperature. LC-MS detects that the reaction is complete.
  • Step 7 1-((4-(6-Fluoroquinolin-4-yl)piperidin-1-yl)methyl)cyclopropylamine hydrochloride 5-7 (100mg, 0.315mmol), 4-cyanobenzene Formic acid (93mg, 0.629mmol) was dissolved in 5ml DMF, HATU (239g, 0.629mmol) was added under stirring at room temperature, followed by diisopropylethylamine (203g, 1.57mmol), the reaction solution was stirred at room temperature for 2 hours, LC-MS The detection reaction is complete.
  • Example 6 Two isoforms of 4-chloro-N-(1-((4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide (J-6) Preparation of constructs (J-6-1 and J-6-2)
  • the preparation method of compound J-6 refers to compound J-1, except that 4-cyanobenzoic acid in step 7 is replaced with 4-chlorobenzoic acid.
  • Compound J-6 was separated by high performance liquid phase (Waters-SunFire Prep 19*250mm, mobile phase: A: acetonitrile, B: water + 0.045% formic acid, wavelength: 214/254nm, gradient: 10-22, needle number: 29) 4-chloro-N-(1-(((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide J-6-1 was obtained. MS (ESI) 437.2 [M+H] + .
  • Example 7 Two isoforms of 4-fluoro-N-(1-((4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide (J-7) Preparation of constructs (J-7-1 and J-7-2)
  • compound J-7 refers to compound J-1, except that 4-cyanobenzoic acid in step 7 is replaced with 4-fluorobenzoic acid.
  • Compound J-7 was separated by high performance liquid phase (Waters-SunFire Prep 19*250mm, mobile phase: A: acetonitrile, B: water + 0.045% formic acid, wavelength: 214/254nm, gradient: 10-22, needle number: 29) 4-Fluoro-N-(1-(((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide J-7-1 is obtained.
  • Step 1 Compound 1-7 (110 mg, 0.37 mmol) and triethylamine (112 mg, 1.11 mmol) were added to dichloromethane (10 mL), and then under nitrogen, compound 3a (130 mg, 0.74 mmol) was added dropwise. After the reaction was completed, dichloromethane and water were added for extraction, the organic phase was washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and the white product 6-chloro- was obtained by column chromatography.
  • Step 2 Combine compound 8-1 (70mg, 0.14mmol), potassium ethylene fluoroborate (210mg, 1.4mmol), anhydrous cesium carbonate (140mg, 0.42mmol), and [1,1'-bis(diphenylphosphine) ) Ferrocene] Palladium dichloride (12 mg, 0.014 mmol) was added to the mixture solution of tetrahydrofuran (5 mL) and water (2 mL), and then reacted under nitrogen at 100° C. in a microwave for half an hour.
  • Step 1 Dissolve 2-chloropyrimidine-5-carboxylic acid (316 mg, 2 mmol) in dichloromethane (10 mL), then lower the internal temperature of the reaction solution to 0°C, add oxalyl chloride (756 mg, 5 mmol) dropwise, and then One drop of DMF was added, the reaction solution was stirred at room temperature for 1 hour, and evaporated to dryness under reduced pressure to obtain the product 2-chloropyrimidine-5-carbonyl chloride (320 mg), which was directly used in the next reaction without purification.
  • Step 2 Add compound 1-7 (180mg, 0.6mmol) and triethylamine (181mg, 1.8mmol) to dichloromethane (10mL), then under nitrogen, add dropwise compound 2-chloropyrimidine-5-carbonyl Chlorine (218mg, 1.2mmol).
  • Step 3 Combine compound 9-1 (150mg, 0.34mmol), potassium ethylene fluoroborate (455mg, 3.4mmol), anhydrous cesium carbonate (1108mg, 3.4mmol), and [1,1'-bis(diphenylphosphine) ) Ferrocene] Palladium dichloride (25 mg, 0.034 mmol) was added to the mixture solution of tetrahydrofuran (10 mL) and water (2 mL), and then reacted under nitrogen at 100° C. for half an hour in a microwave.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and benzoic acid, respectively, to obtain N-(1-(((1s, 4s )-4-(6-Fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide (J-10).
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 2,4-difluorobenzoic acid, respectively.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 3,4-difluorobenzoic acid, respectively.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 6-methylpyridine-3-carboxylic acid, respectively.
  • N-(1-(((1s,4s)-4-(6-fluorocinoline-4-yl)cyclohexyl)methyl)cyclopropyl)-6-methylnicotinamide (J-14) was obtained.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 3-chlorobenzoic acid, respectively.
  • 3-chloro-N-(1-(((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide (J-15) was obtained.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 3-fluorobenzoic acid, respectively.
  • 3-Fluoro-N-(1-(((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)benzamide (J-16) was obtained.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 3-ethynylbenzoic acid, respectively.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 4-ethynylbenzoic acid, respectively.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 3-cyanobenzoic acid, respectively.
  • the preparation method refers to step 7 of Example 1, except that the compound 1-7 and 4-cyanobenzoic acid in step 7 are replaced with compound 4a and 6-ethynylpyridine-3-carboxylic acid, respectively.
  • 6-Ethynyl-N-(1-(((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl)cyclopropyl)nicotinamide (J-20) is obtained.
  • Hela cells are from ATCC; DMEM phenol-free red blood cell culture medium is from Gibco, product number: 21063-029; INF- ⁇ is from Life Technologies, product number: PHC4031 100ug; Fetal bovine serum is from Gibco, product number: 10099-141; 0.25% pancreas Protease is from GIBCO, product number: 25200-072; Phosphate buffer (PBS) is from Hyclone, product number: SH30256.01B; 6.1N trichloroacetic acid is from Sigma, product number: T0699; p-dimethylaminobenzaldehyde (pDMAB) is from Sigma, product number: 15647-7; L-tryptophan is from Sigma, product number: T0254-25G; DMSO is from Sigma, product number: D5879-1L; 96-well cell culture plates are from BD Falcon, product number: 353072.
  • PBS Phosphate buffer
  • pDMAB p-dimethyl
  • the cell culture plate is placed in a cell incubator for 48 hours;
  • HE293-hIDO1-7 stable transfection cell line is from TGZ0172; DMEM phenol-free red blood cell medium is from Gibco, product number: 21063-029; Fetal bovine serum is from Gibco, product number: 10099-141; 0.25% trypsin is from Gibco, product number :25200-072; Phosphate buffer (PBS) from Hyclone, product number: SH30256.01B; 6.1N trichloroacetic acid from Sigma, product number: T0699; p-Dimethylaminobenzaldehyde (pDMAB) from Sigma, product number: 15647 -7; L-tryptophan is from Sigma, product number: T0254-25G; DMSO is from Sigma, product number: D5879-1L; 96-well cell culture plate is from BD Falcon, product number: 353072.
  • PBS Phosphate buffer
  • pDMAB p-Dimethylaminobenzaldehyde
  • the cell culture plate is placed in a cell incubator for 48 hours;

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Abstract

提供环烷基取代的酰胺类衍生物、其制法与医药上的用途。具体地，提供了式(I)化合物或其药学上可接受的盐、或立体异构体，及其制备方法和应用，式中各基团的定义详见说明书。

Description

环烷基取代的酰胺类衍生物、其制法与医药上的用途 技术领域
本发明涉及医药技术领域，特别涉及一种环烷基取代的酰胺类衍生物及其制备方法和作为IDO抑制剂的应用，以及由其制备的药物组合物和药用组合物。
背景技术
吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,简写IDO)是一种与色氨酸代谢有关的蛋白酶。色氨酸是八种必需氨基酸之一，在体内色氨酸可用来合成蛋白质，色氨酸还可作为前体底物通过甲氧基吲哚代谢途径合成5-羟色胺和褪黑激素(N-乙酰-5-甲氧基色胺)。5-羟色胺和褪黑激素是神经递质和神经内分泌激素，参与体内的多种神经与生理过程的调节。此外，色氨酸还可通过犬尿氨酸代谢途径产生犬尿氨酸等代谢产物。犬尿氨酸代谢途径的第一步是在吲哚胺2,3-双加氧酶或色氨酸2，3-双加氧酶(TDO)的催化作用下，色氨酸L-色氨酸降解为N-甲酰基-犬尿氨酸，N-甲酰基-犬尿氨酸在犬尿氨酸甲酰胺酶的催化作用下形成犬尿氨酸，犬尿氨酸还可被进一步代谢形成3-羟基邻氨基苯甲酸，喹啉酸，吡啶甲酸。喹啉酸具有神经毒性，而吡啶甲酸具有神经保护作用。犬尿氨酸和3-羟基邻氨基苯甲酸参与淋巴细胞活性调节从而引起免疫系统被抑制。
除胎盘组织外，正常健康状况下吲哚胺2,3-双加氧酶在多数组织细胞内基本不表达。在炎症发生区域，干扰素γ等炎性细胞因子可诱导吲哚胺2,3-双加氧酶表达量升高。多方面的实验结果证明，吲哚胺2,3-双加氧酶在组织细胞中的高表达可导致该组织微环境的免疫系统被抑制，或称免疫被抑制或免疫检查点(immune checkpoint)。胎盘组织吲哚胺2,3-双加氧酶的高表达可防止对胎儿的免疫排斥反应。炎症区域吲哚胺2,3-双加氧酶的高表达可防止过度的免疫反应，防止细胞组织受到过度的损伤。导致免疫被抑制的机制之一是吲哚胺2,3-双加氧酶高表达造成局部L-色氨酸耗竭，从而被周围的淋巴细胞通过GCN2等机制感受到，引起CD8+细胞毒性T细胞发生细胞周期停滞或凋亡。导致免疫被抑制的另一种机制是吲哚胺2,3-双加氧酶高表达造成犬尿氨酸升高，犬尿氨酸形成后可离开细胞进入细胞外基质，然后进入附近的淋巴细胞通过结合AHR转录因子对CD8+T细胞和调节性TR32g细胞进行调节,CD8+细胞毒性T细胞的活性被抑制，而调节性TR32g细胞的数量增多并且被激活，从而导致免疫被抑制。
在很多不同类型的肿瘤中吲哚胺2,3-双加氧酶发生异常高表达，包括血液肿瘤和直结肠癌、肝癌、肺癌、胰腺癌、咽喉癌等实体瘤。吲哚胺2,3-双加氧酶异常高表达与肿瘤不良预后呈正相关。肿瘤细胞逃脱免疫监控是癌变和癌症进一步发展的关键一步，肿瘤中吲哚胺2,3-双加氧酶的异常高表达可能是肿瘤细胞逃脱。
免疫监控的一种主要机制，抑制吲哚胺2,3-双加氧酶的活性有可能激活被抑制的免疫系 统，达到抑制肿瘤生长的效果，所以吲哚胺2,3-双加氧酶抑制剂作为一种免疫检查点抑制剂(immune checkpoint inhibitor)引起了医药界很大的兴趣。吲哚胺2,3-双加氧酶(IDO)有两种，IDO-1和IDO-2，参与上述免疫被抑制的主要是IDO-1，IDO-2在免疫被抑制中的作用还不是很清楚。色氨酸2，3-双加氧酶(TDO)也在很多类型的肿瘤中发生异常高表达，有的肿瘤还呈现IDO和TDO双阳性，所以有人认为也可通过抑制TDO免疫检查点起到肿瘤治疗的目的。因为正常肝脏细胞表达TDO，尚不清楚TDO抑制剂是否会影响肝脏功能和正常的色氨酸代谢，但TDO敲除得小鼠模型未见异常，表明TDO抑制剂可能不会影响肝脏功能和正常的色氨酸代谢。IDO和TDO导致免疫被抑制的机理基本相同，所以IDO/TDO双特异抑制剂也同样引起了医药界的兴趣，IDO/TDO双特异抑制剂将适用于IDO阳性、TDO阳性、IDO/TDO双阳性的病人。
色氨酸的犬尿氨酸代谢途径的很多代谢产物与精神分裂症，抑郁症，神经元退化有关，吲哚胺2,3-双加氧酶抑制剂可能也可用于这些疾病的治疗。犬尿氨酸在犬尿氨酸氨基转移酶的催化作用下可转化为犬尿喹啉酸，犬尿喹啉酸是一种NMDA拮抗剂，在精神分裂症病人的中枢神经中常见到较高的犬尿喹啉酸水平。喹啉酸具有神经毒性，可导致神经细胞凋亡和神经退化。吲哚胺2,3-双加氧酶不仅参与色氨酸代谢，还参与色氨等的代谢，5-羟色胺在吲哚胺2,3-双加氧酶的催化作用下可转化为5-羟吲哚乙酸，5-羟色胺下降可能是导致抑郁症的因素之一。
目前吲哚胺2,3-双加氧酶抑制剂还处于早期研发阶段，在现有基础上开发活性更好毒性更低的IDO抑制剂具有重要的临床意义。
发明内容
本发明的目的是提供一类结构新颖的IDO抑制剂及其制备方法和用途。
本发明第一方面提供了一种式(I)所示的化合物，或其药学上可接受的盐、或立体异构体：
Figure PCTCN2019130744-appb-000001
式中，
A为取代或未取代的苯基、取代或未取代的8至10元双环杂芳基、或取代或未取代的5至6元单环杂芳基；
B环为取代或未取代的苯环、或取代或未取代的5至6元单环杂芳基环；
L 1为一个键或NR 1；
L 2为一个键或NR 2；
L 1、L 2不同时为一个键并且L 1、L 2不同时含有N；
E 1、E 4各自独立地为CR 3或N；
E 2为(CR 21R 22) m、(CR 21R 22) t-O或(CR 21R 22) t-NR 23；
E 3为CR 31R 32、O或NR 33，且E 2、E 3不同时含O或N；
R 1、R 2各自独立地为氢或C 1-10烷基(优选C 1-6烷基，更优选C 1-3烷基)；
R 3为氢、氰基、羟基、羧基、卤素、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)；
R 21、R 22、R 31、R 32各自独立地为-(CH 2) r-R 0；R 0为氢、卤素、氰基、羟基、C 1-10烷基(优选C 1-6烷基，更优选C 1-3烷基)、-C(O)C 1-10烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或C 1-10烷氧基(优选为C 1-6烷氧基，更优选C 1-3烷氧基)；
R 23、R 33各自独立地为氢、C 1-10烷基(优选C 1-6烷基，更优选C 1-3烷基)、-C(O)C 1-10烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)；
m为0、1或2；
t为0或1；
r为0、1、2或3；
R a、R b、R c、R d为选自下组的一种：
(ⅰ)R a、R b各自独立地为氢、卤素、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)或取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)；
R c、R d与它们连接的碳原子一起形成取代或未取代的3至6元饱和或不饱和单环或取代或未取代的3至6元饱和或不饱和单杂环；
(ⅱ)R b、R d各自独立地为氢、卤素、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)或取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)；
R a、R c与它们连接的碳原子一起形成取代或未取代的3至6元饱和或不饱和单环或取代或未取代的3至6元饱和或不饱和单杂环；
Z 1为N或CR 01；Z 2为N或CR 02；Z 3为N或CR 03；Z 4为N或C；
Figure PCTCN2019130744-appb-000002
为单键或双键；
R 01、R 02、R 03各自独立地为氢、卤素、C 1-10烷基(优选C 1-6烷基，更优选C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 3-10环烷基(优选为C 3-6环烷基)、卤代C 1-10烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、NR a0R b0或-C(O)C 1-10烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)；
所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A1组的取代基所取代；
所述R 21、R 22、R 23、R 31、R 32、R 33、R 01、R 02、R 03中的烷基，以及R 21、R 22、R 31、R 32、R 01、R 02、R 03中的烷氧基为未取代的或被1、2或3个各自独立地选自A1组的取代基所取代；
所述A1组取代基选自：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、5或6元单环杂芳基、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环或4至6元饱和或不饱和单环，其中R a0、R b0各自独立地为氢或C 1-3烷基。
在另一优选例中，所述式(I)化合物具有式(I-1)或式(I-2)所示结构：
Figure PCTCN2019130744-appb-000003
式中各基团同说明书中所定义。
在另一优选例中，所述式(I)化合物具有式(I-a)所示结构：
Figure PCTCN2019130744-appb-000004
其中C环为取代或未取代的3至6元饱和或不饱和单环或取代或未取代的3至6元饱和或不饱和单杂环；其他各基团如说明书中所定义。
在另一优选例中，所述式(I-a)化合物具有式(I-a-1)或式(I-a-2)所示结构：
Figure PCTCN2019130744-appb-000005
式中各基团同说明书中所定义。
在另一优选例中，式(I-a)、式(I-a-1)和式(I-a-2)中，R b、R d各自独立地为氢、卤素、C 1-3 烷基或C 1-3烷氧基。
在另一优选例中，式(I-a)、式(I-a-1)和式(I-a-2)中，R b、R d各自独立地为氢、氟、氯、甲基、乙基、甲氧基或乙氧基。
在另一优选例中，式(I-a)、式(I-a-1)和式(I-a-2)中，R b、R d各自独立地为氢。
在另一优选例中，式(I-a)、式(I-a-1)和式(I-a-2)中，C环为3至6元饱和单环。
在另一优选例中，式(I-a)、式(I-a-1)和式(I-a-2)中，C环为3元饱和单环。
在另一优选例中，式(I-a)、式(I-a-1)和式(I-a-2)中，C环为环丙基环。
在另一优选例中，式(I-a)、式(I-a-1)和式(I-a-2)中，
Figure PCTCN2019130744-appb-000006
在另一优选例中，式(I-a)、式(I-a-1)和式(I-a-2)中，(a)L 1为NH，且L 2为一个键；或(b)L 1为一个键；L 2为NH。
在另一优选例中，所述式(I)化合物具有式(I-b)所示结构：
Figure PCTCN2019130744-appb-000007
其中D环为取代或未取代的3至6元饱和或不饱和单环或取代或未取代的3至6元饱和或不饱和单杂环；其他各基团如说明书中所定义。
在另一优选例中，所述式(I-b)化合物具有式(I-b-1)或式(I-b-2)所示结构：
Figure PCTCN2019130744-appb-000008
式中各基团同说明书中所定义。
在另一优选例中，式(I-b)、式(I-b-1)和式(I-b-2)中，R a、R b各自独立地为氢、卤素、C 1-3烷基或C 1-3烷氧基。
在另一优选例中，式(I-b)、式(I-b-1)和式(I-b-2)中，R a、R b各自独立地为氢、氟、氯、甲基、乙基、甲氧基或乙氧基。
在另一优选例中，式(I-b)、式(I-b-1)和式(I-b-2)中，R a、R b各自独立地为氢。
在另一优选例中，式(I-b)、式(I-b-1)和式(I-b-2)中，D环为3至6元饱和单环。
在另一优选例中，式(I-b)、式(I-b-1)和式(I-b-2)中，D环为3元饱和单环。
在另一优选例中，式(I-b)、式(I-b-1)和式(I-b-2)中，D环为环丙基环。
在另一优选例中，式(I-b)、式(I-b-1)和式(I-b-2)中，
Figure PCTCN2019130744-appb-000009
为
Figure PCTCN2019130744-appb-000010
在另一优选例中，式(I-b)、式(I-b-1)和式(I-b-2)中，L 1为NH，L 2为一个键。
在另一优选例中，所述A1组取代基选自：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-3烷基、卤素(优选为F或Cl)、硝基、苯基、5或6元单环杂芳基、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-4烯基、C 2-4炔基、-CONR a0R b0、-C(O)OC 1-3烷基、-CHO、-OC(O)C 1-3烷基、-SO 2C 1-3烷基、-SO 2-苯基、-CO-苯基、4至6元饱和或不饱和单杂环或4至6元饱和或不饱和单环，其中R a0、R b0各自独立地为氢或C 1-3烷基。
在另一优选例中，Z 1、Z 2、Z 3和Z 4不同时为N。
在另一优选例中，Z 1、Z 2和Z 3中至少一个不为N。
在另一优选例中，Z 1、Z 2和Z 3中的两个不为N。
在另一优选例中，Z 1为N；Z 2为CR 02；Z 3为CR 03；R 02、R 03如上所定义。
在另一优选例中，Z 1为CR 01；Z 2为N；Z 3为CR 03；R 01、R 03如上所定义。
在另一优选例中，Z 1为CR 01；Z 2为CR 02；Z 3为N；R 01、R 02如上所定义。
在另一优选例中，R 02、R 03为氢。
在另一优选例中，B环为苯环、吡啶环、吡唑环、咪唑环或吡咯环，Z 4为N或C；
Figure PCTCN2019130744-appb-000011
为单键或双键。
在另一优选例中，A中所述5至6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。
在另一优选例中，A中所述8至10元双环杂芳基选自：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶。
在另一优选例中，A为取代或未取代的苯基，或取代或未取代的5至6元单环杂芳基，所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-3烷基、卤素、硝基、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-4烯基、C 2-4炔基、-CONR a0R b0、-C(O)OC 1-3烷基、-CHO、-OC(O)C 1-3烷基、-SO 2C 1-3烷基、-SO 2-苯基和-CO-苯基，其中R a0、R b0各自独立地为氢或C 1-3烷基。
在另一优选例中，A为取代或未取代的苯基，或取代或未取代的吡啶基，所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、三氟甲基、氟、氯、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丙基氧基、乙烯基、乙炔基、-CONR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、-SO 2C 1-3烷基，其中R a0、R b0各自独立地为氢或甲基。
在另一优选例中，A1组取代基中所述的4至6元饱和或不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃或1,2,3,6-四氢吡啶。
在另一优选例中，A1组取代基中所述的4至6元饱和或不饱和单环选自：环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环。
在另一优选例中，A1组取代基中所述的5或6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。
在另一优选例中，R c、R d与它们连接的碳原子一起形成的3至6元饱和或不饱和单环选自：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环。
在另一优选例中，R c、R d与它们连接的碳原子一起形成的3至6元饱和或不饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶。
在另一优选例中，R a、R c与它们连接的碳原子一起形成的3至6元饱和或不饱和单环选自：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环。
在另一优选例中，R a、R c与它们连接的碳原子一起形成的3至6元饱和或不饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶。
在另一优选例中，R 3为氢、氰基、羟基、羧基、卤素、取代或未取代的C 1-3烷基，所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自下组的取代基所取代：氰基、乙酰基、羟基、羧基、卤素、C 3-6环烷基。在另一优选例中，L 1为NR 1；L 2为一个键。
在另一优选例中，L 1为一个键；L 2为NR 2。
在另一优选例中，
Figure PCTCN2019130744-appb-000012
为式(IA)、式(IB)或式(IC)所示结构：
Figure PCTCN2019130744-appb-000013
其中Z 5为N或CR 7；Z 1、Z 2、Z 3如说明书中所定义；R 4、R 5、R 6、R 7、R 8、R 9、R 10各自独立地为氢、卤素、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、C 3-10环烷基、卤代C 1-10烷氧基、NR a0R b0或-C(O)C 1-10烷基；其中所述C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、C 3-10环烷基、卤代C 1-10烷氧基以及-C(O)C 1-10烷基中的烷基和烷氧基为未取代的或被1、2或3个各自独立地选自A1组的取代基所取代。
在另一优选例中，R 4、R 5、R 6各自独立地为氢、卤素、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基、C 3-6环烷基、卤代C 1-3烷氧基、NR a0R b0或-C(O)C 1-3烷基，其中R a0、R b0各自独立地为氢或C 1-3烷基。
在另一优选例中，R 7为氢。
在另一优选例中，R 4、R 6为氢。
在另一优选例中，R 5为卤素，优选为氟。
在另一优选例中，
Figure PCTCN2019130744-appb-000014
为式(IA)所示结构。
在另一优选例中，式(IA)中，Z 1为N；Z 2为CR 02；Z 3为CR 03；Z 5为N；R 02、R 03如上所定义。
在另一优选例中，式(IA)中，Z 1为N；Z 2为CR 02；Z 3为CR 03；Z 5为CR 7；R 02、R 03、R 7如上所定义。
在另一优选例中，式(IA)中，Z 1为CR 01；Z 2为CR 02；Z 3为CR 03；Z 5为N；R 01、R 02、R 03如上所定义。
在另一优选例中，式(IB)或式(IC)中，Z 1为N；Z 2为CR 02；Z 3为CR 03；R 02、R 03如上所定义。
在另一优选例中，R 02为氢；R 03为氢。
在另一优选例中，式(IB)中，Z 1为N；Z 2、Z 3为CH；R 8、R 9为氢。
在另一优选例中，式(IC)中，Z 1为N；Z 2、Z 3为CH；R 9为氢；R 10为氢、卤素、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、C 3-10环烷基、卤代C 1-10烷氧基、NR a0R b0或-C(O)C 1-10烷基。
在另一优选例中，E 1、E 4为CH；E 3为CR 31R 32、O或NR 33；E 2为(CR 21R 22) m；m为0、1或2；R 21、R 22、R 31、R 32、R 33如说明书中所定义。
在另一优选例中，E 1、E 4为CH；E 3为CR 31R 32；E 2为(CR 21R 22) t-O或(CR 21R 22) t-NR 23；t 为0或1；R 21、R 22、R 23、R 31、R 32如说明书中所定义。
在另一优选例中，E 1、E 4各自独立地为CH或N；E 2为(CR 21R 22) m；m为0、1或2；E 3为CR 31R 32；R 21、R 22、R 31、R 32如说明书中所定义。
在另一优选例中，E 1为CH，E 4为CH或N；E 2为(CR 21R 22) m；m为0、1或2；E 3为CR 31R 32；R 21、R 22、R 31、R 32如说明书中所定义。
在另一优选例中，E 1为CH，E 4为CH或N；E 2为CH；E 3为CH。
在另一优选例中，
Figure PCTCN2019130744-appb-000015
选自下组的结构：
Figure PCTCN2019130744-appb-000016
在另一优选例中，
Figure PCTCN2019130744-appb-000017
选自下组的结构：
Figure PCTCN2019130744-appb-000018
Figure PCTCN2019130744-appb-000019
其中R 23、R 33如说明书中所定义。
在另一优选例中，E 1、E 4为CH；E 3为CR 31R 32、O或NR 33；E 2为(CR 21R 22) m；m为0、1或2；
Figure PCTCN2019130744-appb-000020
为式(IA)所示结构。
在另一优选例中，E 1、E 4为CH；E 3为CR 31R 32；E 2为CR 21R 22；
Figure PCTCN2019130744-appb-000021
为式(IA)所示结构。
在另一优选例中，E 1、E 4为CH；E 3为CR 31R 32；E 2为(CR 21R 22) t-O或(CR 21R 22) t-NR 23；t为0或1；
Figure PCTCN2019130744-appb-000022
为式(IA)所示结构。
在另一优选例中，E 1、E 4各自独立地为CH或N；E 2为(CR 21R 22) m；m为0、1或2；E 3为CR 31R 32；
Figure PCTCN2019130744-appb-000023
为式(IA)所示结构。
在另一优选例中，E 1为CH；E 4为N；E 2为(CR 21R 22) m；m为0、1或2；E 3为CR 31R 32；
Figure PCTCN2019130744-appb-000024
为式(IA)所示结构。
在另一优选例中，式(IA)为下组结构：
Figure PCTCN2019130744-appb-000025
在另一优选例中，式(IA)为
Figure PCTCN2019130744-appb-000026
在另一优选例中，
Figure PCTCN2019130744-appb-000027
为
Figure PCTCN2019130744-appb-000028
在另一优选例中，所述3至6元饱和单杂环选自以下结构：
Figure PCTCN2019130744-appb-000029
Figure PCTCN2019130744-appb-000030
上述3至6元饱和单杂环任选地被1、2或3个各自独立地选自A1组的取代基所取代。
在另一优选例中，所述5至6元单环杂芳基环或杂芳基选自：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环。
在另一优选例中，所述5至6元单环杂芳基环或杂芳基选自以下结构：
Figure PCTCN2019130744-appb-000031
上述5至6元单环杂芳基环或杂芳基任选地被1、2或3个各自独立地选自A1组的取代基所取代。
在另一优选例中，所述化合物选自表A或表B。
在另一优选例中，表A化合物选自下组：
Figure PCTCN2019130744-appb-000032
Figure PCTCN2019130744-appb-000033
在另一优选例中，表B化合物选自下组：
Figure PCTCN2019130744-appb-000034
在另一优选例中，式(I)化合物具有选自下组的结构：
Figure PCTCN2019130744-appb-000035
Figure PCTCN2019130744-appb-000036
尽管上表列出本发明的优选化合物的结构，但应该了解环己基上呈对位取代的一组取代基所连接的环己基上的两个碳原子并不是手性中心，
Figure PCTCN2019130744-appb-000037
的化学键表示法仅为了表示与呈对位取代的一组取代基所连接的两个化学键相对于环己基基团呈反式或顺式结构，因此将这两个化学键
Figure PCTCN2019130744-appb-000038
彼此交换而表示的化合物同样落在本发明的保护范围内。
本发明第二方面提供了一种药物组合物，所述药物组合物包括本发明第一方面所述的化合物、或其药学上可接受的盐、或立体异构体；以及药学可接受的载体。
本发明第三方面提供了如本发明第一方面所述的化合物、或其药学上可接受的盐、或立体异构体、或如本发明第二方面所述药物组合物在制备药物中的应用，所述药物用于抑制吲哚胺2,3-双加氧酶的活性或者用于抑制患者的免疫抑制。
在另一优选例中，所述药物用于治疗或预防患者的癌症或肿瘤、病毒感染、抑郁症、神经变性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病；优选的，其中所述癌症或肿瘤选自肺癌、骨癌、胃癌、胰腺癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、直肠癌、结肠癌、肛门区癌、乳腺癌、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、尿道癌、阴茎癌、前列腺癌、胰腺癌、脑癌、睾丸癌、淋巴癌、移行细胞癌、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、霍奇金病、非霍奇金淋巴瘤、软组织肉瘤、儿童实体瘤、淋巴细胞性淋巴瘤、中枢神经系统(CNS)肿瘤、原发性中枢神经系统淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、黑素瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、慢性或急性白血病和所述癌的组合。
在另一优选例中，所述的应用是指将治疗有效剂量的前述的式(Ⅰ)化合物、其立体异构体或其药学上可接受盐、或前述药物组合物与抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体、抗病毒剂、化疗剂、免疫抑制剂、辐射、抗肿瘤疫苗、抗病毒疫苗、细胞因子疗法或酪氨酸激酶抑制剂进行联合用药；优选的，所述细胞因子优选IL-2、IL-3、IL-4或IL-5，所述化疗剂优选细胞毒性剂，所述抗PD-1抗体优选Keytruda抗体。
本发明第四方面提供了一种调节吲哚胺2,3-双加氧酶活性的方法，包括将治疗有效剂量的前述式(Ⅰ)化合物、其立体异构体或其药学上可接受盐、或前述药物组合物与吲哚胺2,3-双加氧酶接触。优选的，所述调节优选为抑制作用。
本发明第五方面提供了一种抑制患者的免疫抑制的方法，所述方法包括将治疗有效剂量的前述式(Ⅰ)化合物、其立体异构体或其药学上可接受盐、或前述药物组合物给予患者。
本发明第六方面提供一种治疗癌症的方法，该方法包括向患者施用治疗有效剂量的本发 明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。
在另一优选例中，所述癌症或肿瘤选自肺癌、骨癌、胃癌、胰腺癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、直肠癌、结肠癌、肛门区癌、乳腺癌、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、尿道癌、阴茎癌、前列腺癌、胰腺癌、脑癌、睾丸癌、淋巴癌、移行细胞癌、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、霍奇金病、非霍奇金淋巴瘤、软组织肉瘤、儿童实体瘤、淋巴细胞性淋巴瘤、中枢神经系统(CNS)肿瘤、原发性中枢神经系统淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、黑素瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、慢性或急性白血病和所述癌的组合。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类环烷基取代的酰胺类衍生物，其对IDO抑制剂具有更好的抑制活性和更低的毒性。此外本发明的化合物具有优异的药代动力学特性。因此该系列化合物有望开发成为用于治疗和预防癌症等疾病的药物。在此基础上，发明人完成了本发明。
术语定义
如本文所用，“烷基”指直链和支链的饱和的脂族烃基，C 1-10烷基为包含1至10个碳原子的烷基，优选为C 1-6烷基，更优选为C 1-3烷基，定义类似；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等更优选。
如本文所用，“烯基”是指含有至少一个双键的脂族基团。“C 2-10烯基”为包含2至10个碳原子的烯基，优选为优选为C 2-6烯基，更优选为C 2-4烯基，定义类似；烯基的非限制性的例子包括:乙烯基、1-丙烯基、2-丙烯基、1-丁烯基或2-丁烯基及其各种支链异构体等更优选。如本文所用，“炔基”指含有至少一个三键的脂族基团，C 2-10炔基为包含2至10个碳原子的炔基，优选为优选为C 2-6炔基，更优选为C 2-4炔基，定义类似；炔基的非限制性的例子包括： 乙炔基、1-丙炔基、2-丙炔基、1-丁炔基或2-丁炔基及其各种支链异构体等更优选。
如本文所用，“环烷基”和“环烷基环”可互换使用，均指饱和或不饱和单环环状烃基，“C 3-8环烷基”是指包含3至8个碳原子的环烃基，优选为C 3-6环烷基，定义类似。环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环戊基、环己烯基。
如本文所用，“C 1-10烷氧基”指-O-(C 1-10烷基)，其中烷基的定义如上所述。优选C 1-6烷氧基，更优选C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“C 3-8环烷氧基”指-O-(C 3-8环烷基)，其中环烷基的定义如上所述。优选C 3-6环烷氧基。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
如本文所用，“C 6-10芳基”和“C 6-10芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，更优选苯基。
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。
如本文所用，“卤素”指氟、氯、溴或碘。
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C 1-10烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。选为卤代C 1-6烷基，更优选为卤代C 1-3烷基。卤代C 1-10烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
又例如，“卤代C 1-10烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
如本文所用，“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苄基”指-CH 2-苯基，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CHOHCH 3，“羟基”指-OH。
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。
如本文所用，“3至6元(4至6元)饱和或不饱和单环”是指含3至6个环原子的饱和或部分不饱和的全碳单环。3至6元饱和或不饱和单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环等。
如本文所用，“3至6元(4至6元)饱和或不饱和单杂环”是指3至6元单环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳；优选4至6元，更优选5至6元。3至6元饱和或 部分不饱和单杂环的实例包括(但不限于)环氧丙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、吡咯啉、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶等。
如本文所用，“5至6元单环杂芳基环”和“5至6元单环杂芳基”可互换使用，均是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。
如本文所用，“8至10元双环杂芳基环”和“8至10元双环杂芳基”可互换使用，均是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶。
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
除非另有定义，本发明所述“各自独立地选自……的取代基”是指当基团上的一个以上的氢被取代基取代时，所述的取代基种类可以相同或不同，所选自的取代基为各自独立的种类。
除非另有定义，本发明所述“……相同或不同，且各自独立地为……”是指当通式中存在一个以上的相同取代基团时，该基团可以相同或不同，为各自独立的种类。例如L为(CR 01R 02) s，当s为2时，即L为(CR 01R 02)-(CR 01R 02)，其中的两个R 01或R 02可以相同或不同，为各自独立的种类，例如L可以为C(CH 3)(CN)-C(CH 2CH 3)(OH)，C(CH 3)(CN)-C(CH 3)(OH)或C(CN)(CH 2CH 3)-C(OH)(CH 2CH 3)。
如本文所用，本文任一基团可以是取代的或未取代的。上述基团被取代时，取代基优选为1至5(更优选1、2或3)个以下基团，独立地选自CN、卤素、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷基取代的胺基、胺基、卤代C 1-8烷基取代的胺基、乙酰基、羟基、羟甲基、羟乙基、羧基、硝基、C 6-10芳基(优选苯基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、 C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环、4至6元饱和或不饱和单环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环，其中R a0、R b0各自独立地为氢或C 1-3烷基。
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。
本文所述的4至6元(5至6元)饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：
Figure PCTCN2019130744-appb-000039
Figure PCTCN2019130744-appb-000040
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2019130744-appb-000041
表示与其他原子的连接。
除非另有定义，当本发明所述的4至6元饱和单杂环为取代基时，其自身也可以为取代或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羧基、-C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋 喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。
本发明中相同符号所表示的含义除非本发明具有特别说明，应理解为均具有相同的含义。另外，本发明中的各术语(包括取代基简写、试剂名称缩写等)若未特别声明应理解为本领域通常的含义。
所述“药学上可接受的盐”包括药学可接受的酸加成盐和药学可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。
“药学可接受的碱加成盐”，包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于本发明范围之内。
本发明的化合物中，
Figure PCTCN2019130744-appb-000042
为环己基时，环上呈对位取代的一组取代基所连接的环己基上的两个碳原子并不是手性中心，
Figure PCTCN2019130744-appb-000043
的化学键表示法仅为了表示与呈对位取代的一组取代基所连接的两个化学键相对于环己基基团呈反式或顺式结构，因此将这两个化学键
Figure PCTCN2019130744-appb-000044
彼此交换而表示的化合物同样落在本发明的保护范围内。本发明式(I)、式(I-a)和式(I-b)所示的化合物可以包含反式和顺式结构的混合物形式存在，或以顺式结构形式存在，或以反式结构形式存在。优选以顺式结构形式存在。本发明中环己基上呈对位取代的一组取代基与所连接的环己基上的两个碳原子通过
Figure PCTCN2019130744-appb-000045
键表示的结构的保护范围包括反式或顺式结构。此外化合物结构中环己基对位上连接的一对化学键均为
Figure PCTCN2019130744-appb-000046
或均为
Figure PCTCN2019130744-appb-000047
时，表示相同含义，均表示顺式结构。环己基对位上连接的一对化学键分别为
Figure PCTCN2019130744-appb-000048
或分别为
Figure PCTCN2019130744-appb-000049
时，表示相同含义，均表示反式结构。
本发明式(I)所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式(I)化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括拆分过的光学纯的特定异构体以及非对映异构体的混合物。非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。此外本发明化合物还包括顺式异构体，反式异构体以及顺式和反式异构体的混合物，例如当本发明化合物存在环烃基结构时，环烃基环上的不同取代基可形成顺式异构体或反式异构体。
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994， 4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。
通常，本发明化合物或其药学可接受的盐、或其溶剂化物、或其立体异构体、或前药可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
如本文所用，“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。
本发明的药物组合物中含有的本发明化合物或其药学上可接受的盐、或其溶剂化物、或其立体异构体的治疗有效量优选为0.1mg-5g/kg(体重)。
如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
制备方法
下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。
除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
用于本发明的化合物的制备方法：
本发明式(I)表示的化合物可通过已知的方法制备，例如，通过下述方法、与之等同的方法或实施例中所述的方法。在下面的制备方法中，原料化合物可以是盐的形式，该盐可以是本发明式(I)表示的化合物所示例的任何药学上可接受的盐。
其中E 1、E 4各自独立地为CH，E 2、E 3各自独立地为CH 2，R a、R b各自独立地为氢，D 环为3元饱和单环，L 1为NH，L 2为一个键的式(I-b)表示的化合物(如式(I-8)表示的化合物)可通过反应方案(I)表示的方法制备。
其中E 1为CH，E 4为N，E 2、E 3各自独立地为CH 2，R a、R b各自独立地为氢，D环为3元饱和单环，L 1为NH，L 2为一个键的式(I-b)表示的化合物(如式(Ⅱ-7)表示的化合物)可通过反应方案(Ⅱ)表示的方法制备。
其中E 1、E 4各自独立地为CH，E 2、E 3各自独立地为CH 2，R b、R d各自独立地为氢，C环为3元饱和单环，L 1为一个键，L 2为NH的式(I-a)表示的化合物(如式(Ⅲ-8)表示的化合物)可通过反应方案(Ⅲ)表示的方法制备。
其中E 1、E 4各自独立地为CH，E 2、E 3各自独立地为CH 2，R b、R d各自独立地为氢，C环为3元饱和单环，L 1为NH，L 2为一个键的式(I-a)表示的化合物(如式(Ⅳ-3)表示的化合物)可通过反应方案(Ⅳ)表示的方法制备。
反应方案(I)
Figure PCTCN2019130744-appb-000050
(在上述方案的各式中，所有符号如上所述，X为卤素。)
具体地，式(I-8)表示的化合物可按照以下方法制得：
步骤1：将相应的式(I-1)表示的化合物和1,4-二氧杂-螺[4,5]癸-7-烯-8-硼酸频哪醇酯发生Suzuki偶联反应制得式(I-2)表示的化合物。
步骤2：式(I-2)表示的化合物发生碳碳双键还原反应制得式(I-3)表示的化合物。
步骤3：式(I-3)表示的化合物的羰基脱保护制得式(I-4)表示的化合物。
步骤4：式(I-4)表示的化合物和磷叶立德试剂发生Wittig反应制得式(I-5)表示的化合物。
步骤5：式(I-5)表示的化合物发生碳碳双键还原反应制得式(I-6)表示的化合物。
步骤6：式(I-6)表示的化合物和格氏试剂反应制得式(I-7)表示的化合物。
步骤7：式(I-7)表示的化合物和式A-COOH表示的化合物，或式(I-7)表示的化合物和式A-COCl表示的化合物发生酰胺化反应制得式(I-8)表示的化合物。
反应方案(Ⅱ)
Figure PCTCN2019130744-appb-000051
(在上述方案的各式中，所有符号如上所述，X为卤素。)
具体地，式(Ⅱ-7)表示的化合物可按照以下方法制得：
步骤1：将相应的式(I-1)表示的化合物和联硼酸频那醇酯发生Miyaura硼化反应制得式(Ⅱ-1)表示的化合物。
步骤2：式(Ⅱ-1)表示的化合物和化合物4-(三氟甲基磺酰氧基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯1a发生Suzuki偶联反应制得式(Ⅱ-2)表示的化合物。
步骤3：式(Ⅱ-2)表示的化合物发生碳碳双键还原反应制得式(Ⅱ-3)表示的化合物。
步骤4：式(Ⅱ-3)表示的化合物脱氨基保护基制得式(Ⅱ-4)表示的化合物。
步骤5：式(Ⅱ-4)表示的化合物和化合物1-甲酰基环丙基氨基甲酸叔丁酯2a发生还原胺化反应制得式(Ⅱ-5)表示的化合物。
步骤6：式(Ⅱ-5)表示的化合物脱氨基保护基制得式(Ⅱ-6)表示的化合物。
步骤7：式(Ⅱ-6)表示的化合物和式A-COOH表示的化合物，或式(Ⅱ-6)表示的化合物和式A-COCl表示的化合物发生酰胺化反应制得式(Ⅱ-7)表示的化合物。
反应方案(Ⅲ)
Figure PCTCN2019130744-appb-000052
(在上述方案的各式中，所有符号如上所述，X为卤素。)
具体地，式(Ⅲ-8)表示的化合物可按照以下方法制得：
步骤1：将相应的式(I-1)表示的化合物和1-乙氧基羰基环己-3-烯-4-硼酸频哪醇酯发生 Suzuki偶联反应制得式(Ⅲ-1)表示的化合物。
步骤2：式(Ⅲ-1)表示的化合物发生碳碳双键还原反应制得式(Ⅲ-2)表示的化合物。
步骤3：式(Ⅲ-2)表示的化合物发生酯还原反应制得式(Ⅲ-3)表示的化合物。
步骤4：式(Ⅲ-3)表示的化合物发生氧化反应制得式(Ⅲ-4)表示的化合物。
步骤5：式(Ⅲ-4)表示的化合物和磷叶立德试剂发生Wittig反应制得式(Ⅲ-5)表示的化合物。
步骤6：式(Ⅲ-5)表示的化合物发生Corey-Chaykovsky反应制得式(Ⅲ-6)表示的化合物。
步骤7：式(Ⅲ-6)表示的化合物发生酯水解反应制得式(Ⅲ-7)表示的化合物。
步骤8：式(Ⅲ-7)表示的化合物和式A-NH 2表示的化合物发生酰胺化反应制得式(Ⅲ-8)表示的化合物。
反应方案(Ⅳ)
Figure PCTCN2019130744-appb-000053
(在上述方案的各式中，所有符号如上所述。)
具体地，式(Ⅳ-3)表示的化合物可按照以下方法制得：
步骤1：式(Ⅲ-4)表示的化合物发生Curtius重排反应制得式(Ⅳ-1)表示的化合物。
步骤2：式(Ⅳ-1)表示的化合物发生氨基脱保护反应制得式(Ⅳ-2)表示的化合物。
步骤3：式(Ⅳ-2)表示的化合物和式A-COOH表示的化合物，或式(Ⅳ-2)表示的化合物和式A-COCl表示的化合物发生酰胺化反应制得式(Ⅳ-3)表示的化合物。
所述Suzuki偶联反应是已知的且可为。在溶剂(如1,4-二氧六环、THF或1,4-二氧六环和水的混合溶剂等)中，在存在碱(如碳酸钠、碳酸钾或碳酸铯等)的情况下，使用钯催化剂(Pd(OAc) 2、Pd(Ph 3P) 4、Pd(Ph 3P) 2Cl 2或Pd(dppf)Cl 2等)，1,4-二氧杂-螺[4,5]癸-7-烯-8-硼酸频哪醇酯与卤代芳烃发生交叉偶联。
所述酰胺化反应是已知的且可为。例如，在约0℃至回流温度，在有机溶剂(如DMSO、DCM、DMF或THF等)中或无溶剂的情况下，在存在碱(如DIEA、TEA、二甲基苯胺或二甲基氨基吡啶等)的情况下，使用缩合剂(如HATU、1,3-二环己基碳二亚胺(DCC)、1-乙基-3-[3-(二甲基氨基)丙基]碳二亚胺(EDC)、N,N'-羰基二咪唑(CDI)或1-丙基磷酸酐(T 3P)等)，在含或不含1-羟基苯并三唑(HOBT)的情况下，将羧酸或酰氯和胺反应。
所述双键还原是已知的且可为。在有机溶剂(如EA或THF等)中，使用催化剂(如Pd/C)用还原剂(如氢气)还原碳碳双键。
所述羰基脱保护反应是已知的且可为。在溶剂(如DCM、THF和水的混合溶剂、THF、或乙醇和水的混合溶剂等)中，使用酸催化剂(如TFA、醋酸、盐酸或对甲苯磺酸等)脱羰基保护基，将缩酮转化为相应的羰基化合物。
所述氨基脱保护反应是已知的且可为。在有机溶剂(如DCM、EA或1,4-二氧六环等)中，使用酸催化剂(如TFA)脱羰基保护基，将缩酮转化为相应的羰基化合物。
所述酯水解反应是已知的且可为。在有机溶剂(如DCM、THF、EA或1,4-二氧六环等)中，使用酸催化剂(如TFA或盐酸)将酯水解转化为相应的酸。
所述Wittig反应是已知的且可为。在有机溶剂(如THF或1,4-二氧六环等)中，使用催化剂(如氢化钠等)，羰基与磷叶立德试剂(如二甲氧基膦酰基乙酸叔丁酯或氰基甲基膦酸二乙酯等)反应成烯烃。
所述Miyaura硼化反应是已知的且可为。在有机溶剂(如1,4-二氧六环等)中，在存在碱(如醋酸钾等)的情况下，使用钯催化剂(Pd(dppf)Cl 2等)，卤代芳烃和联硼酸频那醇酯发生Miyaura硼化反应。
所述酯还原反应是已知的且可为。在有机溶剂(如THF等)中，使用还原剂(如氢化铝锂)将酯还原为醇。
所述氧化反应是已知的且可为。在有机溶剂(如EA等)中，使用氧化剂(如2-碘酰基苯甲酸)将醇氧化为醛。
所述Corey-Chaykovsky反应是已知的且可为。在有机溶剂(如DMSO等)中，使用催化剂(如Pd(OAc) 2、乙基碘锌或氢化钠等)，由甲基化试剂(重氮甲烷、三甲基碘化亚砜或二碘甲烷)和烯烃反应成环丙烷环。
所述Curtius重排反应是已知的且可为。在有机溶剂(如甲苯等)中，在存在碱(如三乙胺等)的情况下，由羧基和叠氮磷酸二苯酯反应重排为伯胺，伯胺和叔丁醇再反应形成Boc(叔丁基氧羰基)基团保护的胺。
所述格氏反应是已知的且可为。在有机溶剂(如THF、乙醚等)中，在催化剂(如钛酸四异丙酯)的条件下，使用路易斯酸(如三氟化硼乙醚)的情况下，氰基和格氏试剂(如乙基溴化镁)反应。
所述还原胺化是已知的且可为。在有机溶剂(如DCM、EA或THF等)中，在催化剂(如Pd/C)或无催化剂的条件下，使用还原剂(如氢气、NaBH(OAc) 3)的情况下，仲胺和化合物1-甲酰基环丙基氨基甲酸叔丁酯2a发生还原胺化反应形成C-N键。
用于本发明的具有氨基、羧基或羟基的化合物可使用根据需要已通过常用于该基团的保护基进行保护的化合物来制备，在通过上述反应方案的反应过程后，可进行已知的脱保护反应。
上述化合物之外的式(I)表示的化合物可通过组合描述于本说明书中实施例或组合已知方法来制备。
与现有技术相比，本发明的主要优点在于具有更好的IDO抑制活性和更低的毒性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。除非另外说明，否则百分比和份数按重量计算。如本文所用，室温是指约为20-25℃。
如本文所用，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，DCM为二氯甲烷，Pd(dppf)Cl 2为1,1'-双(二苯基磷)二茂铁]二氯化钯，Pd/C为钯碳催化剂，LiHMDS为二(三甲基硅基)氨基锂，Dess-Martin试剂为(1,1,1-三乙酰氧基)-1,1-二氢-1,2-苯碘酰-3(1H)-酮，HATU为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，AcOK为醋酸钾，DMF为二甲基甲酰胺，CDCl 3为氘代氯仿，DMSO为二甲基亚砜，DMSO-d 6为氘代二甲基亚砜，dioxane为1,4-二氧六环，NaBH(OAc) 3为三乙酰氧基硼氢化钠，AcOH为乙酸，DIEA为N,N-二异丙基乙胺，TEA为三乙胺，
4-(三氟甲基磺酰氧基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(1a)的制备
Figure PCTCN2019130744-appb-000054
将4-氧代哌啶-1-羧酸叔丁酯(2.0g,10.04mmol)溶解在40ml四氢呋喃中氩气保护下降温到-78℃，LiHMDS(12ml,12.05mmol)缓慢滴加到反应液中，滴加完毕后再-78℃搅拌30分钟，化合物M1(4.30g,12.05mmol)溶解在四氢呋喃溶液中缓慢滴加到反应液中，反应液继续在-78℃条件下搅拌1小时，然后缓慢自然升温到室温搅拌过夜。LC-MS检测反应完全。反应液倒入冰水混合物中，用乙酸乙酯萃取(100ml*2)，无水硫酸钠干燥，减压浓缩干，用硅胶柱分离纯化得到化合物1a(1.60g，收率51.12％)。MS(ESI)276.0[M+H-56] +。
1-甲酰基环丙基氨基甲酸叔丁酯(2a)的制备
Figure PCTCN2019130744-appb-000055
将化合物1-(羟甲基)环丙基氨基甲酸叔丁酯(520mg，2.78mmol)加入到二氯甲烷10ml中氩气保护下降温到0℃，加入Dess-Martin试剂(1.53g，3.61mmol),反应液在室温搅拌过夜。LC-MS检测反应完全。反应液过滤减压浓缩干,用硅胶柱分离纯化得到化合物1-甲酰基环丙基氨基甲酸叔丁酯2a(500mg,收率97.28％)。MS(ESI)130.0[M+H-56] +。
6-氯烟酰氯(3a)的制备
Figure PCTCN2019130744-appb-000056
将6-氯烟酸(314mg,2mmol)溶解于二氯甲烷(10mL)中，然后将反应液内温度降至0℃，滴加草酰氯(756mg,5mmol)，然后加入1滴DMF，将反应液在室温搅拌1小时，减压蒸干得到化合物3a(314m g，收率92％)，产物不经纯化直接用于下一步反应。
1-(((1s，4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙烷-1-胺(4a)的制备
Figure PCTCN2019130744-appb-000057
将6.3g化合物1-7采用Waters-SunFire Prep 19*250mm通过以下条件制备得到0.95g化合物4a，其中流动相：A：乙腈，B：水+0.045％甲酸，波长：214/254nm，梯度：10-22，针数：29。
实施例1：4-氰基-N-(1-((4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-1)的两个异构体(J-1-1和J-1-2)的制备
Figure PCTCN2019130744-appb-000058
步骤1：4-氯-6-氟喹啉1-1(1.0g，5.51mmol)，1,4-二氧杂-螺[4,5]癸-7-烯-8-硼酸频哪醇酯(1.47g，5.51mmol)，K 2CO 3(1.52g，11.01mmol)在1,4-二氧六环30ml和水3.0ml的混合溶剂中，在氩气保护下加入Pd(dppf)Cl 2(403mg，0.551mmol)，搅拌升温到110℃反应5小时，LC-MS检测反应完全。反应液过滤旋干，用硅胶柱分离纯化得到化合物1-2(1.3g，纯度：100％，收率83.33％)。MS(ESI)286.1[M+H] +。
步骤2：化合物1-2(1.3g，4.56mmol)加入到30ml乙酸乙酯中，加入Pd/C 150mg，反应液在氢气保护下室温搅拌过夜。LC-MS检测反应完全。反应液过滤减压浓缩干燥得到化合物1-3(1.0g，纯度：95.17％，收率76.92％)。MS(ESI)288.1[M+H] +。
步骤3：化合物1-3(1.0g，3.48mmol)在20ml二氯甲烷中室温搅拌下加入三氟乙酸3.0ml，反应液室温搅拌过夜，LC-MS检测反应完全。反应液减压浓缩干，然后加入饱和碳酸氢钠 100ml，用乙酸乙酯萃取(50ml*2)，无水硫酸钠干燥，最后减压浓缩干得到化合物1-4(0.7g，纯度：97.01％，收率82.68％)。MS(ESI)244.1[M+H] +。
步骤4：氰基甲基膦酸二乙酯(1.09g，6.17mmol)加入到20ml的四氢呋喃中，氩气保护下降温到0℃，缓慢加入钠氢(247mg，6.17mmol)，反应液在0℃搅拌20分钟，缓慢滴加化合物1-4(1.0g，4.11mmol)(化合物1-4溶解在3ml四氢呋喃溶液中)。反应液0℃搅拌30分钟，然后缓慢升温到室温继续搅拌3小时。LC-MS检测反应完全。将上述反应液加入到冰水混合物里面，用乙酸乙酯萃取(100ml*2)，无水硫酸钠干燥，减压浓缩干，经过硅胶柱分离纯化得到化合物1-5(720mg，纯度：99.00％，收率66.05％)。MS(ESI)267.1[M+H] +。
步骤5：化合物1-5(2.5g，2.71mmol)溶解在20ml乙酸乙酯里，加入钯碳(200mg)，反应液在氢气保护下室温下搅拌过夜，LC-MS检测反应完全。反应液过滤，减压浓缩干得到化合物1-6。(700mg，纯度：100％，收率96.50％)。MS(ESI)269.1[M+H] +。
步骤6：化合物1-6(1.67g，6.22mmol)溶解在40ml四氢呋喃里，氩气保护下降温到-78℃，滴加钛酸四异丙酯(1.95g，6.85mmol)，接着加入乙基溴化镁(4.56ml，13.69mmol)，反应液在-78℃搅拌1小时，缓慢升温到室温，继续室温搅拌2小时。反应液再次降温到0℃，缓慢滴加三氟化硼乙醚(1.94g，13.69mmol)，在升温至室温搅拌1小时。反应液加到100ml冰水里，搅拌30分钟，然后加入饱和Na 2CO 3溶液100ml，用乙酸乙酯萃取(100ml*4)，无水硫酸钠干燥，减压浓缩后经过硅胶柱分离纯化得到化合物1-7(700mg，纯度：94％，收率37.69％)。MS(ESI)299.2[M+H] +。
步骤7：化合物1-7(640mg，2.14mmol)，4-氰基苯甲酸(631mg，4.29mmol)溶解在20ml DMF里，室温搅拌下加入HATU(1.63g，4.29mmol)，接着加入二异丙基乙胺(0.832g，6.43mmol)，反应液室温搅拌2小时，LC-MS检测反应完全。反应液加入到100ml水里，用乙酸乙酯萃取(50ml*2)，无水硫酸钠干燥，浓缩得到粗产品经过高效液相分离(Waters-SunFire Prep 19*250mm，流动相：A：乙腈，B：水+0.045％甲酸，波长：214/254nm，梯度：10-22，针数：29)纯化得到4-氰基-N-(1-(((1s，4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺J-1-1(125mg，纯度：100％，收率13.63％)。MS(ESI)428.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.84(s,1H),8.80(d,J＝4.6Hz,1H),8.08(dd,J＝9.2,5.9Hz,1H),7.98-7.92(m,5H),7.70–7.61(m,1H),7.48(d,J＝4.5Hz,1H),3.35-3.30(m,1H),2.02(s,1H),1.85-1.83(m,6H),1.69-1.61(m,4H),0.71-0.76(m,2H),0.72-0.68(m,2H)。
4-氰基-N-(1-(((1r，4r)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺J-1-2。MS(ESI)428.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.85(s,1H),8.78(d,J＝4.5Hz,1H),8.07(dd,J＝9.2,5.9Hz,1H),8.02–7.87(m,5H),7.65(td,J＝8.7,2.7Hz,1H),7.43(d,J＝4.6Hz,1H),3.32-3.23(m,1H),2.06(d,J＝11.7Hz,2H),1.88(d,J＝11.4Hz,2H),1.61-1.50(m,4H),1.32-1.23(m,3H),0.80-0.78(m,2H),0.67-0.64(m,2H).
实施例2：N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)环丙烷甲酰胺(J-2，非对映异构体1，含cis和trans两种构型)的制备
实施例3：N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)环丙烷甲酰胺(J-3，非对映异构体2，含cis和trans两种构型)的制备
Figure PCTCN2019130744-appb-000059
步骤1：将4-环己酮甲酸乙酯2-1(40g,240mmol)和2,6-二叔丁基-4-甲基吡啶(50g,260mmol)溶解于二氯甲烷(700mL)中，然后将反应液内温降至0℃，滴加三氟甲磺酸酐(73g,260mmol)的二氯甲烷(100mL)溶液，滴加完毕，将反应液在38℃搅拌4小时，加入水(200mL)，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，将滤液减压蒸干，通过柱层析得到油状的化合物2-2(52g，收率71％)。MS(ESI)302.1[M+H] +。
步骤2：将化合物2-2(51g,170mmol)，醋酸钾(50g，510mmol)，联硼酸频那醇酯(48g,190mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(5g,6mmol)加入到二甲亚砜(300mL)中，然后在氮气下，将反应加热到90℃并搅拌6小时。待反应完全后，将反应液过滤，滤液中加水(1500mL)，用乙酸乙酯萃取，合并有机相，用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，过滤，将滤液减压蒸干，通过柱层析得到淡黄色油状粗产物2-3(47g)，产物不经纯化直接用于下一步反应。
步骤3：将化合物2-3(15.0g,54mmol)，4-氯-6-氟喹啉(9.7g,54mmol)，无水碳酸钠(17.0g，161mmol)，和[1,1'-双(二苯基膦)二茂铁]二氯化钯(2.3g,3mmol)加入到二氧六环(200mL)和水(40mL)的混合物溶液中，然后在氮气下，将反应加热到110℃并搅拌6小时。待反应完全后，将反应液过滤，滤液中加水(500mL)，用乙酸乙酯萃取，合并有机相，用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，过滤，将滤液减压蒸干，通过柱层析得到油状产物4-(6-氟喹啉-4-基)环己基-3-烯-1-甲酸乙酯2-4(11g，收率69％)。MS(ESI)300.0[M+H] +。
步骤4：将4-(6-氟喹啉-4-基)环己基-3-烯-1-甲酸乙酯2-4(21.0g,70mmol)和钯碳(10％，50％w/w，4.2g)加入到无水四氢呋喃(300mL)中，并在氢气下搅拌16小时，原料反应完全，将反应液过滤，滤液减压蒸干得到粗产物4-(6-氟喹啉-4-基)环己基-1-甲酸乙酯2-5(19.7 g)。MS(ESI)302.2[M+H] +。
步骤5：将氢化铝锂(2.9g,76mmol)加入到-30℃四氢呋喃(300mL)中，然后再将4-(6-氟喹啉-4-基)环己基-1-甲酸乙酯2-5(11.5g,70mmol)的四氢呋喃(50mL)溶液滴入反应液中，控制反应温度不超过-20℃搅拌2小时，原料反应完全，然后分批加入十水硫酸钠直到没有明显的气泡产生，室温搅拌1小时，过滤，滤液减压蒸干得到油状粗产物(4-(6-氟喹啉-4-基)环己基)甲醇2-6(7.9g)，产物不经纯化直接用于下一步反应。MS(ESI)260.1[M+H] +。
步骤6：将(4-(6-氟喹啉-4-基)环己基)甲醇2-6(7.9g,31mmol)和2-碘酰基苯甲酸(25.6g,92mmol)的乙酸乙酯(300mL)溶液加热回流16小时，然后将反应液过滤，滤液减压蒸干，通过柱层析得到油状产物4-(6-氟喹啉-4-基)环己基-1-甲醛2-7(6.7g，收率85％)。MS(ESI)258.1[M+H] +。
步骤7：将氢化钠(60％，480mg，12mmol)加入到四氢呋喃(70mL)中，然后滴加二甲氧基膦酰基乙酸叔丁酯(2.69g，12mmol)的四氢呋喃(10mL)溶液，室温反应10分钟，然后将4-(6-氟喹啉-4-基)环己基-1-甲醛2-7(2.57g，10mmol)的四氢呋喃(10mL)溶液滴入反应液中，反应搅拌过夜，原料反应完毕，将反应液倒入饱和氯化铵水溶液中，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤滤液减压蒸干，通过柱层析得到油状产物3-(4-(6-氟喹啉-4-基)环己基)丙烯酸叔丁酯2-8(2.8g，收率79％)。MS(ESI)356.2[M+H] +。
步骤8：将氢化钠(60％，563mg，14mmol)加入到二甲亚砜(100mL)中，在室温下加入三甲基碘化亚砜(3.10g，14mmol)并搅拌1小时，然后将3-(4-(6-氟喹啉-4-基)环己基)丙烯酸叔丁酯2-8(2.50g，7mmol)的二甲亚砜(40mL)溶液滴入反应液并在室温搅拌16小时。待原料反应完毕，将反应液倒入水(500mL)中，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤滤液减压蒸干，通过柱层析得到油状产物2-(4-(6-氟喹啉-4-基)环己基)环丙烷-1-甲酸叔丁酯2-9(457mg，收率17％)。MS(ESI)370.2[M+H] +。
步骤9：将2-(4-(6-氟喹啉-4-基)环己基)环丙烷-1-甲酸叔丁酯2-9(457mg，1.24mmol)加入到二氯甲烷(5mL)中，在室温下慢慢加入三氟乙酸(4mL)并搅拌1小时，原料反应完全后，将反应液减压浓缩干得到固体粗产物2-(4-(6-氟喹啉-4-基)环己基)环丙烷-1-甲酸2-10(612mg)，产物不经纯化直接用于下一步反应。MS(ESI)314.2[M+H] +。
步骤10：将2-(4-(6-氟喹啉-4-基)环己基)环丙烷-1-甲酸2-10(100mg，0.32mmol)，4-氯苯胺(81mg，0.64mmol)和二异丙基乙胺(295mg，2.29mmol)，加入到二甲亚砜(6mL)中，然后在室温下加入HATU(182mg，0.48mmol)并搅拌1小时，反应完毕，将反应液倒入饱和碳酸氢钠水溶液中，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤滤液减压蒸干，通过高效液相(Waters-SunFire Prep 19*250mm，流动相：A:乙腈,B:水+0.045％甲酸，波长：214/254nm，梯度：48-68)制备分别得到固体产物N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)环丙烷-1-甲酰胺的非对映异构体1(J-2，含cis和trans两种构型)(2.78mg，收率2％)。MS(ESI)423.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),8.75(d,J＝4.5Hz,1H),8.05(dd,J＝9.2,5.9Hz,1H),7.93(dd,J＝10.9,2.6Hz,1H),7.67–7.56(m,3H),7.50(d,J＝4.6 Hz,1H),7.30(d,J＝8.9Hz,2H),1.98–1.63(m,9H),1.60(dd,J＝8.0,4.2Hz,1H),1.20(d,J＝6.6Hz,1H),1.13(s,1H),1.06(dd,J＝8.5,4.2Hz,1H),0.75(t,J＝8.7Hz,1H).
非对映异构体2(J-3，含cis和trans两种构型)(22.30mg，收率17％)。MS(ESI)423.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H),8.77(d,J＝4.5Hz,1H),8.05(dd,J＝8.9,6.0Hz,1H),7.94(dd,J＝10.8,2.5Hz,1H),7.68–7.54(m,3H),7.39(d,J＝4.5Hz,1H),7.30(d,J＝8.4Hz,2H),3.29–3.23(m,1H),1.97–1.81(m,4H),1.65–1.58(m,1H),1.50(dd,J＝21.4,9.9Hz,4H),1.15–1.06(m,1H),0.99(dd,J＝8.5,4.2Hz,1H),0.89(d,J＝8.7Hz,1H),0.76(d,J＝8.4Hz,1H).
实施例4：4-氯-N-(2-(4-(6-氟喹啉-4-基)环己基)环丙基)苯甲酰胺(J-4)的制备
Figure PCTCN2019130744-appb-000060
步骤1：将2-(4-(6-氟喹啉-4-基)环己基)环丙烷-1-甲酸2-10(370mg，1.18mmol)，叠氮磷酸二苯酯(650mg，2.36mmol)，和三乙胺(716mg，7.09mmol)加入到叔丁醇(7mL)和甲苯(10mL)的混合溶液中并加热回流48小时。原料反应完全后，将反应液减压蒸干，加入水，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤滤液减压蒸干，通过柱层析得到油状产物(2-(4-(6-氟喹啉-4-基)环己基)环丙烷)氨基甲酸叔丁酯4-1(120mg，收率26％)。MS(ESI)385.2[M+H] +。
步骤2：将(2-(4-(6-氟喹啉-4-基)环己基)环丙烷)氨基甲酸叔丁酯4-1(120mg，0.31mmol)加入到二氯甲烷(5mL)中，在室温下慢慢加入三氟乙酸(3mL)并搅拌2小时，原料反应完全后，将反应液减压浓缩干得到固体粗产物2-(4-(6-氟喹啉-4-基)环己基)环丙烷-1-胺4-2(139mg)，产物不经纯化直接用于下一步反应。MS(ESI)285.2[M+H] +。
步骤3：将2-(4-(6-氟喹啉-4-基)环己基)环丙烷-1-胺4-2(50mg，0.18mmol)，4-氯苯甲酸(41mg，0.26mmol)，和二异丙基乙胺(114mg，0.88mmol)加入到N，N-二甲基甲酰胺(5mL)中，然后在室温下加入HATU(100mg，0.26mmol)并搅拌2小时，反应完毕，将反应液倒入饱和碳酸氢钠水溶液中，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤滤液减压蒸干，通过高效液相制备得到白色固体产物的异构体混合物J-4(22mg，收率30％)。MS(ESI)423.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝4.5Hz,1H),8.49(d,J＝4.0Hz,1H),8.05(dd,J＝9.2,5.8Hz,1H),7.95(dd,J＝10.9,2.7Hz,1H),7.85–7.78(m,2H),7.67–7.58(m,1H),7.53–7.45(m,2H),7.39(d,J＝4.5Hz,1H),3.26(d,J＝10.7Hz,1H),2.64(dd,J＝7.2,3.4Hz,1H),2.12(d,J＝11.4Hz,1H),1.86(t,J＝15.0Hz,3H),1.57–1.33(m,4H),0.81(t,J＝13.3Hz,2H),0.73(dd,J＝8.6,4.2Hz,1H),0.59(dt,J＝9.9,4.9Hz,1H).
实施例5：4-氰基-N-(1-((4-(6-氟喹啉-4-基)哌啶-1-基)甲基)环丙基)苯甲酰胺(J-5)的制备
Figure PCTCN2019130744-appb-000061
步骤1：将4-氯-6-氟喹啉5-1(5.0g，27.53mmol)，联硼酸频那醇酯(14.0g，55.07mmol)，AcOK(5.4g，55.07mmol)在二氧六环200ml中氩气保护下加入Pd(dppf)Cl 2(1.0g，1.38mmol)，反应液加热到90℃反应4小时，LC-MS检测反应完全。反应液倒入大量水里，用乙酸乙酯萃取(150ml*2)，无水硫酸钠干燥，减压浓缩干，用硅胶柱分离纯化得到6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉5-2(7.0g，纯度：100％,收率：93.09％)。MS(ESI)192.0[M+H-82] +。
步骤2：6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉5-2(500mg,1.83mmol)，化合物1a(607mg，1.83mmol)在1,4-二氧六环15ml和水2.0ml的混合溶液中，氩气保护下加入Pd(dppf)Cl 2(134mg,0.183mmol)，K 2CO 3(649mg，3.66mmol)。反应液加热到95℃反应4小时，LC-MS检测反应完全。将上述反应液加入到水里面，用乙酸乙酯萃取(50ml*2)，无水硫酸钠干燥，减压浓缩干，经过硅胶柱分离纯化得到4-(6-氟喹啉-4-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯5-3(400mg，纯度：97.95％，收率：66.67％)。MS(ESI)329[M+H] +。
步骤3：4-(6-氟喹啉-4-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯5-3(380mg，0.854mmol)溶解在20ml的乙酸乙酯里，加入钯碳(200mg)，反应液在氢气保护下室温搅拌6小时，LC-MS检测反应完全。反应液过滤，加压浓缩干得到4-(6-氟喹啉-4-基)哌啶-1-羧酸叔丁酯5-4(400mg，纯度：81.61％，收率：100％)。MS(ESI)231.0[M+H-56] +。
步骤4：4-(6-氟喹啉-4-基)哌啶-1-羧酸叔丁酯5-4(400mg,1.21mmol)溶解在2.5ml的二氯甲烷里，加入4M的盐酸/二氧六环2.5ml，室温搅拌1小时，LC-MS检测原料有剩余，反应液加入甲醇2.0ml，继续搅拌1小时，LC-MS检测反应完全。反应液减压浓缩干，然后加入饱和Na 2CO 3溶液100ml，用乙酸乙酯萃取(50ml*4)，无水硫酸钠干燥，减压浓缩后得到6-氟-4-(哌啶-4-基)喹啉5-5(270mg，纯度：90％，收率：96.77％)。MS(ESI)400.0[M+H-56] +。
步骤5：6-氟-4-(哌啶-4-基)喹啉5-5(240mg，1.04mmol)，化合物2a(386mg，2.08mmol)溶解在10ml二氯甲烷里，室温搅拌下加入NaBH(OAc) 3(663mg，3.13mmol)，接着加入AcOH(0.5ml)，反应液室温搅拌过夜，LC-MS检测反应完全。反应液加入到饱和NaHCO 3溶液里，用乙酸乙酯萃取(50ml*2)，无水硫酸钠干燥，浓缩得到粗产品经过高效液相分离纯化得到1-((4-(6-氟喹啉-4-基)哌啶-1-基)甲基)环丙基氨基甲酸叔丁酯5-6(200mg，纯度：67.29％， 收率：48.08％)。MS(ESI)300.0[M+H] +。
步骤6：1-((4-(6-氟喹啉-4-基)哌啶-1-基)甲基)环丙基氨基甲酸叔丁酯5-6(200mg，0.501mmol)溶解在2.0ml的二氯甲烷和2.0ml甲醇的混合溶剂中，加入4M的盐酸/二氧六环2.5ml，室温搅拌过夜，LC-MS检测反应完全。反应液减压浓缩干得到1-((4-(6-氟喹啉-4-基)哌啶-1-基)甲基)环丙胺盐酸盐5-7(200mg，纯度：90％，收率：100％)。MS(ESI)429.0[M+H] +。
步骤7：1-((4-(6-氟喹啉-4-基)哌啶-1-基)甲基)环丙胺盐酸盐5-7(100mg,0.315mmol)，4-氰基苯甲酸(93mg，0.629mmol)溶解在5ml DMF里,室温搅拌下加入HATU(239g，0.629mmol)，接着加入二异丙基乙胺(203g，1.57mmol)，反应液室温搅拌2小时，LC-MS检测反应完全。反应液加入到100ml水里，用乙酸乙酯萃取(50ml*2)，无水硫酸钠干燥，浓缩得到粗产品经过高效液相分离纯化得到化合物J-5(35mg，纯度：100％，收率：25.73％)。MS(ESI)429.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.81(s,1H),8.76(d,J＝4.3Hz,1H),8.05(dd,J＝9.1,5.9Hz,1H),7.97-7.91(m,5H),7.69–7.57(m,1H),7.40(d,J＝4.6Hz,1H),3.28–3.05(m,3H),2.57(s,2H),2.21(t,J＝11.0Hz,2H),1.80-1.65(m,4H),0.82-0.76(m,2H),0.72-0.65(m,2H)。
实施例6：4-氯-N-(1-((4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-6)的两个异构体(J-6-1和J-6-2)的制备
Figure PCTCN2019130744-appb-000062
化合物J-6的制备方法参照化合物J-1，不同的是将步骤7中的4-氰基苯甲酸换成4-氯苯甲酸。化合物J-6经过高效液相(Waters-SunFire Prep 19*250mm，流动相：A：乙腈，B：水+0.045％甲酸，波长：214/254nm，梯度：10-22，针数：29)分离得到4-氯-N-(1-(((1s，4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺J-6-1。MS(ESI)437.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.76(d,J＝4.5Hz,1H),8.63(s,1H),8.04(dd,J＝9.2,5.9Hz,1H),7.90(dd,J＝11.0,2.7Hz,1H),7.85–7.74(m,2H),7.62(d,J＝2.0Hz,1H),7.53–7.35(m,3H),3.28-3.28(m,1H),1.98(s,1H),1.82-1.74(m,6H),1.67-1.57(m,4H),0.75-0.70(m,2H),0.65-0.61(m,2H)。
4-氯-N-(1-(((1r，4r)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺J-6-2。MS(ESI)437.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.75(d,J＝4.5Hz,1H),8.64(s,1H),8.04(dd,J＝9.2,5.9Hz,1H),7.91(dd,J＝10.9,2.7Hz,1H),7.86–7.76(m,2H),7.68–7.57(m,1H),7.54–7.44(m,2H),7.39(d,J＝4.5Hz,1H),3.22(t,J＝11.9Hz,1H),2.02(d,J＝11.4Hz,2H),1.84(d,J＝11.6Hz,2H),1.64–1.40(m,5H),1.25-1.21(m,2H),0.75-0.70(m,2H),0.62-0.57(m,2H).
实施例7：4-氟-N-(1-((4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-7)的两个异构体(J-7-1和J-7-2)的制备
Figure PCTCN2019130744-appb-000063
化合物J-7的制备方法参照化合物J-1，不同的是将步骤7中的4-氰基苯甲酸换成4-氟苯甲酸。化合物J-7经过高效液相(Waters-SunFire Prep 19*250mm，流动相：A：乙腈，B：水+0.045％甲酸，波长：214/254nm，梯度：10-22，针数：29)分离得到4-氟-N-(1-(((1s，4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺J-7-1。MS(ESI)421.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.76(d,J＝4.5Hz,1H),8.58(s,1H),8.04(dd,J＝9.2,5.9Hz,1H),7.96–7.79(m,3H),7.68–7.54(m,1H),7.45(d,J＝4.6Hz,1H),7.23(t,J＝8.9Hz,2H),3.28-3.23(m,1H),1.98(s,1H),1.83-1.73(m,5H),1.67-1.57(m,4H),0.74-0.71(m,2H),0.65-0.62(m,2H)。得到4-氟-N-(1-(((1r，4r)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺J-7-2，MS(ESI)421.2[M+H] +。
实施例8：N-(1-((4-(6-氟喹啉-4-基)环己基)甲基)环丙基)-6-乙烯基烟酰胺(J-8)的制备
Figure PCTCN2019130744-appb-000064
步骤1：将化合物1-7(110mg,0.37mmol)和三乙胺(112mg,1.11mmol)加入到二氯甲烷(10mL)中，然后在氮气下，滴加化合物3a(130mg,0.74mmol)。待反应完全后，加入二氯甲烷和水萃取，有机相，饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，过滤，将滤液减压蒸干，通过柱层析得到白色产物6-氯-N-(1-((4-(6-氟喹啉-4-基)环己基)甲基)环丙基)烟酰胺8-1(80mg，收率60％)。MS(ESI)439.0[M+H] +。
步骤2：将化合物8-1(70mg,0.14mmol)，乙烯氟硼酸钾(210mg,1.4mmol)，无水碳酸铯(140mg,0.42mmol)，和[1,1'-双(二苯基膦)二茂铁]二氯化钯(12mg,0.014mmol)加入到四氢呋喃(5mL)和水(2mL)的混合物溶液中，然后在氮气下，微波100℃反应半小时。待反应完全后，将反应液过滤，滤液中加水(20mL)，用乙酸乙酯萃取，合并有机相，用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，过滤，将滤液减压蒸干，通过HPLC制备得到N-(1-((4-(6-氟喹啉-4-基)环己基)甲基)环丙基)-6-乙烯基烟酰胺的异构体混合物J-8(3g，收率5％)。MS(ESI)430.1[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.93(d,J＝1.8Hz,1H),8.84–8.71(m,2H),8.11(m,J＝15.1,8.7,4.1Hz,2H),7.95(dd,J＝10.9,2.7Hz,1H),7.64(m,J＝25.5,15.5,5.5Hz,3H),7.49(d,J＝4.5Hz,1H),6.86(dd,J＝17.5,10.8Hz,1H),6.32(dd,J＝17.5,1.5Hz,1H),5.57(dd,J＝10.8,1.5Hz,1H),2.04(s,1H),1.85(d,J＝7.4Hz,6H),1.66(d,J＝4.5Hz,5H),0.79(t,J＝5.5Hz,2H),0.70(t,J＝5.7Hz,2H).
实施例9：N-(1-((4-(6-氟喹啉-4-基)环己基)甲基)环丙基)-2-乙烯基嘧啶-5-甲酰胺(J-9)的两个异构体(J-9-1和J-9-2)的制备
Figure PCTCN2019130744-appb-000065
步骤1：将2-氯嘧啶-5-羧酸(316mg,2mmol)溶解于二氯甲烷(10mL)中，然后将反应液内温降至0℃，滴加草酰氯(756mg,5mmol)，然后加入1滴DMF，将反应液在室温搅拌1小时，减压蒸干得到产物2-氯嘧啶-5-羰基氯(320mg)，产物不经纯化直接用于下一步反应。
步骤2：将化合物1-7(180mg,0.6mmol)和三乙胺(181mg,1.8mmol)加入到二氯甲烷(10mL)中，然后在氮气下，滴加化合物2-氯嘧啶-5-羰基氯(218mg,1.2mmol)。待反应完全后，加入二氯甲烷和水萃取，有机相，饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，过 滤，将滤液减压蒸干，通过柱层析得到白色产物2-氯-N-(1-((4-(6-氟喹啉-4-基)环己基)甲基)环丙基)嘧啶-5-甲酰胺9-1(160mg，收率58％)。MS(ESI)439.0[M+H] +。
步骤3：将化合物9-1(150mg,0.34mmol)，乙烯氟硼酸钾(455mg,3.4mmol)，无水碳酸铯(1108mg,3.4mmol)，和[1,1'-双(二苯基膦)二茂铁]二氯化钯(25mg,0.034mmol)加入到四氢呋喃(10mL)和水(2mL)的混合物溶液中，然后在氮气下，微波100℃反应半小时。待反应完全后，将反应液过滤，滤液中加水(20mL)，用乙酸乙酯萃取，合并有机相，用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，过滤，将滤液减压蒸干，通过HPLC(Waters-SunFire Prep 19*250mm，流动相：A：乙腈，B：水+0.045％甲酸，波长：214/254nm，梯度：10-22，针数：29)制备得到N-(1-(((1s，4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)-2-乙烯基嘧啶-5-甲酰胺J-9-1(7mg，收率1.5％)白色固体。MS(ESI)431.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ9.07(s,2H),8.87(s,1H),8.76(d,J＝4.3Hz,1H),8.10–7.99(m,1H),7.91(d,J＝10.9Hz,1H),7.62(t,J＝7.6Hz,1H),7.46(d,J＝3.7Hz,1H),6.84(dd,J＝17.2,10.5Hz,1H),6.59(d,J＝17.2Hz,1H),5.81(d,J＝10.8Hz,1H),3.40(s,1H),2.01(s,1H),1.81(d,J＝7.6Hz,6H),1.63(s,4H),0.73(d,J＝33.5Hz,4H)。和N-(1-(((1r，4r)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)-2-乙烯基嘧啶-5-甲酰胺J-9-2(3mg)。MS(ESI)431.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ9.00(s,2H),8.79(s,1H),8.14(s,1H),7.65(s,1H),7.49(d,J＝10.7Hz,2H),6.91(dd,J＝17.2,10.5Hz,1H),6.72(dd,J＝17.3,1.6Hz,1H),6.34(s,1H),5.83(dd,J＝10.5,1.5Hz,1H),3.20(s,1H),2.13(d,J＝17.7Hz,1H),1.97–1.77(m,7H),1.59(dd,J＝64.4,46.8Hz,13H),0.93(d,J＝4.9Hz,2H),0.89–0.75(m,2H).
实施例10：N-(1-(((1s，4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-10)的制备
Figure PCTCN2019130744-appb-000066
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和苯甲酸，得到N-(1-(((1s，4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-10)。MS(ESI)403.2[M+H]+； 1H NMR(400MHz,DMSO-d6)δ8.76(d,J＝4.5Hz,1H),8.54(s,1H),8.04(dd,J＝9.2,5.9Hz,1H),7.91(dd,J＝11.0,2.7Hz,1H),7.82–7.72(m,2H),7.62(td,J＝8.8,2.7Hz,1H),7.51–7.33(m,4H),3.29–3.22(m,1H),1.09-2.04(m, 1H),1.79-1.81(m,6H),1.60-1.64(m,4H),0.73-0.75(d,J＝6.8Hz,2H),0.62-0.65(t,J＝5.6Hz,2H)。
实施例11：4-氟-N-(1-((4-(6-氟噌啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-11)的制备
Figure PCTCN2019130744-appb-000067
以4-氯-6-氟噌啉为起始原料，参照化合物J-7的方法进行制备，得化合物J-11。MS(ESI)422.2[M+H] +。
实施例12：2,4-二氟-N-(1-(((1s,4s)-4-(6-氟噌啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-12)的制备
Figure PCTCN2019130744-appb-000068
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和2,4-二氟苯甲酸。得到2,4-二氟-N-(1-(((1s,4s)-4-(6-氟噌啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-12)。MS(ESI)439.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝4.6Hz,1H),8.51(s,1H),8.05(dd,J＝9.2,5.9Hz,1H),7.92(dd,J＝11.0,2.7Hz,1H),7.69–7.57(m,1H),7.50-7.55(m,1H),7.46(d,J＝4.5Hz,1H),7.28(td,J＝10.4,2.4Hz,1H),7.10(td,J＝8.3,1.9Hz,1H),3.28-3.30(m,1H),2.00-2.10(m,1H),1.79(d,J＝7.0Hz,6H),1.59-1.65(m,4H),0.69-0.74(m,2H),0.62-0.64(m,2H)。
实施例13：3,4-二氟-N-(1-(((1s,4s)-4-(6-氟噌啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-13)的制备
Figure PCTCN2019130744-appb-000069
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和3,4-二氟苯甲酸。得到3,4-二氟-N-(1-(((1s,4s)-4-(6-氟噌啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-13)。MS(ESI)439.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.77(d,J＝4.6Hz,1H),8.51(s,1H),8.05(dd,J＝9.2,5.9Hz,1H),7.92(dd,J＝11.0,2.7Hz,1H),7.82-7.87(m,1H),7.67–7.74(m,1H),7.60-7.64(m,1H),7.468-7.53(m,1H),7.44-7.45(m,1H),3.28-3.30(m,1H),1.97-2.04(m,1H),1.78-1.80(d,J＝7.0Hz,6H),1.61-1.62(m,4H),0.70-0.75(m,2H),0.62-0.67(m,2H)。
实施例14：N-(1-(((1s,4s)-4-(6-氟噌啉-4-基)环己基)甲基)环丙基)-6-甲基烟酰胺(J-14)的制备
Figure PCTCN2019130744-appb-000070
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和6-甲基吡啶-3-甲酸。得到N-(1-(((1s,4s)-4-(6-氟噌啉-4-基)环己基)甲基)环丙基)-6-甲基烟酰胺(J-14)。MS(ESI)418.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.81(d,J＝1.9Hz,1H),8.76(d,J＝4.5Hz,1H),8.66(s,1H),8.10–7.95(m,2H),7.91(dd,J＝11.0,2.7Hz,1H),7.67–7.54(m,1H),7.44(d,J＝4.5Hz,1H),7.29(d,J＝8.1Hz,1H),3.27-3.30(m,1H),1.98-2.01(m,1H),1.75-1.83(m,6H),1.59-1.64(m,4H),0.72-0.76(m,2H),0.63-0.67(m,2H)。
实施例15：3-氯-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-15)的制备
Figure PCTCN2019130744-appb-000071
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和3-氯苯甲酸。得到3-氯-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-15)。MS(ESI)437.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.76(d,J＝4.5Hz,1H),8.68(s,1H),8.04(dd,J＝9.0,5.9Hz,1H),7.91(d,J＝11.1Hz,1H),7.83(s,1H),7.75(d,J＝7.8Hz,1H),7.62(t,J＝10.1Hz,1H),7.55(d,J＝8.7Hz,1H),7.43-7.46(m, 2H),3.29–3.21(m,1H),1.98-2.01(m,1H),1.75-1.83(m,6H),1.58-1.65(m,4H),0.71-0.76(s,2H),0.62-0.67(m,2H)。
实施例16：3-氟-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-16)的制备
Figure PCTCN2019130744-appb-000072
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和3-氟苯甲酸。得到3-氟-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-16)。MS(ESI)421.2[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.76(d,J＝4.6Hz,1H),8.64(s,1H),8.04(dd,J＝9.2,5.9Hz,1H),7.91(dd,J＝10.9,2.5Hz,1H),7.69–7.53(m,3H),7.44-7.49(m,2H),7.33(t,J＝7.5Hz,1H),3.29–3.23(m,1H),1.98-2.01(s,1H),1.73-1.81(m,6H),1.57-1.67(s,4H),0.71-0.76(m,2H),0.62-0.67(m,2H)。
实施例17：3-乙炔基-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-17)的制备
Figure PCTCN2019130744-appb-000073
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和3-乙炔基苯甲酸。得到3-乙炔基-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-17)。MS(ESI)427.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝4.6Hz,1H),8.12(dd,J＝9.1,5.8Hz,1H),7.79(s,1H),7.74(d,J＝7.9Hz,1H),7.55-7.70(m,2H),7.37-7.48(m,2H),7.29(d,J＝4.6Hz,1H),6.35(s,1H),3.19(t,J＝11.2Hz,1H),3.12(s,1H),2.10-2.16(m,1H),1.74-1.99(m,8H),1.66-1.72(m,2H),0.87-0.92(m,2H),0.77-0.82(m,2H)。
实施例18：4-乙炔基-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-18)的制备
Figure PCTCN2019130744-appb-000074
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和4-乙炔基苯甲酸。得到4-乙炔基-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-18)。MS(ESI)427.2[M+H] +； 1H NMR(400MHz,cdcl3)δ8.78(d,J＝4.5Hz,1H),8.10(dd,J＝9.0,5.7Hz,1H),7.77–7.58(m,3H),7.53(d,J＝8.3Hz,2H),7.49–7.39(m,1H),7.28(d,J＝4.3Hz,1H),6.35(s,1H),3.13-3.23(m,2H),2.09-2.15(m,1H),1.95–1.75(m,7H),1.75–1.53(m,3H),0.92-0.87(m,2H),0.82-0.77(m,2H)。
实施例19：3-氰基-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-19)的制备
Figure PCTCN2019130744-appb-000075
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和3-氰基苯甲酸。得到3-氰基-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)苯甲酰胺(J-19)。MS(ESI)428.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝4.5Hz,1H),8.11(dd,J＝8.9,5.6Hz,1H),8.00(s,1H),7.97(d,J＝8.1Hz,1H),7.77(d,J＝7.7Hz,1H),7.64(dd,J＝10.5,2.5Hz,1H),7.56(t,J＝7.8Hz,1H),7.51–7.40(m,1H),7.29(d,J＝4.4Hz,1H),6.41(s,1H),3.20(t,J＝10.8Hz,1H),2.15-2.05(m,1H),1.95–1.74(m,8H),1.76–1.60(m,2H),0.94-0.89(m,2H),0.85-0.79(m,2H)。
实施例20：6-乙炔基-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)烟酰胺(J-20)的制备
Figure PCTCN2019130744-appb-000076
制备方法参照实施例1的步骤7，不同的是将步骤7中的化合物1-7和4-氰基苯甲酸分别换成化合物4a和6-乙炔基吡啶-3-甲酸。得到6-乙炔基-N-(1-(((1s,4s)-4-(6-氟喹啉-4-基)环己基)甲基)环丙基)烟酰胺(J-20)。MS(ESI)428.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.86(s,1H),8.81-8.73(m,1H),8.16-8.09(m,1H),8.07(dd,J＝8.1,2.2Hz,1H),7.64(d,J＝9.8Hz,1H),7.54(d,J＝8.2Hz,1H),7.45(t,J＝7.0Hz,1H),7.31-7.27(m,1H),6.39(s,1H),3.27(s,1H),3.20(t,J＝10.9Hz,1H),2.15-2.06(m,1H),1.99–1.72(m,8H),1.72-1.66(m,2H),0.95-0.90(m,2H),0.84-0.79(m,2H)。
测试例1 Hela细胞的抑制活性测试
试剂
Hela细胞来自ATCC；DMEM无酚红细胞培养基来自Gibco，产品编号：21063-029；INF-γ来自Life Technologies，产品编号：PHC4031 100ug；胎牛血清来自Gibco，产品编号：10099-141；0.25％胰蛋白酶来自GIBCO，产品编号：25200-072；磷酸缓冲液(PBS)来自Hyclone，产品编号：SH30256.01B；6.1N三氯乙酸来自Sigma，产品编号：T0699；对二甲氨基苯甲醛(pDMAB)来自Sigma，产品编号：15647-7；左旋色氨酸来自Sigma，产品编号：T0254-25G；DMSO来自Sigma，产品编号：D5879-1L；96孔细胞培养板来自BD Falcon，产品编号：353072。
试剂准备
1、1克pDMAB溶解于50ml醋酸中(避光，现配现用)；
2、用PBS配置左旋色氨酸至浓度200ug/ml备用；
3、用无酚红培养基配置INF-γ至250ng/ml备用；
实验步骤
1、第一天，以4E3个细胞每孔将Hela细胞种植于细胞培养板中，体积为每孔70ul,置细胞培养箱孵育24小时；
2、第二天，每一孔分别加入10ul浓度10X的待测化合物、10ul左旋色氨酸和10ul INF-γ，DMSO反应浓度为0.5％，左旋色氨酸反应浓度为20ug/ml，INF-γ反应浓度为25ng/ml；
3、细胞培养板置细胞培养箱培养48小时；
4、第四天,取70ul细胞培养上清加入另一块反应板中，每孔加入5ul 6.1N三氯乙酸，置50℃反应30分钟；
5、反应板2500rpm离心10分钟，每孔取50ul上清至一新的反应板；加入50ul pDMAB(2％)置摇床轻轻摇匀；用酶标仪读取480nm吸光度，使用XLfit软件计算化合物IC50值。测试结果如表1所示。
表1本发明示例化合物对Hela细胞的抑制活性
化合物编号 Hela/nM 化合物编号 Hela/nM
J-1-1 2 J-1-2 9
J-2 8 J-4 175
J-5 86 J-6-1 3
J-6-2 8 J-7-1 4
J-8 9 J-9-1 80
J-9-2 96 J-10 2
J-12 3 J-13 2
J-14 3 J-15 3
J-16 2 J-17 4
J-18 2 J-19 4
J-20 3    
测试例2 HEK293-hIDO1细胞的抑制活性测试
试剂
HE293-hIDO1-7稳转细胞系来自TGZ0172；DMEM无酚红细胞培养基来自Gibco，产品编号：21063-029；胎牛血清来自Gibco，产品编号：10099-141；0.25％胰蛋白酶来自Gibco，产品编号：25200-072；磷酸缓冲液(PBS)来自Hyclone，产品编号：SH30256.01B；6.1N三氯乙酸来自Sigma，产品编号：T0699；对二甲氨基苯甲醛(pDMAB)来自Sigma，产品编号：15647-7；左旋色氨酸来自Sigma，产品编号：T0254-25G；DMSO来自Sigma，产品编号：D5879-1L；96孔细胞培养板来自BD Falcon，产品编号：353072。
试剂准备
1、1克pDMAB溶解于50ml醋酸中(避光，现配现用)；
2、用PBS配置左旋色氨酸至浓度200ug/ml备用；
实验步骤
1、第一天，以4E4个细胞每孔种植293-hIDO1细胞种植于细胞培养板中，体积为每孔80ul；
2、每一孔加入10ul浓度10X的待测化合物和10ul左旋色氨酸，DMSO终浓度为0.5％，左旋色氨酸终浓度为20ug/ml；
3、细胞培养板置细胞培养箱培养48小时；
4、第三天,取70ul细胞培养上清加入另一块反应板中，每孔加入5ul 6.1N三氯乙酸，置50℃反应30分钟；
5、反应板2500rpm离心10分钟，每孔取50ul上清至一新的反应板；加入50ul pDMAB(2％)置摇床轻轻摇匀；用酶标仪读取480nm吸光度，使用XLfit软件计算化合物IC50值。测试结果如表2所示。
表2本发明示例化合物对HEK-293细胞的抑制活性
化合物编号 HEK-293/nM 化合物编号 HEK-293/nM
J-1-1 2 J-1-2 48
J-2 57 J-4 657
J-5 447 J-6-1 2
J-6-2 17 J-7-1 3
J-8 6 J-9-1 249
J-9-2 356 J-10 2
J-12 3 J-13 3
J-14 2 J-15 4
J-16 1 J-17 5
J-18 2 J-19 10
J-20 2    
从表1和2可以看出，本发明示例化合物对Hela和HEK-293细胞具有较好的抑制活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (23)

  1. 一种式(I)所示的化合物，或其药学上可接受的盐、或立体异构体：
    Figure PCTCN2019130744-appb-100001
    式中，
    A为取代或未取代的苯基、取代或未取代的8至10元双环杂芳基、或取代或未取代的5至6元单环杂芳基；
    B环为取代或未取代的苯环、或取代或未取代的5至6元单环杂芳基环；
    L 1为一个键或NR 1；
    L 2为一个键或NR 2；
    L 1、L 2不同时为一个键并且L 1、L 2不同时含有N；
    E 1、E 4各自独立地为CR 3或N；
    E 2为(CR 21R 22) m、(CR 21R 22) t-O或(CR 21R 22) t-NR 23；
    E 3为CR 31R 32、O或NR 33，且E 2、E 3不同时含O或N；
    R 1、R 2各自独立地为氢或C 1-10烷基；
    R 3为氢、氰基、羟基、羧基、卤素、取代或未取代的C1-10烷基；
    R 21、R 22、R 31、R 32各自独立地为-(CH 2) r-R 0；R 0为氢、卤素、氰基、羟基、C 1-10烷基、-C(O)C 1-10烷基或C 1-10烷氧基；
    R 23、R 33各自独立地为氢、C 1-10烷基、-C(O)C 1-10烷基；
    m为0、1或2；
    t为0或1；
    r为0、1、2或3；
    R a、R b、R c、R d为选自下组的一种：
    (ⅰ)R a、R b各自独立地为氢、卤素、取代或未取代的C 1-10烷基或取代或未取代的C 1-10烷氧基；
    R c、R d与它们连接的碳原子一起形成取代或未取代的3至6元饱和或不饱和单环或取代或未取代的3至6元饱和或不饱和单杂环；
    (ⅱ)R b、R d各自独立地为氢、卤素、取代或未取代的C 1-10烷基或取代或未取代的C 1-10烷氧基；
    R a、R c与它们连接的碳原子一起形成取代或未取代的3至6元饱和或不饱和单环或取代 或未取代的3至6元饱和或不饱和单杂环；
    Z 1为N或CR 01；Z 2为N或CR 02；Z 3为N或CR 03；Z 4为N或C；
    Figure PCTCN2019130744-appb-100002
    为单键或双键；
    R 01、R 02、R 03各自独立地为氢、卤素、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、C 3-10环烷基、卤代C 1-10烷氧基、NR a0R b0或-C(O)C 1-10烷基；
    所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A1组的取代基所取代；
    所述R 21、R 22、R 23、R 31、R 32、R 33、R 01、R 02、R 03中的烷基，以及R 21、R 22、R 31、R 32、R 01、R 02、R 03中的烷氧基为未取代的或被1、2或3个各自独立地选自A1组的取代基所取代；
    所述A1组取代基选自：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基、卤素、硝基、C 6-10芳基、5或6元单环杂芳基、C 1-10烷基、C 1-10烷氧基、C 3-8环烷基、C 3-8环烷氧基、C 2-10烯基、C 2-10炔基、-CONR a0R b0、-C(O)OC 1-10烷基、-CHO、-OC(O)C 1-10烷基、-SO 2C 1-10烷基、-SO 2C 6-10芳基、-COC 6-10芳基、4至6元饱和或不饱和单杂环或4至6元饱和或不饱和单环，其中R a0、R b0各自独立地为氢或C 1-3烷基。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，所述式(I)化合物具有式(I-a)所示结构：
    Figure PCTCN2019130744-appb-100003
    其中C环为取代或未取代的3至6元饱和或不饱和单环或取代或未取代的3至6元饱和或不饱和单杂环。
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，所述式(I)化合物具有选自式(I-b)所示结构：
    Figure PCTCN2019130744-appb-100004
    其中D环为取代或未取代的3至6元饱和或不饱和单环或取代或未取代的3至6元饱和或不饱和单杂环。
  4. 如权利要求1、2或3所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，
    Figure PCTCN2019130744-appb-100005
    为选自式(IA)、式(IB)或式(IC)所示结构：
    Figure PCTCN2019130744-appb-100006
    其中Z 5为N或CR 7；R 4、R 5、R 6、R 7、R 8、R 9、R 10各自独立地为氢、卤素、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、C 3-10环烷基、卤代C 1-10烷氧基、NR a0R b0或-C(O)C 1-10烷基；其中所述C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、C 3-10环烷基、卤代C 1-10烷氧基、和-C(O)C 1-10烷基中的烷基和烷氧基为未取代的或被1、2或3个各自独立地选自A1组的取代基所取代。
  5. 如权利要求4所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，
    Figure PCTCN2019130744-appb-100007
    为式(IA)所示结构。
  6. 如权利要求1、2或3所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，E 1、E 4为CH；E 3为CR 31R 32、O或NR 33；E 2为(CR 21R 22) m；m为0、1或2。
  7. 如权利要求1、2或3所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，E 1、E 4为CH；E 3为CR 31R 32；E 2为(CR 21R 22) t-O或(CR 21R 22) t-NR 23；t为0或1。
  8. 如权利要求1、2或3所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，E 1、E 4各自独立地为CH或N；E 2为(CR 21R 22) m；m为0、1或2；E 3为CR 31R 32。
  9. 如权利要求1、2或3所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，
    Figure PCTCN2019130744-appb-100008
    选自下组的结构：
    Figure PCTCN2019130744-appb-100009
  10. 如权利要求4所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，E 1、E 4为CH；E 3为CR 31R 32、O或NR 33；E 2为(CR 21R 22) m；m为0、1或2；
    Figure PCTCN2019130744-appb-100010
    为式(IA)所示结构。
  11. 如权利要求4所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于， E 1、E 4为CH；E 3为CR 31R 32；E 2为CR 21R 22；
    Figure PCTCN2019130744-appb-100011
    为式(IA)所示结构。
  12. 如权利要求4所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，E 1、E 4为CH；E 3为CR 31R 32；E 2为(CR 21R 22) t-O或(CR 21R 22) t-NR 23；t为0或1；
    Figure PCTCN2019130744-appb-100012
    为式(IA)所示结构。
  13. 如权利要求4所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，E 1、E 4各自独立地为CH或N；E 2为(CR 21R 22) m；m为0、1或2；E 3为CR 31R 32；
    Figure PCTCN2019130744-appb-100013
    为式(IA)所示结构。
  14. 如权利要求4所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，E 1为CH；E 4为N；E 2为(CR 21R 22) m；m为0、1或2；E 3为CR 31R 32；
    Figure PCTCN2019130744-appb-100014
    为式(IA)所示结构。
  15. 如权利要求4所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，式(IA)所示结构为选自下组的结构：
    Figure PCTCN2019130744-appb-100015
  16. 如权利要求1、2或3所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，
    Figure PCTCN2019130744-appb-100016
    为
    Figure PCTCN2019130744-appb-100017
  17. 如权利要求1所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，所述化合物选自表A。
  18. 如权利要求1所述的化合物、或其药学上可接受的盐、或立体异构体，其特征在于，所述化合物选自表B。
  19. 一种药物组合物，所述药物组合物包括权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、或立体异构体；以及药学可接受的载体。
  20. 如权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、或立体异构体、 或如权利要求19所述药物组合物在制备药物中的应用，所述药物用于抑制吲哚胺2,3-双加氧酶的活性或者用于抑制患者的免疫抑制。
  21. 一种调节吲哚胺2,3-双加氧酶活性的方法，包括将治疗有效剂量的权利要求1所述化合物、其立体异构体或其药学上可接受盐、或权利要求19所述药物组合物与吲哚胺2,3-双加氧酶接触。优选的，所述调节优选为抑制作用。
  22. 一种抑制患者的免疫抑制的方法，所述方法包括将治疗有效剂量的权利要求1所述化合物、其立体异构体或其药学上可接受盐、或权利要求19所述药物组合物给予患者。
  23. 一种治疗癌症的方法，该方法包括向患者施用治疗有效剂量的如下物质：权利要求1所述化合物；其互变异构体，内消旋体，外消旋体，对映异构体，非对映异构体，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体的混合物；或其药学上可接受盐。
PCT/CN2019/130744 2019-01-16 2019-12-31 环烷基取代的酰胺类衍生物、其制法与医药上的用途 WO2020147582A1 (zh)

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CN107207437A (zh) * 2015-01-30 2017-09-26 悉尼大学 抗癌化合物
WO2017192844A1 (en) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2017192840A1 (en) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN107427499A (zh) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 免疫调节剂

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WO2004041210A2 (en) * 2002-11-05 2004-05-21 Smithkline Beecham Corporation Antibacterial agents
CN107427499A (zh) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 免疫调节剂
CN107207437A (zh) * 2015-01-30 2017-09-26 悉尼大学 抗癌化合物
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