CN112384502B - Cycloalkyl-substituted amide derivatives, preparation method and medical application thereof - Google Patents
Cycloalkyl-substituted amide derivatives, preparation method and medical application thereof Download PDFInfo
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- 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
Abstract
Provides a cycloalkyl-substituted amide derivative, a preparation method and a medical application thereof. Specifically, the compound of formula (I) or pharmaceutically acceptable salt, or stereoisomer thereof, and preparation method and application thereof are provided, wherein the definition of each group in the formula is shown in the specification.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a cycloalkyl substituted amide derivative, a preparation method thereof, an application of the derivative as an IDO inhibitor, a pharmaceutical composition prepared from the derivative and a pharmaceutical composition.
Background
Indoleamine 2,3-dioxygenase (indole 2,3-dioxygenase, abbreviated IDO) is a protease involved in tryptophan metabolism. Tryptophan is one of eight essential amino acids, and can be used for synthesizing protein in vivo, and also be used as precursor substrate for synthesizing 5-hydroxytryptamine and melatonin (N-acetyl-5-methoxytryptamine) via methoxyindole metabolic pathway. 5-hydroxytryptamine and melatonin are neurotransmitters and neuroendocrine hormones involved in the regulation of various neurological and physiological processes in the body. In addition, tryptophan may also produce metabolites such as kynurenine through the kynurenine metabolic pathway. The first step of the kynurenine metabolic pathway is the degradation of tryptophan L-tryptophan to N-formyl-kynurenine catalyzed by indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase (TDO), which forms kynurenine catalyzed by kynurenine formamidase, which can be further metabolized to 3-hydroxyanthranilic acid, quinolinic acid, picolinic acid. Quinolinic acid has neurotoxicity, while picolinic acid has neuroprotective effect. Kynurenine and 3-hydroxyanthranilic acid are involved in the regulation of lymphocyte activity to cause the suppression of the immune system.
Indoleamine 2,3-dioxygenase is not substantially expressed in most tissue cells under normal healthy conditions except placental tissue. In the inflammation occurrence area, inflammatory cytokines such as interferon gamma and the like can induce the expression level of indoleamine 2,3-dioxygenase to be increased. The results of various experiments prove that the high expression of indoleamine 2,3-dioxygenase in tissue cells can cause the immune system of the tissue microenvironment to be inhibited, or immune inhibited or immune checkpoint (immunecheckpoint). High expression of indoleamine 2,3-dioxygenase in placenta tissue prevents immune rejection in the fetus. High expression of indoleamine 2,3-dioxygenase in the inflammatory region prevents excessive immune response and prevents excessive damage to cellular tissues. One of the mechanisms leading to immunosuppression is that indoleamine 2,3-dioxygenase is overexpressed to cause local L-tryptophan depletion, which is sensed by peripheral lymphocytes via mechanisms such as GCN2, causing the CD8+ cytotoxic T cells to arrest their cell cycle or undergo apoptosis. Another mechanism leading to immunosuppression is that high expression of indoleamine 2,3-dioxygenase causes elevated kynurenine, which can leave the cell after its formation into the extracellular matrix and then enter nearby lymphocytes to regulate CD8+ T cells and regulatory TR32g cells by binding AHR transcription factors, the activity of CD8+ cytotoxic T cells is inhibited, while the regulatory TR32g cells increase in number and are activated, resulting in immunosuppression.
Indoleamine 2,3-dioxygenase is abnormally and highly expressed 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. The abnormally high expression of indoleamine 2,3-dioxygenase is positively correlated with the prognosis of tumor poor. Tumor cell escape immune surveillance is a key step in the development of cancer and cancer, and the abnormally high expression of indoleamine 2,3-dioxygenase in tumors may be tumor cell escape.
A main mechanism of immune monitoring, namely the inhibition of the activity of indoleamine 2,3-dioxygenase can possibly activate the inhibited immune system to achieve the effect of inhibiting tumor growth, so that the indoleamine 2,3-dioxygenase inhibitor as an immune checkpoint inhibitor (immune checkpoint inhibitor) arouses great interest in the medical field. Indoleamine 2,3-dioxygenase (IDO) have two kinds, IDO-1 and IDO-2, and the role of IDO-1, IDO-2 in immune suppression, which is involved in the above immune suppression, is not clear. Tryptophan 2,3-dioxygenase (TDO) is also aberrantly overexpressed in many types of tumors, and some tumors also display dual IDO and TDO positivity, so it is thought that inhibition of TDO immune checkpoints may also serve the purpose of tumor therapy. Since normal liver cells express TDO, it is not clear whether TDO inhibitors will affect liver function and normal tryptophan metabolism, but no abnormality is found in the TDO knockout mouse model, suggesting that TDO inhibitors may not affect liver function and normal tryptophan metabolism. The mechanisms by which IDO and TDO cause immunosuppression are essentially the same, and so dual inhibitors of IDO/TDO, which would be appropriate for patients who are IDO-positive, TDO-positive, or IDO/TDO-double-positive, have also attracted interest in the medical community.
Many metabolites of the tryptophan kynurenine metabolic pathway are associated with schizophrenia, depression, neuronal degeneration and indoleamine 2,3-dioxygenase inhibitors may also be useful in the treatment of these diseases. Kynurenine is converted to kynurenic acid, an NMDA antagonist, by catalysis by kynurenine aminotransferase, which is commonly found in higher kynurenic acid levels in the central nervous system of schizophrenic patients. Quinolinic acid has neurotoxicity and can cause apoptosis and neurodegeneration of nerve cells. Indoleamine 2,3-dioxygenase is not only involved in tryptophan metabolism, but also in tryptophan metabolism, 5-hydroxytryptamine can be converted into 5-oxindole acetic acid under the catalytic action of indoleamine 2,3-dioxygenase, and the decrease of 5-hydroxytryptamine can be one of factors causing depression.
Currently, indoleamine 2,3-dioxygenase inhibitor is still in early development stage, and the development of IDO inhibitor with better activity and lower toxicity on the basis of the prior art has important clinical significance.
Disclosure of Invention
The invention aims to provide an IDO inhibitor with a novel structure, a preparation method and application thereof.
In a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, or stereoisomer thereof:
in the formula (I), the compound is shown in the specification,
a is substituted or unsubstituted phenyl, substituted or unsubstituted 8 to 10 membered bicyclic heteroaryl, or substituted or unsubstituted 5 to 6 membered monocyclic heteroaryl;
ring B is a substituted or unsubstituted phenyl ring, or a substituted or unsubstituted 5-to 6-membered monocyclic heteroaryl ring;
L 1 is a bond or NR 1 ；
L 2 Is a bond or NR 2 ；
L 1 、L 2 Not simultaneously a bond and L 1 、L 2 Does not contain N at the same time;
E 1 、E 4 each independently is 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 is 2 、E 3 Does not contain O or N at the same time;
R 1 、R 2 each independently is hydrogen or C 1-10 Alkyl (preferably C) 1-6 Alkyl, more preferably C 1-3 Alkyl groups);
R 3 is hydrogen, cyano, hydroxy, carboxyl, 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 groups);
R 21 、R 22 、R 31 、R 32 each independently is- (CH) 2 ) r -R 0 ；R 0 Is hydrogen, halogen, cyano, hydroxy, 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) or C 1-10 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups);
R 23 、R 33 each independently is 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 groups);
m is 0, 1 or 2;
t is 0 or 1;
r is 0, 1,2 or 3;
R a 、R b 、R c 、R d is one selected from the group consisting of:
(ⅰ)R a 、R b 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 groups);
R c 、R d together with the carbon atom 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 heterocycle;
(ⅱ)R b 、R d 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 groups);
R a 、R c together with the carbon atom 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 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 each independently of the others is hydrogen, halogen, C 1-10 Alkyl (preferably C) 1-6 Alkyl, more preferablyC 1-3 Alkyl group), C 1-10 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halo 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), halo C 1-10 Alkoxy (preferably halo C) 1-6 Alkoxy, more preferably halo 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 groups);
the "substitution" means that 1,2 or 3 hydrogen atoms in the group are substituted by substituents each independently selected from group A1;
the R is 21 、R 22 、R 23 、R 31 、R 32 、R 33 、R 01 、R 02 、R 03 Alkyl in (1), and R 21 、R 22 、R 31 、R 32 、R 01 、R 02 、R 03 The alkoxy group in (a) is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group A1;
the substituent in the A1 group is selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, halogeno C 1-8 Alkyl (preferably halogenated C) 1-6 Alkyl, more preferably halogenated 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 group), 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, more preferably C 2-4 Alkynyl), -CONR a0 R b0 、-C(O)OC 1-10 Alkyl (preferably)is-C (O) OC 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -CHO, -OC (O) C 1-10 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), -SO 2 C 1-10 Alkyl (preferably-SO) 2 C 1-6 Alkyl, more preferably-SO 2 C 1-3 Alkyl), -SO 2 C 6-10 Aryl (preferably-SO) 2 C 6 Aryl radicals, e.g. SO 2 -phenyl), -COC 6-10 Aryl (preferably-COC) 6 Aryl, such as-CO-phenyl), 4-to 6-membered saturated or unsaturated mono-heterocyclic ring or 4-to 6-membered saturated or unsaturated monocyclic ring, wherein R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In another preferred embodiment, the compound of formula (I) has a structure represented by formula (I-1) or formula (I-2):
wherein each group is defined in the specification.
In another preferred embodiment, the compound of formula (I) has the structure of formula (I-a):
wherein ring C 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 defined in the specification.
In another preferred embodiment, the compound of formula (I-a) has a structure represented by formula (I-a-1) or formula (I-a-2):
wherein each group is defined in the specification.
In another preferred embodiment, the formula (I-a), the formula (II-a) and the formula (III-b)In I-a-1) and formula (I-a-2), R b 、R d Each independently of the others is hydrogen, halogen, C 1-3 Alkyl or C 1-3 An alkoxy group.
In another preferred embodiment, in the formula (I-a), the formula (I-a-1) and the formula (I-a-2), R b 、R d Each independently hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.
In another preferred embodiment, in the formula (I-a), the formula (I-a-1) and the formula (I-a-2), R b 、R d Each independently hydrogen.
In another preferred embodiment, in formula (I-a), formula (I-a-1) and formula (I-a-2), the C ring is a 3-to 6-membered saturated monocyclic ring.
In another preferred embodiment, in formula (I-a), formula (I-a-1) and formula (I-a-2), the C ring is a 3-membered saturated monocyclic ring.
In another preferred embodiment, in formula (I-a), formula (I-a-1) and formula (I-a-2), the C ring is a cyclopropyl ring.
In another preferred embodiment, in the formula (I-a), the formula (I-a-1) and the formula (I-a-2),
is composed of
In another preferred embodiment, in the formula (I-a), the formula (I-a-1) and the formula (I-a-2), (a) L 1 Is NH, and L 2 Is a bond; or (b) L 1 Is a bond; l is 2 Is NH.
In another preferred embodiment, the compound of formula (I) has the structure of formula (I-b):
wherein 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; the other groups are defined in the specification.
In another preferred embodiment, the compound of formula (I-b) has a structure represented by formula (I-b-1) or formula (I-b-2):
wherein each group is defined in the specification.
In another preferred embodiment, in the formula (I-b), the formula (I-b-1) and the formula (I-b-2), R a 、R b Each independently of the others is hydrogen, halogen, C 1-3 Alkyl or C 1-3 An alkoxy group.
In another preferred embodiment, in the formula (I-b), the formula (I-b-1) and the formula (I-b-2), R a 、R b Each independently hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or ethoxy.
In another preferred embodiment, in the formula (I-b), the formula (I-b-1) and the formula (I-b-2), R a 、R b Each independently hydrogen.
In another preferred embodiment, in formula (I-b), formula (I-b-1) and formula (I-b-2), the D ring is a 3-to 6-membered saturated monocyclic ring.
In another preferred embodiment, in formula (I-b), formula (I-b-1) and formula (I-b-2), the D ring is a 3-membered saturated monocyclic ring.
In another preferred embodiment, in formula (I-b), formula (I-b-1) and formula (I-b-2), the D ring is a cyclopropyl ring.
In another preferred embodiment, in the formula (I-b), the formula (I-b-1) and the formula (I-b-2),
is composed of
In another preferred embodiment, in the formula (I-b), the formula (I-b-1) and the formula (I-b-2), L 1 Is NH, L 2 Is a bond.
In another preferred embodiment, the substituents of group A1 are selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, halogeno C 1-3 Alkyl, halogen (preferably F or Cl), nitro, phenyl, 5-or 6-membered monocyclic heteroaryl, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, C 2-4 Alkenyl radical, 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, a 4 to 6 membered saturated or unsaturated mono-heterocyclic ring or a 4 to 6 membered saturated or unsaturated monocyclic ring, wherein R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In another preferred embodiment, Z 1 、Z 2 、Z 3 And Z 4 Not N at the same time.
In another preferred embodiment, Z 1 、Z 2 And Z 3 At least one of which is not N.
In another preferred embodiment, Z 1 、Z 2 And Z 3 Are not N.
In another preferred embodiment, Z 1 Is N; z 2 Is CR 02 ；Z 3 Is CR 03 ；R 02 、R 03 As defined above.
In another preferred embodiment, Z 1 Is CR 01 ；Z 2 Is N; z is a linear or branched member 3 Is CR 03 ；R 01 、R 03 As defined above.
In another preferred embodiment, Z 1 Is CR 01 ；Z 2 Is CR 02 ；Z 3 Is N; r 01 、R 02 As defined above.
In another preferred embodiment, R 02 、R 03 Is hydrogen.
In another preferred embodiment, the B ring is a benzene ring, a pyridine ring, a pyrazole ring, an imidazole ring or a pyrrole ring, and Z is 4 Is N or C;
is a single bond or a double bond.
In another preferred embodiment, the 5-to 6-membered monocyclic heteroaryl in a is selected from: thiophene, N-alkylcyclopyrrole, 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.
In another preferred embodiment, the 8-to 10-membered bicyclic heteroaryl 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.
In another preferred embodiment, a is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5 to 6 membered monocyclic heteroaryl, said "substituted" meaning that 1,2 or 3 hydrogen atoms in the group are substituted by substituents each independently selected from the group consisting of: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, halogeno C 1-3 Alkyl, halogen, nitro, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C 2-4 Alkenyl radical, 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-phenyl, wherein R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In another preferred embodiment, a is substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl, said "substituted" meaning that 1,2 or 3 hydrogen atoms in the group are substituted with substituents each independently selected from the group consisting of: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, trifluoromethyl, fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclopropyloxy, vinyl, ethynyl, -CONR a0 R b0 、-C(O)OC 1-3 Alkyl, -OC (O) C 1-3 Alkyl, -SO 2 C 1-3 Alkyl radical, wherein R a0 、R b0 Each independently hydrogen or methyl.
In another preferred embodiment, the 4-to 6-membered saturated or unsaturated mono-heterocyclic ring in the substituent of group A1 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydrooxetane, 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.
In another preferred embodiment, the 4 to 6 membered saturated or unsaturated monocyclic ring in the substituents of group A1 is selected from: cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings.
In another preferred embodiment, the 5 or 6 membered monocyclic heteroaryl group in the substituents of group A1 is selected from: thiophene, N-alkylcyclopyrrole, 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.
In another preferred embodiment, R c 、R d The 3 to 6 membered saturated or unsaturated monocyclic ring formed together with the carbon atom to which they are attached is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl rings.
In another preferred embodiment, R c 、R d The 3 to 6 membered saturated or unsaturated mono-heterocyclic ring formed together with the carbon atom to which they are attached is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydrooxetane, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydrofuranHydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine.
In another preferred embodiment, R a 、R c The 3 to 6 membered saturated or unsaturated monocyclic ring formed together with the carbon atom to which they are attached is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadiene rings.
In another preferred embodiment, R a 、R c The 3 to 6 membered saturated or unsaturated mono-heterocyclic ring formed together with the carbon atom to which they are attached is selected from: aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydrooxetane, 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, 1,2,3,6-tetrahydropyridine.
In another preferred embodiment, R 3 Is hydrogen, cyano, hydroxy, carboxyl, halogen, substituted or unsubstituted C 1-3 Alkyl, said "substituted" meaning that 1,2 or 3 hydrogen atoms in the group are substituted with substituents each independently selected from the group consisting of: cyano, acetyl, hydroxy, carboxyl, halogen, C 3-6 A cycloalkyl group. In another preferred embodiment, L 1 Is NR 1 ；L 2 Is a key.
In another preferred embodiment, L 1 Is a bond; l is 2 Is NR 2 。
In a further preferred embodiment of the method,
is a structure shown in formula (IA), formula (IB) or formula (IC):
wherein Z 5 Is N or CR 7 ；Z 1 、Z 2 、Z 3 As defined in the specification; r 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Each independently of the others is hydrogen, halogen, C 1-10 Alkyl radical, C 1-10 Alkoxy, halo C 1-10 Alkyl radical, C 3-10 Cycloalkyl, halo C 1-10 Alkoxy, NR a0 R b0 or-C (O) C 1-10 An alkyl group; wherein said C 1-10 Alkyl radical, C 1-10 Alkoxy, halo C 1-10 Alkyl radical, C 3-10 Cycloalkyl, halo C 1-10 Alkoxy and-C (O) C 1-10 The alkyl and alkoxy groups in the alkyl group are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group A1.
In another preferred embodiment, R 4 、R 5 、R 6 Each independently of the others is hydrogen, halogen, C 1-3 Alkyl radical, C 1-3 Alkoxy, halo C 1-3 Alkyl radical, C 3-6 Cycloalkyl, halo C 1-3 Alkoxy, NR a0 R b0 or-C (O) C 1-3 Alkyl radical, wherein R a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
In another preferred embodiment, R 7 Is hydrogen.
In another preferred embodiment, R 4 、R 6 Is hydrogen.
In another preferred embodiment, R 5 Is halogen, preferably fluorine.
In a further preferred embodiment of the method,
has a structure shown in formula (IA).
In another preferred embodiment, in formula (IA), Z 1 Is N; z 2 Is CR 02 ；Z 3 Is CR 03 ；Z 5 Is N; r 02 、R 03 As defined above.
In another preferred embodiment, in formula (IA), Z 1 Is N; z 2 Is CR 02 ；Z 3 Is CR 03 ；Z 5 Is CR 7 ；R 02 、R 03 、R 7 As defined above.
In another preferred embodiment, in formula (IA), Z 1 Is CR 01 ；Z 2 Is CR 02 ；Z 3 Is CR 03 ；Z 5 Is N; r 01 、R 02 、R 03 As defined above.
In another preferred embodiment, in formula (IB) or formula (IC), Z 1 Is N; z 2 Is CR 02 ；Z 3 Is CR 03 ；R 02 、R 03 As defined above.
In another preferred embodiment, R 02 Is hydrogen; r 03 Is hydrogen.
In another preferred embodiment, in formula (IB), Z 1 Is N; z 2 、Z 3 Is CH; r 8 、R 9 Is hydrogen.
In another preferred embodiment, in formula (IC), Z 1 Is N; z 2 、Z 3 Is CH; r 9 Is hydrogen; r 10 Is hydrogen, halogen, C 1-10 Alkyl radical, C 1-10 Alkoxy, halo C 1-10 Alkyl radical, C 3-10 Cycloalkyl, halo C 1-10 Alkoxy, NR a0 R b0 or-C (O) C 1-10 An alkyl group.
In another preferred embodiment, E 1 、E 4 Is CH; e 3 Is CR 31 R 32 O or NR 33 ；E 2 Is (CR) 21 R 22 ) m (ii) a m is 0, 1 or 2; r 21 、R 22 、R 31 、R 32 、R 33 As defined in the specification.
In another preferred embodiment, E 1 、E 4 Is 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 (ii) a t is 0 or 1; r 21 、R 22 、R 23 、R 31 、R 32 As defined in the specification.
In another preferred embodiment, E 1 、E 4 Each independently is CH or N; e 2 Is (CR) 21 R 22 ) m (ii) a m is 0, 1 or 2; e 3 Is CR 31 R 32 ；R 21 、R 22 、R 31 、R 32 As defined in the specification.
In another preferred embodiment, E 1 Is CH, E 4 Is CH or N; e 2 Is (CR) 21 R 22 ) m (ii) a m is 0, 1 or 2; e 3 Is CR 31 R 32 ；R 21 、R 22 、R 31 、R 32 As defined in the specification.
In another preferred embodiment, E 1 Is CH, E 4 Is CH or N; e 2 Is CH; e 3 Is CH.
In a further preferred embodiment of the present invention,
a structure selected from the group consisting of:
in a further preferred embodiment of the method,
a structure selected from the group consisting of:
In another preferred embodiment, E 1 、E 4 Is CH; e 3 Is CR 31 R 32 O or NR 33 ；E 2 Is (CR) 21 R 22 ) m (ii) a m is 0, 1 or 2;
has a structure shown in formula (IA).
In another preferred embodiment, E 1 、E 4 Is CH; e 3 Is CR 31 R 32 ；E 2 Is CR 21 R 22 ；
Has a structure shown in formula (IA).
In another preferred embodiment, E 1 、E 4 Is 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 (ii) a t is 0 or 1;
has a structure shown in formula (IA).
In another preferred embodiment, E 1 、E 4 Each independently is CH or N; e 2 Is (CR) 21 R 22 ) m (ii) a m is 0, 1 or 2; e 3 Is CR 31 R 32 ；
Has a structure shown in formula (IA).
In another preferred embodiment, E 1 Is CH; e 4 Is N; e 2 Is (CR) 21 R 22 ) m (ii) a m is 0, 1 or 2; e 3 Is CR 31 R 32 ；
Has a structure shown in formula (IA).
In another preferred embodiment, formula (IA) is of the structure:
in another preferred embodiment, formula (IA) is
In a further preferred embodiment of the method,
is composed of
In another preferred embodiment, the 3-to 6-membered saturated mono-heterocyclic ring is selected from the following structures:
In another preferred embodiment, the 5-to 6-membered monocyclic heteroaryl ring or heteroaryl is selected from: thiophene rings, N-alkyl ring pyrrole rings, furan rings, thiazole rings, imidazole rings, oxazole rings, pyrrole rings, pyrazole rings, triazole rings, 1,2,3-triazole rings, 1,2,4-triazole rings, 1,2,5-triazole rings, 1,3,4-triazole rings, tetrazole rings, isoxazole rings, oxadiazole rings, 1,2,3-oxadiazole rings, 1,2,4-oxadiazole rings, 1,2,5-oxadiazole rings, 1,3,4-oxadiazole rings, thiadiazole rings, pyridine rings, pyridazine rings, pyrimidine rings, or pyrazine rings.
In another preferred embodiment, the 5-to 6-membered monocyclic heteroaryl ring or heteroaryl 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.
In another preferred embodiment, the compound is selected from table a or table B.
In another preferred embodiment, the compounds of table a are selected from the group consisting of:
in another preferred embodiment, the compounds of table B are selected from the group consisting of:
in another preferred embodiment, the compound of formula (I) has a structure selected from the group consisting of:
while the above table lists the structures of preferred compounds of the invention, it should be understood that the two carbon atoms of the cyclohexyl group to which a para-substituted group of substituents on the cyclohexyl group is attached are not chiral centers,
and
the chemical bond representation of (a) is merely intended to indicate that the two chemical bonds attached to the group of substituents that are para-substituted are in either a trans or cis configuration relative to the cyclohexyl group, and thus are both bonded
And
compounds which are shown in exchange for one another likewise fall within the scope of protection of the present invention.
In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, or stereoisomer thereof; and a pharmaceutically acceptable carrier.
In a third aspect, the invention provides the use of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition according to the second aspect of the invention, in the manufacture of a medicament for inhibiting the activity of indoleamine 2,3-dioxygenase, or for inhibiting immunosuppression in a subject.
In another preferred embodiment, the medicament is for treating or preventing cancer or tumor, viral infection, depression, neurodegenerative disorder, trauma, age-related cataract, organ transplant rejection or autoimmune disease in a patient; preferably, wherein the cancer or tumor is selected from the group consisting of lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, cancer of the head and neck, uterus, ovary cancer, testicular cancer, uterus cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, rectal cancer, colon cancer, cancer of the anal region, breast cancer, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the urethra, cancer of the penis, prostate cancer, pancreatic cancer, brain cancer, testicular cancer, lymphatic cancer, transitional cell cancer, bladder cancer, cancer of the kidney or ureter, renal cell cancer, carcinoma of the renal pelvis, hodgkin's disease, non-hodgkin's lymphoma, soft tissue sarcoma, solid tumor of childhood, lymphocytic lymphoma, central Nervous System (CNS) tumor, primary central nervous system lymphoma, tumor angiogenesis, spinal tumor, brain stem glioma, pituitary adenoma, melanoma, kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, chronic or acute leukemia, and combinations of said cancers.
In another preferred embodiment, the use is a combination of a therapeutically effective amount of a compound of formula (i), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described above, or a pharmaceutical composition thereof, with an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an antiviral agent, a chemotherapeutic agent, an immunosuppressive agent, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy, or a tyrosine kinase inhibitor; preferably, the cytokine is preferably IL-2, IL-3, IL-4 or IL-5, the chemotherapeutic agent is preferably a cytotoxic agent, and the anti-PD-1 antibody is preferably a Keytruda antibody.
In a fourth aspect, the present invention provides a method of modulating indoleamine 2,3-dioxygenase activity comprising contacting a therapeutically effective amount of a compound of formula (i), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described above, or a pharmaceutical composition thereof, with indoleamine 2,3-dioxygenase. Preferably, the modulation is preferably an inhibitory effect.
In a fifth aspect, the present invention provides a method of inhibiting immunosuppression in a subject, which comprises administering to the subject a therapeutically effective amount of a compound of formula (i) as hereinbefore defined, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as hereinbefore defined.
In a sixth aspect, the present invention provides a method for treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another preferred example, the cancer or tumor is selected from the group consisting of lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, cancer of the head and neck, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, rectal cancer, colon cancer, cancer of the anal region, breast cancer, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the urethra, cancer of the penis, prostate cancer, pancreatic cancer, cancer of the brain, testicular cancer, lymphatic cancer, transitional cell cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, hodgkin's disease, non-hodgkin's lymphoma, soft tissue sarcoma, solid tumor of a child, lymphocytic lymphoma, central Nervous System (CNS) tumor, primary central nervous system lymphoma, tumor angiogenesis, spinal tumor, brain stem glioma, pituitary adenoma, melanoma, kaposi's sarcoma, epidermoid carcinoma, T-cell lymphoma, chronic or acute leukemia, and combinations of said cancers.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments.
Detailed Description
The inventor has conducted extensive and intensive studies for a long time, and unexpectedly found a class of cycloalkyl-substituted amide derivatives, which have better inhibitory activity and lower toxicity against IDO inhibitors. In addition, the compounds of the present invention have excellent pharmacokinetic properties. Therefore, the series of compounds are expected to be developed into medicaments for treating and preventing diseases such as cancers. On this basis, the inventors have completed the present invention.
Definition of terms
As used herein, "alkyl" refers to straight and branched chain 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 C 1-3 Alkyl, defined similarly; 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-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 43-dimethylpentyl, 2,4-dimethylpentyl, 3754, 4984, 4972-dimethylpentyl, 497972, ethyl-hexyl, 3-methylhexyl, 5-methylhexyl, 43-dimethylpentyl, 35985224-dimethylpentyl, 3524-dimethylpentyl, 3754, 497954, 497972, ethyl-hexylhexyl, 497972, ethyl-dimethylpentyl, ethyl-octyl-pentyl, n-octyl-3-ethylpentyl, and n-pentylMore preferred are a cyclohexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, various branched chain isomers thereof, and the like.
As used herein, "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 C 2-6 Alkenyl, more preferably C 2-4 Alkenyl, defined analogously; non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl or 2-butenyl, various branched isomers thereof, and the like are more preferred. As used herein, "alkynyl" refers to an aliphatic group containing at least one triple bond, C 2-10 Alkynyl is an alkynyl group containing 2 to 10 carbon atoms, preferably C 2-6 Alkynyl, more preferably C 2-4 Alkynyl, defined similarly; non-limiting examples of alkynyl groups include: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl or 2-butynyl, and various branched isomers thereof and the like are more preferred.
As used herein, "cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to a saturated or unsaturated monocyclic cyclic hydrocarbon group, "C 3-8 Cycloalkyl "refers to a cyclic hydrocarbon group containing 3 to 8 carbon atoms, preferably C 3-6 Cycloalkyl radicals are defined analogously. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like, with cyclopropyl, cyclopentyl, cyclohexenyl being preferred.
As used herein, "C" is 1-10 Alkoxy means-O- (C) 1-10 Alkyl) wherein alkyl is as defined above. Preferably C 1-6 Alkoxy, more preferably C 1-3 An alkoxy group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, pentoxy and the like.
As used herein, "C" is 3-8 Cycloalkoxy means-O- (C) 3-8 Cycloalkyl), wherein cycloalkyl is as defined above. Preferably C 3-6 A cycloalkoxy group. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
As used herein, "C" is 6-10 Aryl "and" C 6-10 Aromatic rings "are used interchangeably and each refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and refers to aryl groups containing from 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
As used herein, "a bond" means that the two groups connected by it are linked by a covalent bond.
As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.
As used herein, "halo" refers to a group in which one or more (e.g., 1,2,3,4, or 5) hydrogens are replaced with a halogen.
For example, "halo C 1-10 Alkyl "means an alkyl group substituted with one or more (e.g., 1,2,3,4, or 5) halogens, wherein alkyl is as defined above. Is selected from halo C 1-6 Alkyl, more preferably halogenated C 1-3 An alkyl group. Halogen substituted C 1-10 Examples of alkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
Also for example, "halo C 1-10 Alkoxy "means an alkoxy group substituted with one or more (e.g., 1,2,3,4, or 5) halogens, wherein the alkoxy group is as defined above. Preferably a halogen atom 1-6 Alkoxy, more preferably halo C 1-3 An alkoxy group. Including, but not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
As used herein, "amino" refers to NH 2 "cyano" means CN, "nitro" means NO 2 "benzyl" means-CH 2 -phenyl, "carboxy" means-C (O) OH, and "acetyl" means-C (O) CH 3 And "hydroxymethyl" means-CH 2 OH, "hydroxyethyl" means-CH 2 CH 2 OH or-CHOHCH 3 And "hydroxy" means-OH.
As used herein, "heteroaryl ring" is used interchangeably with "heteroaryl" and refers to a monocyclic heteroaryl group having 5 to 10 ring atoms, preferably 5 or 6 membered or a bicyclic heteroaryl group having 8 to 10 membered ring atoms; 6, 10 or 14 pi electrons are shared in the ring array; and a group having 1 to 5 hetero atoms in addition to carbon atoms. "heteroatom" means nitrogen, oxygen or sulfur.
As used herein, "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. Examples of 3-to 6-membered saturated or unsaturated monocyclic rings include (but are not limited to): cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like.
As used herein, "3 to 6 membered (4 to 6 membered) saturated or unsaturated monoheterocycle" means that 1,2 or 3 carbon atoms in the 3 to 6 membered monocyclic ring are selected from nitrogen, oxygen or S (O) t (wherein t is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon; preferably 4 to 6, more preferably 5 to 6. Examples of 3-to 6-membered saturated or partially unsaturated mono-heterocycles include, but are not limited to, propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydrooxetane, 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, 1,2,3,6-tetrahydropyridine, and the like.
As used herein, "5-to 6-membered monocyclic heteroaryl ring" and "5-to 6-membered monocyclic heteroaryl" are used interchangeably and both refer to monocyclic heteroaryl rings containing 5 to 6 ring atoms, including for example (but not limited to): thiophene rings, N-alkyl ring pyrrole rings, furan rings, thiazole rings, imidazole rings, oxazole rings, pyrrole rings, pyrazole rings, triazole rings, 1,2,3-triazole rings, 1,2,4-triazole rings, 1,2,5-triazole rings, 1,3,4-triazole rings, tetrazole rings, isoxazole rings, oxadiazole rings, 1,2,3-oxadiazole rings, 1,2,4-oxadiazole rings, 1,2,5-oxadiazole rings, 1,3,4-oxadiazole rings, thiadiazole rings, pyridine rings, pyridazine rings, pyrimidine rings, pyrazine rings and the like.
As used herein, "8-to 10-membered bicyclic heteroaryl ring" and "8-to 10-membered bicyclic heteroaryl" are used interchangeably and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, including for example (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-naphthyridine.
As used herein, "substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are substituted independently of each other with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are substituted independently of each other with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
The "substituents each independently selected from … …" as used herein means, unless otherwise defined, that when more than one hydrogen on a group is substituted with a substituent, the substituent species may be the same or different, and the substituents selected are each independently species.
As used herein, unless otherwise defined, "… … are the same or different and each is independently … …" means that when more than one of the same substituent groups is present in the formula, the groups may be the same or different and are each independently. For example L is (CR) 01 R 02 ) s When s is 2, i.e. LIs (CR) 01 R 02 )-(CR 01 R 02 ) Wherein two R are 01 Or R 02 May be the same or different and are each independently of the other, e.g., L may 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 )。
As used herein, any group herein may be substituted or unsubstituted. When the above groups are substituted, 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 Alkyl, more preferably C 1-3 Alkyl), C 1-10 Alkoxy (preferably C) 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halo C 1-8 Alkyl (preferably halogenated C) 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl group), C 3-8 Cycloalkyl (preferably C) 3-6 Cycloalkyl), halo C 1-8 Alkoxy (preferably halo C) 1-6 Alkoxy, more preferably halo C 1-3 Alkoxy group), C 1-8 Alkyl substituted amino, halo C 1-8 Alkyl substituted amino, acetyl, hydroxyl, hydroxymethyl, hydroxyethyl, carboxyl, nitro, C 6-10 Aryl (preferably phenyl), 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, more preferably C 2-4 Alkynyl), -CONR a0 R b0 、-C(O)OC 1-10 Alkyl (preferably-C (O) OC) 1-6 Alkyl, more preferably-C (O) OC 1-3 Alkyl), -CHO, -OC (O) C 1-10 Alkyl (preferably-OC (O) C) 1-6 Alkyl, more preferably-OC (O) C 1-3 Alkyl), -SO 2 C 1-10 Alkyl (preferably-SO) 2 C 1-6 Alkyl, more preferably-SO 2 C 1-3 Alkyl), -SO 2 C 6-10 Aryl (preferably-SO) 2 C 6 Aryl radicals, e.g. SO 2 -phenyl), -COC 6-10 Aryl (preferably-COC) 6 Aryl, such as-CO-phenyl), 4-to 6-membered saturated or unsaturated monocyclic ring, 5-to 6-membered monocyclic heteroaryl ring, 8-to 10-membered bicyclic heteroaryl ring, spiro ring, bridged ring or bridged heterocyclic ring, wherein R is a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
The various substituent groups described herein above may themselves be substituted with groups described herein.
When the 4-to 6-membered (5-to 6-membered) saturated mono-heterocyclic rings described herein are substituted, the positions of the substituents may be at their possible chemical positions, and representative substitution of exemplary mono-heterocyclic rings are as follows:
Unless otherwise defined, when a 4-to 6-membered saturated monocyclic heterocyclic ring described herein is a substituent, it may itself be substituted or substituted with 1,2 or 3 substituents selected from the group consisting of: halogen, hydroxy, C 1-3 Alkyl, O =, NR a0 R b0 Hydroxymethyl, hydroxyethyl, carboxy, -C (O) OC 1-3 Alkyl, acetyl, halo C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 3-6 Cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyrazine ringA pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring; wherein R is a0 、R b0 Each independently is hydrogen or C 1-3 An alkyl group.
The same symbols in the present invention are to be understood as having the same meaning unless otherwise specified. In addition, terms (including substituent abbreviations, reagent name abbreviations, etc.) in the present invention should be understood as meanings commonly used in the art unless otherwise specified.
The "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects.
"pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases such as sodium, potassium, calcium, and magnesium salts, and the like. Including but not limited to salts with organic bases such as ammonium, triethylamine, lysine, arginine, and the like.
Reference to a "solvate" in the present invention refers to a complex formed between a compound of the present invention and a solvent. They either react in a solvent or precipitate out of a solvent or crystallize out. For example, a complex with water is called a "hydrate". Solvates of the compounds of formula (I) are within the scope of the invention.
In the compound of the present invention,
in the case of cyclohexyl, the two carbon atoms in the cyclohexyl group to which a group of substituents para-substituted on the ring is attached are not chiral centers,
and
the chemical bond representation of (A) is only intended to indicate that the two chemical bonds connecting the group of substituents which are para-substituted are present with respect to the cyclohexyl groupTrans or cis structure, thus linking the two chemical bonds
And
compounds which are shown in exchange for one another likewise fall within the scope of protection of the present invention. The compounds of formula (I), formula (I-a) and formula (I-b) according to the invention may be present as a mixture comprising trans and cis structures, or as trans structures. Preferably in cis-configuration. In the present invention, a group of substituents para-substituted on the cyclohexyl group and two carbon atoms of the cyclohexyl group to which they are bonded via
The scope of protection of the structures represented by the bonds includes trans or cis structures. In addition, the compound structure has a pair of chemical bonds connected with the cyclohexyl para position
Or are all
The same meaning is true for all cases, and they all represent cis-structures. A pair of chemical bonds connected at the para-position of cyclohexyl are respectively
And
or respectively is
And
when used, the same meanings are given, and all represent trans structures.
The compounds of formula (I) according to the invention may contain one or more chiral centres and exist in different optically active forms. When the compound contains one chiral center, the compound comprises enantiomers. The present invention includes both 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. When the compounds of formula (I) contain more than one chiral center, diastereoisomers may be present. The present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography. In addition, the compounds of the present invention also include cis-isomers, trans-isomers and mixtures of cis-and trans-isomers, for example, when the compounds of the present invention have a cycloalkyl structure, different substituents on the cycloalkyl ring may form cis-isomers or trans-isomers.
The present invention includes prodrugs of the above compounds. Prodrugs include known amino protecting groups and carboxy protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to give the parent compound. Specific methods of prodrug preparation are referred to (Saulnier, M.G.; frannesson, D.B.; deshpande, M.S.; hansel, S.B and Vysa, D.M.Bioorg.Med.Chem Lett.1994,4, 1985-1990; and Greenwald, R.B.; choe, Y.H.; conover, C.D.; shum, K.; wu D.; royzen, M.J.Med.Chem.2000, 43, 475.).
In general, a compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, may be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the 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 compounds and one or more carriers or adjuvants by customary pharmaceutical methods. The above-mentioned carriers need to be compatible with the active compound or other adjuvants. For solid formulations, non-toxic carriers that are commonly used 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 glucose solution, ethylene glycol, polyethylene glycol and the like. The active compound may be in solution or suspension with the carrier(s) mentioned above.
The compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice specifications. The "therapeutically effective amount" of a compound to be administered will depend on the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
As used herein, "therapeutically effective amount" refers to an amount of a compound of the invention that will elicit the biological or medical response of an individual, e.g., decrease or inhibit enzyme or protein activity or ameliorate symptoms, alleviate a condition, slow or delay disease progression or prevent disease, etc.
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 0.1mg to 5g/kg (body weight).
As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of adjuvant that is compatible with the patient, preferably a mammal, more preferably a human, and that is suitable for delivering an active agent to a target site without terminating the activity of the agent.
As used herein, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.
As used herein, "treating" or "treatment" refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or disorder (e.g., cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent one or more symptoms of the disease or disorder.
Preparation method
Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: conditions described in a Laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations.
Unless otherwise defined, terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present invention.
The preparation method of the compound used in the invention comprises the following steps:
the compound represented by the formula (I) of the present invention can be produced by a known method, for example, by the following method, a method equivalent thereto or a method described in examples. In the following preparation methods, the starting compound may be in the form of a salt, which may be any pharmaceutically acceptable salt exemplified by the compound represented by formula (I) of the present invention.
Wherein E 1 、E 4 Each independently is CH, E 2 、E 3 Each independently is CH 2 ，R a 、R b Each independently is hydrogen, the D ring is a 3-membered saturated monocyclic ring, L 1 Is NH, L 2 The compound represented by the formula (I-b) which is a bond (e.g., the compound represented by the formula (I-8)) can be produced by the method represented by the reaction scheme (I).
Wherein E 1 Is CH, E 4 Is N, E 2 、E 3 Each independently is CH 2 ，R a 、R b Each independently hydrogen, ring D is a 3-membered saturated monocyclic ring, L 1 Is NH, L 2 The compound represented by the formula (I-b) which is a bond (e.g., the compound represented by the formula (II-7)) can be produced by the method represented by the reaction scheme (II).
Wherein E 1 、E 4 Each independently is CH, E 2 、E 3 Each independently is CH 2 ，R b 、R d Each independently is hydrogen, the C ring is a 3-membered saturated monocyclic ring, L 1 Is a bond, L 2 The compound represented by the formula (I-a) which is NH (e.g., the compound represented by the formula (III-8)) can be produced by the method represented by the reaction scheme (III).
Wherein E 1 、E 4 Each independently is CH, E 2 、E 3 Each independently is CH 2 ，R b 、R d Each independently is hydrogen, the C ring is a 3-membered saturated monocyclic ring, L 1 Is NH, L 2 The compound represented by the formula (I-a) which is a bond (e.g., the compound represented by the formula (IV-3)) can be produced by the method represented by the reaction scheme (IV).
Reaction scheme (I)
(in each of the formulae of the above schemes, all symbols are as defined above, and X is halogen.)
Specifically, the compound represented by the formula (I-8) can be prepared by the following method:
step 1: the compound represented by the formula (I-2) is prepared by subjecting the corresponding compound represented by the formula (I-1) and 1,4-dioxa-spiro [4,5] dec-7-ene-8-boronic acid pinacol ester to a Suzuki coupling reaction.
Step 2: the compound represented by the formula (I-2) is subjected to a carbon-carbon double bond reduction reaction to produce a compound represented by the formula (I-3).
And step 3: deprotection of the carbonyl group of the compound represented by the formula (I-3) gives a compound represented by the formula (I-4).
And 4, step 4: the compound represented by the formula (I-4) and a phosphorus ylide reagent are subjected to a Wittig reaction to prepare the compound represented by the formula (I-5).
And 5: the compound represented by the formula (I-5) is subjected to a carbon-carbon double bond reduction reaction to produce a compound represented by the formula (I-6).
Step 6: the compound represented by the formula (I-6) is reacted with a Grignard reagent to produce a compound represented by the formula (I-7).
And 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 are subjected to amidation reaction to obtain the compound represented by the formula (I-8).
Reaction scheme (II)
(in each of the formulae of the above schemes, all symbols are as defined above, and X is halogen.)
Specifically, the compound represented by the formula (II-7) can be prepared by the following method:
step 1: the compound represented by the formula (II-1) is obtained by subjecting a corresponding compound represented by the formula (I-1) and pinacol diboron diborate to a Miyaura boronation reaction.
Step 2: the compound represented by the formula (II-1) and the compound 4- (trifluoromethylsulfonyloxy) -5,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 1a were subjected to a Suzuki coupling reaction to prepare a compound represented by the formula (II-2).
And step 3: the compound represented by the formula (II-2) is subjected to a carbon-carbon double bond reduction reaction to produce a compound represented by the formula (II-3).
And 4, step 4: the compound represented by the formula (II-3) is deprotected to produce a compound represented by the formula (II-4).
And 5: the compound represented by the formula (II-4) and the compound 1-formylcyclopropylcarbamic acid tert-butyl ester 2a are subjected to reductive amination reaction to prepare a compound represented by the formula (II-5).
And 6: the compound represented by the formula (II-5) is deprotected to produce a compound represented by the formula (II-6).
And 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 are subjected to an amidation reaction to obtain the compound represented by the formula (II-7).
Reaction scheme (III)
(in each of the formulae of the above schemes, all symbols are as defined above, and X is halogen.)
Specifically, the compound represented by the formula (III-8) can be produced by the following method:
step 1: the compound represented by the formula (III-1) is prepared by carrying out Suzuki coupling reaction on the corresponding compound represented by the formula (I-1) and 1-ethoxycarbonylcyclohex-3-ene-4-boronic acid pinacol ester.
Step 2: the compound represented by the formula (III-1) is subjected to a carbon-carbon double bond reduction reaction to produce a compound represented by the formula (III-2).
And step 3: the compound represented by the formula (III-2) is subjected to an ester reduction reaction to produce a compound represented by the formula (III-3).
And 4, step 4: the compound represented by the formula (III-3) is subjected to an oxidation reaction to produce a compound represented by the formula (III-4).
And 5: the compound represented by the formula (III-4) and a phosphorus ylide reagent are subjected to a Wittig reaction to prepare a compound represented by the formula (III-5).
Step 6: the compound represented by the formula (III-5) is subjected to a Corey-Chaykovsky reaction to obtain a compound represented by the formula (III-6).
And 7: the compound represented by the formula (III-6) is subjected to an ester hydrolysis reaction to produce a compound represented by the formula (III-7).
And 8: a compound represented by the formula (III-7) and a compound represented by the formula A-NH 2 The compound represented by the formula (III-8) is obtained by amidation of the compound represented by the formula (III-8).
Reaction scheme (IV)
(in each of the above schemes, all symbols are as described above.)
Specifically, the compound represented by the formula (IV-3) can be prepared by the following method:
step 1: carrying out Curtius rearrangement reaction on the compound represented by the formula (III-4) to obtain the compound represented by the formula (IV-1).
And 2, step: the compound represented by the formula (IV-1) is subjected to an amino deprotection reaction to obtain a compound represented by the formula (IV-2).
And 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 produce the compound represented by the formula (IV-3).
The Suzuki coupling reaction is known and may be. In a solvent (e.g., 1,4-dioxane, THF or a mixed solvent of 1,4-dioxane and water, etc.), a palladium catalyst (Pd (OAc) is used in the presence of a base (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.) 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]The decyl-7-ene-8-boronic acid pinacol ester and the halogenated aromatic hydrocarbon are subjected to cross coupling.
The amidation reaction is known and may be. For example, a condensing agent (e.g., HATU, 1,3-Dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl) carbodiimide (DCC), in the presence of a base (e.g., DIEA, TEA, dimethylaniline, dimethylaminopyridine, etc.), in an organic solvent (e.g., DMSO, DCM, DMF, THF, etc.) or in the absence of a solvent, at about 0 deg.C to reflux temperature]Carbodiimide (EDC), N' -Carbonyldiimidazole (CDI) or 1-propylphosphoric anhydride (T) 3 P), etc.) by reacting a carboxylic acid or acid chloride with an amine, with or without 1-Hydroxybenzotriazole (HOBT).
The double bond reduction is known and may be. The carbon-carbon double bond is reduced with a reducing agent (e.g., hydrogen) using a catalyst (e.g., pd/C) in an organic solvent (e.g., EA or THF, etc.).
The carbonyl deprotection reaction is known and may be. The ketal is converted to the corresponding carbonyl compound by decarbonylation of the protecting group using an acid catalyst (e.g., TFA, acetic acid, hydrochloric acid, p-toluenesulfonic acid, or the like) in a solvent (e.g., DCM, a mixed solvent of THF and water, THF, or a mixed solvent of ethanol and water, or the like).
The amino deprotection reaction is known and may be. The ketal is converted to the corresponding carbonyl compound by decarbonylation of the protecting group using an acid catalyst (e.g., TFA) in an organic solvent (e.g., DCM, EA, or 1,4-dioxane, etc.).
The ester hydrolysis reaction is known and may be. The ester is hydrolytically converted to the corresponding acid using an acid catalyst (such as TFA or hydrochloric acid) in an organic solvent (such as DCM, THF, EA, or 1,4-dioxane, etc.).
The Wittig reaction is known and may be. The carbonyl group is reacted with a phosphonium ylide reagent (e.g., t-butyl dimethoxyphosphonoacetate or diethyl cyanomethylphosphonate, etc.) in an organic solvent (e.g., THF or 1,4-dioxane, etc.) using a catalyst (e.g., sodium hydride, etc.) to form the alkene.
The Miyaura boronation reaction is known and may be. In an organic solvent (e.g., 1,4-dioxane, etc.) in the presence of a base (e.g., potassium acetate, etc.), a palladium catalyst (Pd (dppf) Cl) is used 2 Etc.), the halogenated aromatic hydrocarbon and the pinacol ester diborate undergo a Miyaura boronation reaction.
The ester reduction reaction is known and may be. The ester is reduced to the alcohol using a reducing agent such as lithium aluminum hydride in an organic solvent such as THF or the like.
The oxidation reaction is known and may be. An oxidizing agent (e.g., 2-iodoxybenzoic acid) is used to oxidize the alcohol to an aldehyde in an organic solvent (e.g., EA, etc.).
The Corey-Chaykovsky reaction is known and may be. In an organic solvent (e.g., DMSO, etc.), a catalyst (e.g., pd (OAc)) is used 2 Ethyl zinc iodide or sodium hydride, etc.) from a methylating agent (diazomethane, trimethyl sulfoxide iodide or diiodomethane) and an olefin to form a cyclopropane ring.
The Curtius rearrangement reaction is known and can be. In an organic solvent (such as toluene and the like), in the presence of a base (such as triethylamine and the like), a carboxyl group reacts with diphenylphosphorylazide to rearrange to a primary amine, and the primary amine reacts with t-butanol to form an amine protected by a Boc (t-butyloxycarbonyl) group.
The grignard reaction is known and can be. The cyano group is reacted with a grignard reagent (e.g., ethylmagnesium bromide) in an organic solvent (e.g., THF, diethyl ether, etc.) under the presence of a catalyst (e.g., tetraisopropyl titanate) using a lewis acid (e.g., boron trifluoride diethyl etherate).
The reductive amination is known and can be. In an organic solvent (such as DCM, EA or THF, etc.), in the presence of a catalyst (such as Pd/C) or without a catalyst, using reductionAgents (e.g. Hydrogen, naBH (OAc) 3 ) In the case of (2), a reductive amination reaction of the secondary amine with the compound tert-butyl 1-formylcyclopropylcarbamate 2a forms a C-N 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 which has been protected as necessary by a protecting group commonly used for the group, and after the reaction process by the above reaction scheme, a known deprotection reaction can be performed.
The compounds represented by the formula (I) other than the above-mentioned compounds can be prepared by combining the examples described in the present specification or combining known methods.
The main advantages of the present invention compared to the prior art are better IDO inhibitory activity and lower toxicity.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Unless otherwise indicated, percentages and parts are by weight. As used herein, room temperature means about 20-25 ℃.
As used herein, THF is tetrahydrofuran, EA is ethyl acetate, PE is petroleum ether, DCM is dichloromethane, pd (dppf) Cl 2 Is 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, pd/C as a palladium-carbon catalyst, liHMDS as lithium bis (trimethylsilyl) amide, dess-Martin reagent as (1,1,1-triacetoxy) -1,1-dihydro-1,2-phenyliodoxy-3 (1H) -one, HATU as 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, acOK as potassium acetate, DMF as dimethylformamide, CDCl 3 Is deuterated chloroform, DMSO is dimethyl sulfoxide, DMSO-d 6 Deuterated dimethyl sulfoxide, dioxane is 1,4-dioxane, naBH (OAc) 3 Is sodium triacetoxyborohydride, acOH is acetic acid, DIEA is N, N-diisopropylethylamine, TEA is triethylamine,
preparation of 4- (trifluoromethylsulfonyloxy) -5,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (1 a)
Dissolving 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0g, 10.04mmol) in 40ml tetrahydrofuran, cooling to-78 ℃ under the protection of argon, slowly dropwise adding LiHMDS (12ml, 12.05mmol) into the reaction solution, stirring for 30 minutes at-78 ℃ after dropwise adding, dissolving a compound M1 (4.30g, 12.05mmol) in the tetrahydrofuran solution, slowly dropwise adding the compound M1 into the reaction solution, continuously stirring for 1 hour at-78 ℃, slowly and naturally heating to room temperature, and stirring overnight. The LC-MS detection reaction is complete. The reaction mixture was poured into an ice-water mixture, extracted with ethyl acetate (100ml. Multidot.2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated and purified by a silica gel column to obtain compound 1a (1.60 g, yield 51.12%). MS (ESI) 276.0[ 2 ], [ M ] +H-56] + 。
Preparation of tert-butyl 1-formylcyclopropylcarbamate (2 a)
Compound 1- (hydroxymethyl) cyclopropyl carbamic acid tert-butyl ester (520mg, 2.78mmol) is added to 10ml dichloromethane and cooled to 0 ℃ under argon shield, dess-Martin reagent (1.53g, 3.61mmol) is added, and the reaction is stirred at room temperature overnight. The LC-MS detection reaction is complete. The reaction mixture was filtered, concentrated under reduced pressure and dried, and then separated and purified by a silica gel column to give the compound tert-butyl 1-formylcyclopropylcarbamate 2a (500 mg, yield 97.28%). MS (ESI) 130.0[ 2 ] M + H-56] + 。
Preparation of 6-chloronicotinoyl chloride (3 a)
6-Chloronicotinic acid (314mg, 2mmol) was dissolved in dichloromethane (10 mL), the temperature in the reaction solution was then lowered to 0 deg.C, oxalyl chloride (756mg, 5mmol) was added dropwise, then 1 drop of DMF was added, the reaction solution was stirred at room temperature for 1 hour, and evaporated to dryness under reduced pressure to give Compound 3a (314 m g, 92% yield), which was used in the next reaction without purification.
Preparation of 1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropane-1-amine (4 a)
6.3g of compounds 1-7 were prepared using Waters-SunFire Prep 19 x 250mm by the following conditions to give 0.95g of compound 4a, mobile phase: a: acetonitrile, B: water +0.045% formic acid, wavelength: 214/254nm, gradient: 10-22, number of needles: 29.
example 1: preparation of two isomers (J-1-1 and J-1-2) of 4-cyano-N- (1- ((4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-1)
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, pd (dppf) Cl is added under the protection of argon 2 (403mg, 0.551mmol), stirring and heating to 110 ℃ for reaction for 5 hours, and detecting the reaction completion by LC-MS. The reaction mixture was filtered, spun-dried, and separated and purified by a silica gel column to obtain Compound 1-2 (1.3 g, purity: 100%, yield 83.33%). MS (ESI) 286.1[ deg. ] M + H ]] + 。
And 2, step: compound 1-2 (1.3 g, 4.56mmol) was added to 30ml of ethyl acetate, pd/C150 mg was added, and the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight. The LC-MS detection reaction is complete. The reaction mixture was filtered, concentrated under reduced pressure and dried to obtain Compound 1-3 (1.0 g, purity: 95.17%, yield 76.92%). MS (ESI) 288.1[ deg. ] M + H ]] + 。
And step 3: compound 1-3 (1.0 g, 3.48mmol) was added to trifluoroacetic acid 3.0ml in 20ml of dichloromethane with stirring at room temperature, the reaction solution was stirred overnight at room temperature, and the reaction was checked by LC-MS for completion. Concentrating the reaction solution under reduced pressure, adding saturated sodium bicarbonate 100ml, extracting with ethyl acetate (50ml. Times.2), drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtainTo compounds 1-4 (0.7 g, purity: 97.01%, yield 82.68%). MS (ESI) 244.1[ 2 ], [ M ] +H] + 。
And 4, step 4: diethyl cyanomethylphosphonate (1.09g, 6.17mmol) was added to 20ml of tetrahydrofuran, the temperature was reduced to 0 ℃ under argon, sodium hydrogen (247mg, 6.17mmol) was slowly added, the reaction mixture was stirred at 0 ℃ for 20 minutes, and compound 1-4 (1.0g, 4.11mmol) was slowly added dropwise (compound 1-4 was dissolved in 3ml of tetrahydrofuran solution). The reaction mixture was stirred at 0 ℃ for 30 minutes, then slowly warmed to room temperature and stirred for 3 hours. The LC-MS detection reaction is complete. The reaction mixture was added to an ice-water mixture, extracted with ethyl acetate (100ml. Multidot.2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to separation and purification on a silica gel column to obtain compounds 1 to 5 (720 mg, purity: 99.00%, yield 66.05%). MS (ESI) 267.1[ deg. ] M + H ]] + 。
And 5: the compound 1-5 (2.5g, 2.71mmol) was dissolved in 20ml of ethyl acetate, palladium on carbon (200 mg) was added, the reaction solution was stirred overnight at room temperature under protection of hydrogen gas, and the completion of the reaction was detected by LC-MS. Filtering the reaction solution, and concentrating under reduced pressure to obtain the compounds 1-6. (700 mg, purity: 100%, yield 96.50%). MS (ESI) 269.1[ alpha ] M + H ], [ beta ] C] + 。
Step 6: compound 1-6 (1.67g, 6.22mmol) was dissolved in 40ml of tetrahydrofuran, cooled to-78 ℃ under argon, tetraisopropyl titanate (1.95g, 6.85mmol) was added dropwise, ethyl magnesium bromide (4.56ml, 13.69mmol) was added subsequently, the reaction mixture was stirred at-78 ℃ for 1 hour, slowly warmed to room temperature, and stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ℃ again, boron trifluoride diethyl etherate (1.94g, 13.69mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to 100ml of ice water, stirred for 30 minutes, and then saturated Na was added 2 CO 3 The solution (100 ml) was extracted with ethyl acetate (100ml. Multidot.4), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to separation and purification on a silica gel column to obtain compounds 1 to 7 (700 mg, purity: 94%, yield 37.69%). MS (ESI) 299.2[ deg. ] M + H ]] + 。
And 7: compound 1-7 (640mg, 2.14mmol), 4-cyanobenzoic acid (631mg, 4.29mmol) were dissolved in 20ml of DMF, and HATU (1.63g, 4.29mmol) was added thereto under stirring at room temperature, followed by addition of diisopropyl groupEthylamine (0.832g, 6.43mmol), the reaction solution was stirred at room temperature for 2 hours and the reaction was checked by LC-MS to be complete. The reaction mixture was added to 100ml of water, extracted with ethyl acetate (50ml. Times.2), dried over anhydrous sodium sulfate, and concentrated to give a crude product which was purified by high performance liquid separation (Waters-SunAire Prep 19. Times.250mm, mobile phase: A: acetonitrile, B: water +0.045% formic acid, wavelength: 214/254nm, gradient: 10-22, needle number: 29) to give 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%). MS (ESI) 428.2[ deg. ] M + H ]] + 。 1 H 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-cyano-N- (1- (((1r, 4r) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide J-1-2.MS (ESI) 428.2[ 2 ] M + H] + 。 1 H 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).
Example 2: preparation of N- (4-chlorophenyl) -2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) cyclopropanecarboxamide (J-2, diastereomer 1, having both cis and trans configurations)
Example 3: preparation of N- (4-chlorophenyl) -2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) cyclopropanecarboxamide (J-3, diastereomer 2, having both cis and trans configurations)
Step 1: ethyl 4-Cyclohexanonate formate 2-1 (40g, 240mmol) and 2,6-di-tert-butyl-4-methylpyridine (50g, 260mmol) were dissolved in dichloromethane (700 mL), the internal temperature of the reaction solution was lowered to 0 ℃ and trifluoromethanesulfonic anhydride (73g, 260mmol) in dichloromethane was added dropwise(100 mL), after completion of the dropwise addition, the reaction mixture was stirred at 38 ℃ for 4 hours, water (200 mL) was added, extraction was performed with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to dryness, and compound 2-2 was obtained as an oil by column chromatography (52 g, yield 71%). MS (ESI) 302.1[ deg. ] M + H ]] + 。
And 2, step: compound 2-2 (51g, 170mmol), potassium acetate (50g, 510mmol), pinacol diboron ester (48g, 190mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (5g, 6 mmol) were added to dimethyl sulfoxide (300 mL), and then the reaction was heated to 90 ℃ under nitrogen and stirred for 6 hours. After the reaction was completed, the reaction solution was filtered, water (1500 mL) was added to the filtrate, extraction was performed with ethyl acetate, the organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and a crude product 2-3 (47 g) was obtained as a pale yellow oil by column chromatography, and the product was used in the next reaction without purification.
And step 3: compounds 2-3 (15.0g, 54mmol), 4-chloro-6-fluoroquinoline (9.7g, 54mmol), anhydrous sodium carbonate (17.0g, 161mmol), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (2.3g, 3mmol) was added to a solution of a mixture of dioxane (200 mL) and water (40 mL), and the reaction was heated to 110 ℃ and stirred under nitrogen for 6 hours. After the reaction was completed, the reaction solution was filtered, water (500 mL) was added to the filtrate, extraction was performed with ethyl acetate, organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and an oily product, ethyl 4- (6-fluoroquinolin-4-yl) cyclohexyl-3-ene-1-carboxylate 2-4 (11 g, yield 69%) was obtained by column chromatography. MS (ESI) 300.0[ deg. ] M + H ]] + 。
And 4, step 4: ethyl 4- (6-fluoroquinolin-4-yl) cyclohexyl-3-en-1-carboxylate 2-4 (21.0g, 70mmol) and palladium on charcoal (10%, 50% w/w,4.2 g) were added to anhydrous tetrahydrofuran (300 mL) and stirred under hydrogen for 16 hours to complete the reaction of the starting materials, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to dryness to give crude ethyl 4- (6-fluoroquinolin-4-yl) cyclohexyl-1-carboxylate 2-5 (19.7 g). MS (ESI) 302.2[ deg. ] M + H ]] + 。
And 5: lithium aluminum hydride (2.9g, 76mmo)l) is added into tetrahydrofuran (300 mL) at the temperature of minus 30 ℃, then tetrahydrofuran (50 mL) solution of 4- (6-fluoroquinolin-4-yl) cyclohexyl-1-ethyl formate 2-5 (11.5 g, 70mmol) is dripped into the reaction solution, the reaction temperature is controlled not to exceed minus 20 ℃, the stirring is carried out for 2 hours, the raw materials are completely reacted, then sodium sulfate decahydrate is added in batches until no obvious bubbles are generated, the stirring is carried out for 1 hour at the room temperature, the filtration is carried out, the filtrate is decompressed and evaporated to dryness to obtain oily crude product (4- (6-fluoroquinolin-4-yl) cyclohexyl) methanol 2-6 (7.9 g), and the product is directly used for the next reaction without purification. MS (ESI) 260.1[ 2 ], [ M ] +H] + 。
Step 6: a solution of (4- (6-fluoroquinolin-4-yl) cyclohexyl) methanol 2-6 (7.9g, 31mmol) and 2-iodoxybenzoic acid (25.6g, 92mmol) in ethyl acetate (300 mL) was heated under reflux for 16 hours, then the reaction mixture was filtered, the filtrate was evaporated under reduced pressure to dryness, and the product 4- (6-fluoroquinolin-4-yl) cyclohexyl-1-carbaldehyde 2-7 (6.7 g, 85% yield) was obtained as an oily product by column chromatography. MS (ESI) 258.1[ deg. ] M + H ] +] + 。
And 7: sodium hydride (60%, 480mg, 12mmol) was added to tetrahydrofuran (70 mL), a solution of dimethoxyphosphonoacetic acid tert-butyl ester (2.69g, 12mmol) in tetrahydrofuran (10 mL) was added dropwise thereto, the reaction was carried out at room temperature for 10 minutes, a solution of 4- (6-fluoroquinolin-4-yl) cyclohexyl-1-carbaldehyde 2-7 (2.57g, 10mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture, the reaction was stirred overnight, the reaction mixture was poured into a saturated aqueous ammonium chloride solution after completion of the reaction, extraction was carried out with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the filtrate was evaporated under reduced pressure, and an oily product, i.e., tert-butyl 3- (4- (6-fluoroquinolin-4-yl) cyclohexyl) acrylate 2-8 (2.8 g, yield 79%, was obtained by column chromatography. MS (ESI) 356.2[ 2 ], [ M ] +H] + 。
And step 8: sodium hydride (60%, 5632 mg, 14mmol) was added to dimethyl sulfoxide (100 mL), trimethyl sulfoxide iodide (3.10g, 14mmol) was added thereto at room temperature and stirred for 1 hour, and then a solution of tert-butyl 3- (4- (6-fluoroquinolin-4-yl) cyclohexyl) acrylate 2-8 (2.50g, 7mmol) in dimethyl sulfoxide (40 mL) was dropped to the reaction solution and stirred at room temperature for 16 hours. After the reaction of the raw materials is finished, pouring the reaction solution into water (500 mL), extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering the filtrate, evaporating to dryness under reduced pressure, and passing through a column layerThe product, tert-butyl 2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) cyclopropane-1-carboxylate, was isolated as an oil (457 mg, yield 17%). MS (ESI) 370.2[ deg. ] M + H ]] + 。
And step 9: 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) cyclopropane-1-carboxylic acid tert-butyl ester 2-9 (457mg, 1.24mmol) was added to dichloromethane (5 mL), trifluoroacetic acid (4 mL) was slowly added thereto at room temperature and stirred for 1 hour, and after completion of the reaction of the starting materials, the reaction solution was concentrated to dryness under reduced pressure to give a crude solid product, 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) cyclopropane-1-carboxylic acid 2-10 (612 mg), which was used in the next reaction without purification. MS (ESI) 314.2[ 2 ], [ M ] +H] + 。
Step 10: 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) were added to dimethylsulfoxide (6 mL), HATU (182mg, 0.48mmol) was then added at room temperature and stirred for 1 hour, the reaction was completed, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the filtrate was evaporated to dryness under reduced pressure, and a solid product, diastereomer 1 (J-2, containing two forms of trans and 2.78%) of N- (4-chlorophenyl) -2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) cyclopropane-1-carboxamide was prepared by high performance liquid phase (Waters-SunAire Prep 19 x 250mm, mobile phase: A: acetonitrile, B: water +0.045% formic acid, wavelength: 214/254nm, gradient: 48-68) to yield, respectively. MS (ESI) 423.2[ 2 ] M + H] + ； 1 H 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＝4.6Hz,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).
Diastereomer 2 (J-3, both cis and trans configurations) (22.30 mg, 17% yield). MS (ESI) 423.2[ 2 ] M + H] + ； 1 H 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).
Example 4: preparation of 4-chloro-N- (2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) cyclopropyl) benzamide (J-4)
Step 1: 2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) cyclopropane-1-carboxylic acid 2-10 (370mg, 1.18mmol), diphenylphosphorylazide (650mg, 2.36mmol), and triethylamine (716mg, 7.09mmol) were added to a mixed solution of t-butanol (7 mL) and toluene (10 mL) and heated at reflux for 48 hours. After the reaction of the raw materials was completed, the reaction solution was evaporated to dryness under reduced pressure, water was added, extraction was performed with ethyl acetate, organic phases were combined, dried over anhydrous sodium sulfate, filtered filtrate was evaporated to dryness under reduced pressure, and an oily product (tert-butyl 2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) cyclopropane) carbamate 4-1 (120 mg, yield 26%) was obtained by column chromatography. MS (ESI) 385.2[ alpha ] M + H] + 。
Step 2: (2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) cyclopropane) carbamic acid tert-butyl ester 4-1 (120mg, 0.31mmol) was added to dichloromethane (5 mL), trifluoroacetic acid (3 mL) was slowly added at room temperature and stirred for 2 hours, and after completion of the starting material reaction, the reaction solution was concentrated under reduced pressure to dryness to give a solid crude product, 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) cyclopropane-1-amine 4-2 (139 mg), which was used in the next reaction without purification. MS (ESI) 285.2[ m ] +H] + 。
And 3, step 3: 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 (5 mL), HATU (100mg, 0.26mmol) was then added at room temperature and stirred for 2 hours, the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the filtrate was evaporated to dryness under reduced pressure, and an isomer mixture J-4 (22 mg),yield 30%). MS (ESI) 423.2[ 2 ] M + H] + ； 1 H 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).
Example 5: preparation of 4-cyano-N- (1- ((4- (6-fluoroquinolin-4-yl) piperidin-1-yl) methyl) cyclopropyl) benzamide (J-5)
Step 1: 4-chloro-6-fluoroquinoline 5-1 (5.0g, 27.53mmol), pinacol diboron ester (14.0g, 55.07mmol) and AcOK (5.4g, 55.07mmol) were added with Pd (dppf) Cl in 200ml of dioxane under the protection of argon 2 (1.0 g, 1.38mmol), the reaction mixture was heated to 90 ℃ and reacted for 4 hours, and LC-MS checked that the reaction was complete. The reaction mixture was poured into a large volume of water, extracted with ethyl acetate (150ml. Times.2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated and purified by a silica gel column to give 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%). MS (ESI) 192.0[ m ] +H-82] + 。
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, pd (dppf) Cl under argon protection 2 (134mg,0.183mmol)，K 2 CO 3 (649mg, 3.66mmol). The reaction solution is heated to 95 ℃ for reaction for 4 hours, and the LC-MS detects that the reaction is complete. The reaction mixture was poured into water, extracted with ethyl acetate (50ml. Times.2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to separation and purification on a silica gel column to obtain 4- (6-fluoroquinolin-4-yl) -5,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 5-3 (400 mg, purity: 97.95%, yield: 66.67%). MS (ESI) 329[ m ] +H] + 。
And 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, palladium on carbon (200 mg) was added, the reaction mixture was stirred at room temperature for 6 hours under hydrogen protection, and the completion of the reaction was detected by LC-MS. The reaction mixture was filtered, and concentrated under pressure to dryness to give 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] + 。
And 4, step 4:4- (6-Fluoroquinolin-4-yl) piperidine-1-carboxylic acid tert-butyl ester 5-4 (400mg, 1.21mmol) was dissolved in 2.5ml dichloromethane, 2.5ml 4M hydrochloric acid/dioxane was added, stirring was carried out at room temperature for 1 hour, LC-MS showed that the starting material remained, 2.0ml methanol was added to the reaction mixture, stirring was continued for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and then saturated Na was added thereto 2 CO 3 The solution (100 ml) was extracted with ethyl acetate (50ml. Multidot.4), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6-fluoro-4- (piperidin-4-yl) quinoline 5-5 (270 mg, purity: 90%, yield: 96.77%). MS (ESI) 400.0[ 2 ], [ M ] +H-56] + 。
And 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 (OAc) was added with stirring at room temperature 3 (663mg, 3.13mmol), then AcOH (0.5 ml) was added, the reaction was stirred overnight at room temperature, and the completion of the reaction was checked by LC-MS. The reaction solution was added to saturated NaHCO 3 The solution was extracted with ethyl acetate (50ml. Times.2), dried over anhydrous sodium sulfate, and concentrated to give a crude product which was subjected to high performance liquid chromatography to give tert-butyl 1- ((4- (6-fluoroquinolin-4-yl) piperidin-1-yl) methyl) cyclopropylcarbamate 5-6 (200 mg, purity: 67.29%, yield: 48.08%). MS (ESI) 300.0[ deg. ] M + H ]] + 。
Step 6: tert-butyl 1- ((4- (6-fluoroquinolin-4-yl) piperidin-1-yl) methyl) cyclopropylcarbamate 5-6 (200mg, 0.501mmol) was dissolved in a mixed solvent of 2.0ml of methylene chloride and 2.0ml of methanol, 2.5ml of 4M hydrochloric acid/dioxane was added, and the mixture was stirred at room temperature overnight and the reaction was detected by LC-MS to be complete. The reaction solution was concentrated under reduced pressure to dryness to give 1- ((4- (6-fluoroquinolin-4-yl) piperidin-1-yl) methyl) cyclopropylamine hydrochloride 5-7 (200 mg,purity: 90%, yield: 100%). MS (ESI) 429.0[ 2 ], [ M ] +H] + 。
And 7:1- ((4- (6-Fluoroquinolin-4-yl) piperidin-1-yl) methyl) cyclopropylamine hydrochloride 5-7 (100mg, 0.315mmol), 4-cyanobenzoic acid (93mg, 0.629mmol) were dissolved in 5ml of DMF, HATU (239g, 0.629mmol) was added with stirring at room temperature, diisopropylethylamine (203g, 1.57mmol) was then added, the reaction solution was stirred at room temperature for 2 hours, and the reaction was checked by LC-MS for completion. The reaction mixture was added to 100ml of water, extracted with ethyl acetate (50ml. Times.2), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was subjected to high performance liquid phase separation and purification to give Compound J-5 (35 mg, purity: 100%, yield: 25.73%). MS (ESI) 429.2[ deg. ] M + H ]] + 。 1 H 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)。
Example 6: preparation of two isomers (J-6-1 and J-6-2) of 4-chloro-N- (1- ((4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-6)
Compound J-6 was prepared by reference to compound J-1, except that the 4-cyanobenzoic acid in step 7 was replaced with 4-chlorobenzoic acid. Compound J-6 was isolated by high performance liquid chromatography (Waters-SunAire Prep 19 × 250mm, mobile phase: A: acetonitrile, B: water +0.045% formic acid, wavelength: 214/254nm, gradient: 10-22, needle number: 29) to give 4-chloro-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide J-6-1.MS (ESI) 437.2[ deg. ] M + H ]] + 。 1 H 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-chloro-N- (1- (((1 r,4 r) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide J-6-2.MS (ESI) 437.2[ deg. ] M + H ]] + 。 1 H 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).
Example 7: preparation of two isomers (J-7-1 and J-7-2) of 4-fluoro-N- (1- ((4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-7)
Compound J-7 was prepared by referring to compound J-1, except that 4-cyanobenzoic acid in step 7 was changed to 4-fluorobenzoic acid. Compound J-7 was isolated by high performance liquid chromatography (Waters-SunAire Prep 19 × 250mm, mobile phase: A: acetonitrile, B: water +0.045% formic acid, wavelength: 214/254nm, gradient: 10-22, needle number: 29) to give 4-fluoro-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide J-7-1.MS (ESI) 421.2[ deg. ] M + H ]] + 。 1 H NMR(400MHz,DMSO-d 6 ) δ 8.76 (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). To obtain 4-fluoro-N- (1- (((1r, 4r) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide J-7-2, MS (ESI) 421.2[ m + h ] +] + 。
Example 8: preparation of N- (1- ((4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) -6-vinylnicotinamide (J-8)
Step 1: mixing the compounds 1-7 (11)0mg, 0.37mmol) and triethylamine (112mg, 1.11mmol) were added to methylene chloride (10 mL), and then compound 3a (130mg, 0.74mmol) was added dropwise under nitrogen. After the reaction was completed, dichloromethane and water were added for extraction, the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and the white product, 6-chloro-N- (1- ((4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) nicotinamide 8-1 (80 mg, yield 60%), was obtained by column chromatography. MS (ESI) 439.0[ 2 ], [ M ] +H] + 。
Step 2: compounds 8-1 (70mg, 0.14mmol), potassium vinylfluoroborate (210mg, 1.4mmol), cesium carbonate anhydrous (140mg, 0.42mmol), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (12mg, 0.014mmol) was added to a mixture solution of tetrahydrofuran (5 mL) and water (2 mL), and then reacted at 100 ℃ for half an hour under nitrogen by microwave. After completion of the reaction, the reaction solution was filtered, water (20 mL) was added to the filtrate, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain N- (1- ((4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) -6-vinylnicotinamide isomer mixture J-8 (3 g, yield 5%) by HPLC. MS (ESI) 430.1[ deg. ] M + H ]] + ； 1 H 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).
Example 9: preparation of two isomers (J-9-1 and J-9-2) of N- (1- ((4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) -2-vinylpyrimidine-5-carboxamide (J-9)
Step 1: dissolving 2-chloropyrimidine-5-carboxylic acid (316mg, 2mmol) in dichloromethane (10 mL), then cooling the temperature in the reaction solution to 0 ℃, dropwise adding oxalyl chloride (756mg, 5mmol), then adding 1 drop of DMF, stirring the reaction solution at room temperature for 1 hour, and evaporating under reduced pressure to dryness to obtain a product, namely 2-chloropyrimidine-5-carbonyl chloride (320 mg), wherein the product is directly used for the next reaction without purification.
And 2, step: compound 1-7 (180mg, 0.6mmol) and triethylamine (181mg, 1.8mmol) were added to dichloromethane (10 mL), and then compound 2-chloropyrimidine-5-carbonyl chloride (218mg, 1.2mmol) was added dropwise under nitrogen. After completion of the reaction, dichloromethane and water were added for extraction, the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and a white product, 2-chloro-N- (1- ((4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) pyrimidine-5-carboxamide 9-1, was obtained by column chromatography (160 mg, yield 58%). MS (ESI) 439.0[ m ] +H] + 。
And step 3: compounds No. 9-1 (150mg, 0.34mmol), potassium vinylfluoroborate (455mg, 3.4mmol), cesium carbonate anhydrous (1108mg, 3.4mmol), and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (25mg, 0.034mmol) was added to a solution of a mixture of tetrahydrofuran (10 mL) and water (2 mL) and then reacted under nitrogen at 100 ℃ for half an hour with a microwave. After completion of the reaction, the reaction solution was filtered, water (20 mL) was added to the filtrate, extraction was performed with ethyl acetate, the organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) -2-vinylpyrimidine-5-carboxamide J-9-1 (7 mg, yield 1.5%) as a white solid by HPLC (Waters-SunAire Prep 19X 250mm, mobile phase: A: acetonitrile, B: water +0.045% formic acid, wavelength: 214/254nm, gradient: 10-22, needle number: 29). MS (ESI) 431.2[ deg. ] M + H ]] + ； 1 H 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)。
And N- (1- (((1r, 4r) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) -2-vinylpyrimidine-5-carboxamide J-9-2(3mg)。MS(ESI)431.2[M+H] + ； 1 H 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).
Example 10: preparation of N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-10)
Preparation method referring to step 7 of example 1, except for changing compounds 1-7 and 4-cyanobenzoic acid in step 7 to compound 4a and benzoic acid, respectively, N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-10) was obtained. MS (ESI) 403.2[ deg. ] M + H ]]+； 1 H 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)。
Example 11: preparation of 4-fluoro-N- (1- ((4- (6-fluorocinnolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-11)
4-chloro-6-fluorocinnoline as a starting material was prepared in accordance with the method for the compound J-7 to obtain a compound J-11.MS (ESI) 422.2[ deg. ] M + H ]] + 。
Example 12: preparation of 2,4-difluoro-N- (1- (((1s, 4s) -4- (6-fluorocinnolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-12)
The preparation method was referenced to step 7 of example 1, except that the compounds 1 to 7 and 4-cyanobenzoic acid in step 7 were changed to the compounds 4a and 2,4-difluorobenzoic acid, respectively. 2,4-difluoro-N- (1- (((1s, 4s) -4- (6-fluorocinnolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-12) was obtained. MS (ESI) 439.2[ alpha ], [ M ] +H] + ； 1 H 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)。
Example 13: preparation of 3,4-difluoro-N- (1- (((1s, 4s) -4- (6-fluorocinnolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-13)
Preparation method referring to step 7 of example 1, except that the compounds 1-7 and 4-cyanobenzoic acid in step 7 were changed to the compounds 4a and 3,4-difluorobenzoic acid, respectively. 3,4-difluoro-N- (1- (((1s, 4s) -4- (6-fluorocinnolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-13) was obtained. MS (ESI) 439.2[ 2 ], [ M ] +H] + ； 1 H 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)。
Example 14: preparation of N- (1- (((1s, 4s) -4- (6-fluorocinnolin-4-yl) cyclohexyl) methyl) cyclopropyl) -6-methylnicotinamide (J-14)
The preparation method was referenced to step 7 of example 1, except that the compounds 1-7 and 4-cyanobenzoic acid in step 7 were changed to compound 4a and 6-methylpyridine-3-carboxylic acid, respectively. N- (1- (((1s, 4s) -4- (6-fluorocinnolin-4-yl) cyclohexyl) methyl) cyclopropyl) -6-methylnicotinamide (J-14) is obtained. MS (ESI) 418.2[ 2 ], [ M ] +H] + ； 1 H 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)。
Example 15: preparation of 3-chloro-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-15)
Preparation method reference was made to step 7 of example 1, except that compounds 1-7 and 4-cyanobenzoic acid in step 7 were replaced with compound 4a and 3-chlorobenzoic acid, respectively. To give 3-chloro-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-15). MS (ESI) 437.2[ deg. ] M + H ]] + ； 1 H 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)。
Example 16: preparation of 3-fluoro-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-16)
The preparation method was referenced to step 7 of example 1, except that the compounds 1-7 and 4-cyanobenzene in step 7 were usedThe formic acid was replaced with compound 4a and 3-fluorobenzoic acid, respectively. To give 3-fluoro-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-16). MS (ESI) 421.2[ deg. ] M + H ]] + ； 1 H 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)。
Example 17: preparation of 3-ethynyl-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-17)
The preparation method was conducted in accordance with step 7 of example 1, except that the compounds 1-7 and 4-cyanobenzoic acid in step 7 were changed to the compounds 4a and 3-ethynylbenzoic acid, respectively. To give 3-ethynyl-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-17). MS (ESI) 427.2[ 2 ], [ M ] +H] + ； 1 H 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)。
Example 18: preparation of 4-ethynyl-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-18)
The preparation method was conducted in accordance with step 7 of example 1, except that the compounds 1-7 and 4-cyanobenzoic acid in step 7 were changed to the compounds 4a and 4-ethynylbenzoic acid, respectively. To give 4-ethynyl-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide(J-18)。MS(ESI)427.2[M+H] + ； 1 H 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)。
Example 19: preparation of 3-cyano-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-19)
The preparation method was conducted in accordance with step 7 of example 1, except that the compounds 1-7 and 4-cyanobenzoic acid in step 7 were changed to the compounds 4a and 3-cyanobenzoic acid, respectively. To give 3-cyano-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) benzamide (J-19). MS (ESI) 428.2[ deg. ] M + H ]] + ； 1 H 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)。
Example 20: preparation of 6-ethynyl-N- (1- (((1s, 4s) -4- (6-fluoroquinolin-4-yl) cyclohexyl) methyl) cyclopropyl) nicotinamide (J-20)
The preparation method was referenced to step 7 of example 1, except that compounds 1-7 and 4-cyanobenzoic acid in step 7 were changed to 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. MS (ESI) 428.2[ deg. ] M + H ]] + ； 1 H 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)。
Test example 1 inhibitory Activity test of Hela cells
Reagent
HeLa cells were from ATCC; DMEM phenol-free red blood cell medium was from Gibco, product no: 21063-029; INF- γ from Life Technologies, product number: PHC4031 μ g; fetal bovine serum was from Gibco, product number: 10099-141;0.25% trypsin from GIBCO, product No.: 25200-072; phosphate Buffered Saline (PBS) was from Hyclone, product No.: SH30256.01B;6.1N trichloroacetic acid from Sigma, product number: t0699; p-dimethylaminobenzaldehyde (pDMAB) was from Sigma, product No.: 15647-7; l-tryptophan was from Sigma, product No.: T0254-25G; DMSO from Sigma, product No.: D5879-1L;96 well cell culture plates from BD Falcon, product No.: 353072.
reagent preparation
1.1 g pDMAB is dissolved in 50ml acetic acid (protected from light, ready for use);
2. preparing L-tryptophan with PBS to a concentration of 200 μ g/ml for later use;
3. preparing INF-gamma to 250ng/ml by using a phenol red-free culture medium for later use;
experimental procedure
1. The first day, 4E3 cells per well were seeded into cell culture plates with a volume of 70. Mu.l per well, and incubated in a cell incubator for 24 hours;
2. in the next day, 10ul of the compound to be detected with the concentration of 10X, 10ul of L-tryptophan and 10ul of INF-gamma are respectively added into each hole, the reaction concentration of DMSO is 0.5%, the reaction concentration of L-tryptophan is 20ug/ml, and the reaction concentration of INF-gamma is 25ng/ml;
3. placing the cell culture plate in a cell culture box for culturing for 48 hours;
4. on the fourth day, 70. Mu.l of the cell culture supernatant was added to another reaction plate, and 5ul of 6.1N trichloroacetic acid was added to each well, followed by reaction at 50 ℃ for 30 minutes;
5. the reaction plate was centrifuged at 2500rpm for 10 minutes, and 50. Mu.l of supernatant per well was transferred to a new reaction plate; adding 50 mul pDMAB (2%) and placing the mixture on a shaking table to shake the mixture evenly; absorbance at 480nm was read with a microplate reader and compound IC50 values were calculated using XLfit software. The test results are shown in table 1.
TABLE 1 inhibitory Activity of exemplary Compounds of the invention on Hela cells
| Compound numbering | Hela/nM | Compound numbering | 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 |
Test example 2 inhibition Activity test of HEK293-hIDO1 cells
Reagent
The HE293-hIDO1-7 stable transfected cell line is from TGZ0172; DMEM phenol-free red blood cell medium was from Gibco, product no: 21063-029; fetal bovine serum was from Gibco, product number: 10099-141;0.25% trypsin from Gibco, product No.: 25200-072; phosphate Buffered Saline (PBS) was from Hyclone, product No.: SH30256.01B;6.1N trichloroacetic acid from Sigma, product number: t0699; p-dimethylaminobenzaldehyde (pDMAB) from Sigma, product No.: 15647-7; l-tryptophan was from Sigma, product No.: T0254-25G; DMSO from Sigma, product No.: D5879-1L;96 well cell culture plates were from BD Falcon, product No.: 353072.
reagent preparation
1.1 g pDMAB is dissolved in 50ml acetic acid (protected from light, ready for use);
2. preparing L-tryptophan with PBS to a concentration of 200 μ g/ml for later use;
experimental procedure
1. The first day, 4E4 cells were seeded 293-hIDO1 cells per well in cell culture plates at a volume of 80ul per well;
2. 10ul of a compound to be detected with a concentration of 10X and 10 mul of L-tryptophan are added into each hole, the final concentration of DMSO is 0.5%, and the final concentration of L-tryptophan is 20 mug/ml;
3. placing the cell culture plate in a cell culture box for culturing for 48 hours;
4. on the third day, 70. Mu.l of the cell culture supernatant was added to another reaction plate, 5. Mu.l of 6.1N trichloroacetic acid was added to each well, and the mixture was allowed to react at 50 ℃ for 30 minutes;
5. the reaction plate was centrifuged at 2500rpm for 10 minutes, 50ul of supernatant per well was taken to a new reaction plate; adding 50ul pDMAB (2%) and placing the mixture in a shaking table to shake the mixture evenly; absorbance at 480nm was read with a microplate reader and compound IC50 values were calculated using XLfit software. The test results are shown in table 2.
TABLE 2 inhibitory Activity of exemplary Compounds of the invention on HEK-293 cells
| Compound numbering | HEK-293/nM | Compound number | 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 |
As can be seen from tables 1 and 2, the exemplified compounds of the present invention have superior inhibitory activity against Hela and HEK-293 cells.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.
Claims (20)
1. A compound of formula (I-b), or a pharmaceutically acceptable salt, or stereoisomer thereof:
in the formula (I), the compound is shown in the specification,
a is substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl; the "substitution" means that 1,2 or 3 hydrogen atoms in the group are substituted with substituents each independently selected from the group consisting of: cyano, trifluoromethyl, fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, vinyl, and ethynyl;
wherein the content of the first and second substances,
Z 1 is N; z is a linear or branched member 2 Is CR 02 ；Z 3 Is CR 03 ；Z 4 Is C; r is 02 、R 03 Each independently is hydrogen;
Z 5 is CR 7 ；R 4 、R 5 、R 6 、R 7 Each independently of the others is hydrogen, halogen, halogeno C 1-10 An alkyl group; wherein is halo C 1-10 The alkyl group in the alkyl group is unsubstituted;
L 1 is an NR 1 ；R 1 Is hydrogen;
L 2 is a bond;
E 1 、E 4 each independently is CR 3 ；R 3 Is hydrogen;
E 2 is (CR) 21 R 22 ) m ；
E 3 Is CR 31 R 32 ；
R 21 、R 22 、R 31 、R 32 Each independently is- (CH) 2 ) r -R 0 ；R 0 Is hydrogen;
m is 1;
r is 0;
R a 、R b each independently is hydrogen;
ring D is an unsubstituted 3 to 6 membered saturated monocyclic ring.
2. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, based on
The compound represented by the formula (I-b) comprises a mixture of trans and cis structures, or exists in the form of cis structure, or exists in the form of trans structure.
3. The compound of claim 2, or a pharmaceutically acceptable salt, or stereoisomer thereof, based on
The compound represented by the formula (I-b) exists in a cis-structure form.
4. The compound of claim 1, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein ring D is an unsubstituted 3-membered saturated monocyclic ring.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, orStereoisomers, characterised in that they are based on
The compound represented by the formula (I-b) comprises a mixture of trans and cis structures, or exists in the form of cis structure, or exists in the form of trans structure.
6. The compound of claim 5, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein the compound of formula (I-b) has the structure of formula (I-b-1):
7. the compound of claim 5, or a pharmaceutically acceptable salt, or stereoisomer thereof,
wherein, a pair of chemical bonds connected at the para position of cyclohexyl are respectively
And
or respectively is
And
8. the compound of any one of claims 4 to 7, or a pharmaceutically acceptable salt, or a stereoisomer thereof,
is composed of
9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein a is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the "substitution" means that 1,2 or 3 hydrogen atoms in the group are substituted with substituents each independently selected from the group consisting of: cyano, trifluoromethyl, fluoro, chloro, methyl, ethenyl and ethynyl.
10. The compound of claim 9, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein a is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the "substituted" means that 1 or 2 hydrogen atoms in the group are substituted with substituents each independently selected from the group consisting of: cyano, fluoro, chloro, methyl, ethenyl and ethynyl.
11. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R is 4 、R 5 、R 6 And R 7 Each independently is hydrogen, halogen or halogeno C 1-3 An alkyl group.
12. The compound, or a pharmaceutically acceptable salt, or a stereoisomer thereof, of claim 11, wherein R is 4 、R 5 、R 6 And R 7 Each independently hydrogen or halogen.
13. The compound of claim 12, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein R is 4 、R 5 、R 6 And R 7 Each independently of the other is hydrogen orAnd (4) fluorine.
14. The compound, or a pharmaceutically acceptable salt, or a stereoisomer thereof, of claim 13, wherein R is 4 、R 6 And R 7 Each independently is hydrogen; r 5 Is halogen.
15. The compound of claim 14, or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein the structure of formula (IA) is selected from any of the following:
16. a compound, or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is selected from any one of:
17. a compound, or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is selected from any one of:
18. a pharmaceutical composition comprising a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, or stereoisomer thereof; and a pharmaceutically acceptable carrier.
19. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for inhibiting the activity of indoleamine 2,3-dioxygenase or for inhibiting immunosuppression in a subject.
20. The use of claim 19, wherein the medicament is for treating or preventing cancer or a tumor, a viral infection, depression, a neurodegenerative disorder, trauma, age-related cataract, organ transplant rejection or an autoimmune disease in a patient.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019100416132 | 2019-01-16 | ||
| CN201910041613 | 2019-01-16 | ||
| PCT/CN2019/130744 WO2020147582A1 (en) | 2019-01-16 | 2019-12-31 | Amide derivative substituted by cycloalkyl, preparation method for amide derivative, and use in medicine |
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| Publication Number | Publication Date |
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| CN112384502A CN112384502A (en) | 2021-02-19 |
| CN112384502B true CN112384502B (en) | 2022-11-08 |
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| WO (1) | WO2020147582A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004041210A2 (en) * | 2002-11-05 | 2004-05-21 | Smithkline Beecham Corporation | Antibacterial agents |
| CN107207437A (en) * | 2015-01-30 | 2017-09-26 | 悉尼大学 | anticancer compound |
| 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 (en) * | 2014-11-05 | 2017-12-01 | 弗莱塞斯生物科学公司 | Immunomodulator |
-
2019
- 2019-12-31 WO PCT/CN2019/130744 patent/WO2020147582A1/en active Application Filing
- 2019-12-31 CN CN201980042108.8A patent/CN112384502B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004041210A2 (en) * | 2002-11-05 | 2004-05-21 | Smithkline Beecham Corporation | Antibacterial agents |
| CN107427499A (en) * | 2014-11-05 | 2017-12-01 | 弗莱塞斯生物科学公司 | Immunomodulator |
| CN107207437A (en) * | 2015-01-30 | 2017-09-26 | 悉尼大学 | anticancer compound |
| 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 |
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| Publication number | Publication date |
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| CN112384502A (en) | 2021-02-19 |
| WO2020147582A1 (en) | 2020-07-23 |
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