TW201736373A - Tricyclic compound acting as immunomodulator - Google Patents

Abstract

The present application relates to the compound of formula (I), or a pharmaceutically acceptable salt and pharmaceutical composition thereof, the compound of formula (I) or the pharmaceutically acceptable salt and pharmaceutical composition thereof having indole-2, 3-dioxygenase (IDO) inhibitory activity, and being able to treat immunosuppressive diseases mediated by indole-2, 3-dioxygenase (IDO), such as infectious diseases or cancer.

Description

Tri-cyclic compound as an immunomodulator

The present invention pertains to the field of medicine, and in particular to a tricyclic compound or a pharmaceutically acceptable salt thereof as an immunomodulator.

Tryptophan (Trp) is an amino acid essential for the biosynthesis of protein, niacin and neurotransmitter serotonin. Indoleamine 2,3-dioxygenase (also known as INDO or IDO) catalyzes the L-color The first rate-limiting step in the degradation of tyrosine to N-formin guanine. In human cells, IFN-y stimulation induces the initiation of IDO, leading to depletion of tryptophan, thereby preventing the growth of tryptophan-dependent cellular pathogens such as Toxoplasma gondii and Chlamydia trachomatis. The activity of IDO also has anti-proliferative effects on many tumor cells. In the process of rejection of allogeneic tumors, IDO induction in vivo has been found, indicating that this enzyme may play a role in tumor rejection.

Small molecule inhibitors of IDO can be developed to treat or prevent IDO-related diseases. For example, PCT Publication WO 99/29310 reports a method of altering T cell-mediated immunity, including the use of IDO inhibitors to alter the local extracellular concentration of tryptophan and tryptophan metabolites, such as 1-methyl. -DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3-benzo(b)thienyl]-DL-alanine and 6-nitro-L - tryptophan) (Munn, 1999). A method for preparing antigen presenting cells for increasing or decreasing T cell tolerance is also reported in WO 03/087347 (Munn, 2003). Compounds having indoleamine-2,3-dioxygenase (IDO) inhibitory activity are also reported in WO 2004/094409, WO 2009/073620, WO 2009/132238, WO 2011/056652 and WO 2012/142237. In particular, the compound of WO 2012/142237 comprises a series of trycyclic imidazoisoindoles having strong IDO inhibitory activity, including NLG-919, having the structural formula shown below:

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, Wherein D ^{41 is} selected from the group consisting of NH, N(OH), O, S, -NHC(=O)NH-, -NHC(=O)CH ₂ -, -NHC(=O)CH(CH ₃ )-, - NHC(=O)-, S(=O) and S(=O) ₂ ; R ^{41 is} selected from C _5-6 cycloalkyl, 5- to 12-membered heterocyclic ring optionally substituted by 1, 2 or 3 R An alkyl group, a 6 to 12 membered aryl group, a 5 to 12 membered heteroaryl group, N(R ⁴² R ⁴³ ), and R ⁴⁴ —LR ⁴⁵ ; R ⁴² and R ⁴³ are each independently selected from the group consisting of 1, 2 or 3 R substituted C _1-3 alkyl, C _3-6 cycloalkyl and 5-6 membered aryl C _1-3 alkyl; R ^{44 is} selected from 5~ optionally substituted by 1, 2 or 3 R 6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl and 5-9 membered heteroaryl; R ^{45 is} selected from C _1-6 optionally substituted by 1, 2 or 3 R Alkyl, 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl and 5-9 membered heteroaryl; L is selected from the group consisting of a single bond, O, S, C (=O) And C(=O)O; R is selected from the group consisting of OH, NH ₂ , F, Cl, Br, I, CN, COOH, oxo, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , NHCH ₃ , N (CH ₃ ) ₂ and .

In one embodiment of the compounds of formula I of the present invention, D ⁴¹ is selected from N (OH), S, -NHC (= O) NH -, - NHC (= O) CH 2 -, - NHC (= O) CH ( CH ₃ )-, -NHC(=O)-, S(=O) and S(=O) ₂ . In one embodiment of the compounds of Formula I of the present invention, ^{R41 is} selected from _C5-6 cycloalkyl, _5-6 heterocycloalkyl, 5-12 aryl, optionally substituted by 1, 2 or 3 R Base, 5 to 12 membered heteroaryl, N(R ⁴² R ⁴³ ) and R ⁴⁴ -LR ⁴⁵ .

In one embodiment of the compounds of formula I according to the invention, R ^{41 is} selected from cyclopentyl, cyclohexyl, optionally substituted by 1, 2 or 3 R, , , , , , , , Losing a hydrogen atom at any position , ,

In one embodiment of the compounds of formula I according to the invention, R ^{41 is} selected from the group consisting of optionally substituted by 1, 2 or 3 R , , , , , , ,

In one embodiment of the compounds of formula I according to the invention, R ^{41 is} selected from the group consisting of optionally substituted by 1, 2 or 3 R , , , , ,

In one embodiment of the compounds of formula I of the invention, R ^{41 is} selected from ,

In one embodiment of the compounds of formula I of the invention, R ^{41 is} selected from ,

In one embodiment of the compounds of formula I according to the invention, R ⁴² and R ⁴³ are each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl optionally substituted by 1, 2 or 3 R. , cyclobutyl, cyclopentyl, cyclohexyl, phenyl CH ₂ , phenyl CH ₂ CH ₂ , phenyl CH ₂ CH ₂ CH ₂ and phenyl CH(CH ₃ )CH ₂ .

In one embodiment of the compounds of formula I according to the invention, R ⁴² and R ⁴³ are each independently selected from methyl optionally substituted by 1, 2 or 3 R, , , with .

In one embodiment of the compounds of Formula I of the present invention, R ⁴² and R ⁴³ are each independently selected from methyl, , , with .

In one embodiment of the compounds of formula I of the invention, N(R ⁴² R ⁴³ ) is selected from

In one embodiment of the compounds of formula I of the present invention, R ^{44 is} selected from any of the positions optionally substituted by 1, 2 or 3 R to lose 2 hydrogen atoms. , , , , , , And benzene.

In one embodiment of the compounds of formula I according to the invention, ^{R44 is} selected from phenylene and acridinyl optionally substituted by 1, 2 or 3 R.

In one embodiment of the compounds of formula I of the invention, R ^{44 is} selected from ,

In one embodiment of the compounds of formula I of the invention, R ^{44 is} selected from ,

In one embodiment of the compounds of Formula I of the present invention, ^{R45 is} selected from 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl and 5~, optionally substituted by 1, 2 or 3 R. 9 members of heteroaryl.

In one embodiment of the compounds of formula I according to the invention, R ^{45 is} selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl optionally substituted by 1, 2 or 3 R Base, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, pyridazinyl, phenyl, pyrimidinyl, pyrazolyl, imidazolyl, thienyl, evil Azolyl, isoxazolyl, thiazolyl and [1,2,4]triazolo[4,3-a]pyridinyl.

In one embodiment of the compounds of formula I according to the invention, R ^{45 is} selected from cyclohexyl, pyridazinyl, phenyl, pyrimidinyl, pyrazolyl, imidazolyl, thienyl optionally substituted by 1, 2 or 3 R , oxazolyl, isoxazolyl, thiazolyl and [1,2,4]triazolo[4,3-a]pyridinyl.

In one embodiment of the compounds of formula I according to the invention, R ^{45 is} selected from the group consisting of t-butyl, cyclohexyl optionally substituted by 1, 2 or 3 R, phenyl, pyrimidinyl, pyridyl which loses 1 hydrogen atom at any position. Azyl and [1,2,4]triazolo[4,3-a]pyridinyl.

In one embodiment of the compounds of formula I according to the invention, R ^{45 is} selected from t-butyl optionally substituted by 1, 2 or 3 R, , , , with .

In one embodiment of the compounds of formula I according to the invention, R ^{45 is} selected from the group consisting of optionally substituted by 1, 2 or 3 R , , , with .

In one embodiment of the compounds of formula I of the invention, R ^{45 is} selected from ,

In one embodiment of the compounds of formula I of the invention, R ^{45 is} selected from ,

In one embodiment of the compounds of formula I of the invention, L is selected from the group consisting of a single bond, O, S and C (=O).

In one embodiment of the compounds of formula I according to the invention, L is selected from the group consisting of a single bond, O, C(=O) and C(=O)O.

In one embodiment of the compounds of formula I according to the invention, R ⁴⁴ -LR ^{45 is} selected from

In one embodiment of the compounds of formula I of the present invention, R is selected from the group consisting of OH, NH ₂ , F, Cl, Br, I, CN, COOH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , NHCH ₃ , N (CH ₃ ) ₂ and .

In one embodiment of the compounds of formula I of the present invention, R is selected from the group consisting of F, Cl, CN, oxo, Me, CF ₃ and .

One aspect of the present invention provides a compound having the structure: or a pharmaceutically acceptable salt thereof:

Another aspect of the present invention provides a compound having the structure: or a pharmaceutically acceptable salt thereof:

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

In another aspect, the invention provides a method of treating an immunosuppressive disorder mediated by guanidine 2,3-dioxygenase (IDO), the method comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable compound thereof Salt or a pharmaceutical composition thereof.

In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment of an immunosuppressive disorder mediated by 2,3-dioxygenase (IDO) Use in.

In another aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of an immunosuppressive disorder mediated by 2,3-dioxygenase (IDO).

In some embodiments of the invention, the immunosuppressive disease is associated with an infectious disease or cancer.

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

Definition and description

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

Unless otherwise required by the present invention, the word "comprise" and its English variants such as "comprises" and "comprising" should be interpreted as open-ended throughout the specification and subsequent claims. The meaning of inclusion, that is, "including but not limited to".

References to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" throughout the specification are meant to include in the at least one embodiment Relevant specific reference elements, structures or features. Thus, the appearance of the phrase "in one embodiment" or "in an embodiment" or In an embodiment, or in some embodiments, it is not necessary to refer to the same embodiment. In addition, the specific elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

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

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

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

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

The range of digits in this document refers to each integer in a given range. For example, "C _1-10 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.

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

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

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

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

When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit or It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.

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

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, and as a pharmaceutically acceptable salt of the compound of the formula I, for example, a metal salt, an ammonium salt, a salt with an organic base, and a salt formed of an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, or the like. Non-limiting examples of metal salts include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like. Non-limiting examples of salts formed with organic bases include, but are not limited to, with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, A salt formed by dicyclohexylamine or the like. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.

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

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

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

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

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

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

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

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

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

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

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

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Moreover, the term "haloalkyl" is meant to include monohaloalkyl and polyhaloalkyl; for example, the term "halo (C ₁ -C ₄₎ alkyl" is meant to include, but are not limited to trifluoromethyl, 2,2,2 -Trifluoroethyl, 4-chlorobutyl and 3-bromopropyl, and the like. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The term "hydroxy" refers to -OH.

The term "cyano" refers to -CN.

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

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

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

"Alkoxy" represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge. The C _1-6 alkoxy group includes a C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.

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

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

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocyclic ring herein can undergo a substitution at the carbon or nitrogen position. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4a H -carbazolyl , porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2 H , 6 H -1,5,2-dithiazinyl, dihydrofuran [2,3 - b ] tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H -carbazolyl, nonenyl, indanyl, mesoindolyl, fluorenyl , 3 H -indolyl, isobenzofuranyl, isodecyl, isoindoline, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholine , naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxymethyl, pyrimidinyl, phenanthryl, phenanthroline, phenanth , phenothiazine, benzoxanthyl, phenoloxazinyl, pyridazinyl, pyridazinyl, acridinyl, acridone, 4-acridone, piperonyl, pteridinyl, fluorenyl, Pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl, pyrrolidinyl, pyrrolinyl, 2 H -pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4 H -quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl , tetrazolyl, 6 H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazole 1,1,3,4-thiadiazolyl, thiazide, thiazolyl, isothiazolylthiophenyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1 , 2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ ,- CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

The term "heteroalicyclic" refers to a monocyclic or fused ring having from 3 to 12 ring atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1 or The two ring atoms are heteroatoms selected from N, O, S(O) _n (where n is 0, 1, or 2), and the remaining ring atoms are C. Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated π-electron system. Examples of 3-membered saturated heteroalicyclic rings include, but are not limited to, , , Examples of 4-member saturated heteroalicyclic rings include, but are not limited to, , , Examples of 5-membered saturated heteroalicyclic rings include, but are not limited to, , , , , , , , , Examples of 6-member saturated heteroalicyclic rings include, but are not limited to, , , , , , , , , Examples of 7-member saturated heteroalicyclic rings include, but are not limited to, , , , , , , , , Examples of 5-membered unsaturated heteroalicyclic rings include, but are not limited to, , , , , , , Examples of 6-membered unsaturated heteroalicyclic rings include, but are not limited to, , , , , , , , ,

The term "heterocycloalkyl" refers to a group remaining after the "heteroalicyclic" molecule has one hydrogen atom removed, and the heterocycloalkyl group may be unsubstituted or the hydrogen atom therein may be optionally substituted with a substituent which is substituted. These include, but are not limited to, alkyl, alkoxy, =0, aryl, aralkyl, -COOH, -CN, amino, halogen or hydroxy.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which are fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the following acceptable substituents.

Unless otherwise specified, aryl groups, when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Therefore, the term "aralkyl" means Those radicals including an aryl group attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including those wherein a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom, such as benzene Oxymethyl group, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl group and the like.

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

The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: DBU for 1,8-diazabicycloundec-7-ene; DMAP for 4-dimethylaminopyridine; TBSCl for tert-butyldimethylchloromethane; DMF for N,N-dimethylformamide; Pd(OAc) ₂ represents palladium acetate; PPh ₃ represents triphenylphosphine; SFC represents a palmitic supercritical column; EtOAc represents ethyl acetate; t-Bu- represents tert-butyl m-CPBA stands for m-chloroperoxybenzoic acid; DCM stands for dichloromethane; CDI stands for carbonyl diimidazole; Boc- stands for t-butylcarbonyl; HATU stands for O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate; DIEA stands for N,N-diisopropylethylamine; TLC stands for thin layer chromatography plates.

Compounds are named by hand or by ChemDraw® software, and commercial compounds are listed under the supplier's catalogue.

When the compound of the embodiment of the invention has multiple palmar centers, different stereoisomers can be separated by a palmar supercritical chromatography column, and different retention times correspond to isomers of different nature.

In order to explain the present invention in more detail, the following examples are given, but the scope of the invention is not limited thereto.

Example 1-3: N-((5H-imidazo[5,1-a]isoindol-5-yl)methyl)-N-cyclohexylhydroxylamine

Example 1A: Methyl 2-(2-iodophenyl)acetate

A mixture of 2-(2-iodophenyl)acetic acid (22.50 g, 85.86 mmol) and concentrated sulfuric acid (4.46 g, 45.51 mmol) in MeOH (300 mL) was stirred at 80 ° C for 20 hr. The solvent was removed under reduced pressure. EtOAc EtOAc m. Yellow liquid, 22.50 g, 94.92% yield) was used directly in the next step without further purification. ¹ H NMR (400 MHz, CHLOROFORM-d): δ = 7.94 - 7.74 (m, 1H), 7.36-7.27 (m, 2H), 6.97 (dt, J = 2.0, 7.4 Hz, 1H), 3.81 (s, 2H) ), 3.73 (s, 3H).

Example 1B: Methyl 2-bromo-2-(2-iodophenyl)acetate

To a solution of methyl 2-(2-iodophenyl)acetate (22.50 g, 81.50 mmol) in THF (300 mL) The mixture was stirred at 0 ° C for 30 minutes, cooled to -78 ° C, to which was added carbon tetrabromide (29.73 g, 89.65 mmol), and stirred at -78 ° C for further 1.5 hours. The mixture was quenched with EtOAc (EtOAc) (EtOAc) The combined organic phases were washed with EtOAc EtOAc m. ¹ H NMR (400 MHz, CHLOROFORM-d): δ = 7.85 (dd, J = 1.1, 7.9 Hz, 1H), 7.77 (dd, J = 1.6, 7.9 Hz, 1H), 7.39 (dt, J = 1.0, 7.7) Hz, 1H), 7.02 (dt, J = 1.8, 7.7 Hz, 1H), 5.79 (s, 1H), 3.81 (s, 3H).

Example 1C: Methyl 2-(1H-imidazol-1-yl)-2-(2-iodophenyl)acetate

A solution of methyl 2-bromo-2-(2-iodophenyl)acetate (40 g, 81.13 mmol) and imidazole (27.62 g, 405.67 mmol) in tetrahydrofuran (350 mL) was stirred at <RTIgt; The solvent was removed under reduced pressure and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Methyl (1H-imidazol-1-yl)-2-(2-iodophenyl)acetate (21.70 g, 78.18% yield). ^{1 H NMR (400MHz, CHLOROFORM-} d): δ = 7.92 (dd, J = 1.1,7.9Hz, 1H), 7.56 (s, 1H), 7.44-7.38 (m, 1H), 7.31 (dd, J = 1.6 , 7.9 Hz, 1H), 7.13-7.06 (m, 2H), 6.99-6.94 (m, 1H), 6.26 (s, 1H), 3.82 (s, 3H).

Example 1D: 2-(1H-imidazol-1-yl)-2-(2-iodophenyl)ethanol

To a solution of methyl 2-(1H-imidazol-1-yl)-2-(2-iodophenyl)acetate (21.7 g, 63.43 mmol) in methanol (300 mL) , 380.58 mmol), and the reaction was stirred at 20 ° C for 1 hour. It was quenched with water (100 mL) EtOAc. The organic phase was washed with EtOAc EtOAc m. ¹ H NMR (400 MHz, CHLOROFORM-d): δ = 7.88 (dd, J = 1.1, 7.9 Hz, 1H), 7.60 (s, 1H), 7.33 (dt, J = 1.0, 7.5 Hz, 1H), 7.12 ( Dd, J=1.5, 7.8 Hz, 1H), 7.05-6.94 (m, 3H), 5.58 (dd, J=4.4, 7.4 Hz, 1H), 4.61 (br.s., 1H), 4.26-4.15 (m) , 2H).

Example 1E: 1-(2-((tert-Butyldimethylmethyl)oxy)-1-(2-iodophenyl)ethyl)-1H-imidazole

Add DMAP (1.28 g, 10.51) to a solution of 2-(1H-imidazol-1-yl)-2-(2-iodophenyl)ethanol (16.50 g, 52.53 mmol) in dichloromethane (100 mL). Methyl), TBSCl (7.88 g, 52.53 mmol) and triethylamine (21.26 g, 210.11 mmol). The reaction was stirred at 20 ° C for 20 hours. Saturated ammonium chloride (200 mL) was added to the reaction mixture, and the mixture was evaporated. The combined organic phases were washed with EtOAc EtOAc m. ¹ H NMR (400 MHz, METHANOL-d4): δ = 7.93 (dd, J = 1.3, 8.0 Hz, 1H), 7.82 (s, 1H), 7.38 (dt, J = 1.0, 7.5 Hz, 1H), 7.22 ( Dd, J = 1.6, 7.9 Hz, 1H), 7.14 (t, J = 1.3 Hz, 1H), 7.07 (dt, J = 1.6, 7.6 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 5.63 (dd, J=4.0, 7.0 Hz, 1H), 4.35-4.28 (m, 1H), 4.26-4.20 (m, 1H), 0.85-0.81 (m, 9H), 0.04-0.00 (m, 3H), -0.02--0.06 (m, 3H).

Example 1F: 5-(((tert-Butyldimethylmethyl)oxy)methyl)-5H-imidazo[5,1-a]isoindole

1-(2-((tert-Butyldimethylmethyl)oxy)-1-(2-iodophenyl)ethyl)-1H-imidazole (13 g, 30.35 mmol), N-ring under nitrogen hexyl methyl -N- cyclohexylamine (9.48g, 48.56mmol), and PPh ₃ (3.18g, 12.14mmol) in DMF (150mL) was added _{Pd (OAc) 2 (1.36g,} 6.07mmol). The mixture was stirred at 95 ° C for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc EtOAc (EtOAc) The organic phase was washed with EtOAc EtOAc m. ¹ H NMR (400 MHz, METHANOL-d4): δ = 7.60 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.0 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.33 -7.26 (m, 1H), 7.13 (s, 1H), 5.36 (dd, J = 4.3, 7.0 Hz, 1H), 4.27 (dd, J = 4.3, 10.5 Hz, 1H), 3.76 (dd, J = 7.3 , 10.5 Hz, 1H), 0.88-0.79 (m, 9H), 0.05 (s, 3H), 0.01 (s, 3H).

Example 1G: (5H-imidazo[5,1-a]isoindol-5-yl)methanol

A solution of 5-(((tert-butyldimethylmethyl)oxy)methyl)-5H-imidazo[5,1-a]isoindole (5.2 g, 17.31 mmol) in trifluoroacetic acid (50 mL) Stir at 70 ° C for 3 hours. The solvent was removed under reduced pressure. EtOAc m. The organic layer was washed with EtOAc EtOAc. ¹ H NMR (400 MHz, METHANOL-d4): δ = 7.92 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.14 (s, 1H), 5.32 (dd, J = 4.1, 7.9 Hz, 1H), 4.19 (dd, J = 4.1, 11.4 Hz, 1H), 3.60 (dd, J = 7.9, 11.4 Hz, 1H).

Example 1H: 5-(Chloromethyl)-5H-imidazo[5,1-a]isoindole

(5H-Imidazo[5,1-a]isoindol-5-yl)methanol (1.4 g, 7.52 mmol) in dichloromethane (28.69 g, 241.19 mmol, 17.50 mL) was stirred at 80 ° C. hour. The solvent was removed under reduced pressure.

Preparation of the title compound (Example 1-3): N-((5H-imidazo[5,1-a]isoindol-5-yl)methyl)-N-cyclohexylhydroxylamine

To a solution of 5-(chloromethyl)-5H-imidazo[5,1-a]isoindole (500 mg, 2.44 mmol) in tetrahydrofuran was added N-cyclohexylhydroxylamine (337.22 mg, 2.93). Methyl) and potassium carbonate (674.46 mg, 4.88 mmol). The mixture was stirred at 70 ° C for 16 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The racemic Example 1 (220 mg, 31.82% yield) was obtained by preparative HPLC. LCMS (ESI) (m / z ):. 284 (M + 1) 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.15 (s, 1H), 7.95 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.11 (s, 1H), 5.39 (dd, J =3.8, 9.8 Hz, 1H), 3.20 (dd, J = 4.0, 12.5 Hz, 1H), 2.65 (d, J = 15.1 Hz, 1H), 2.46-2.41 (m, 1H), 1.84 (d, J = 11.5 Hz, 1H), 1.74 (br.s., 2H), 1.64 (br.s., 1H), 1.53 (d, J = 8.5 Hz, 1H), 1.34-1.08 (m, 5H).

Racemic Example 1 (160 mg, 564.63 mmol) was subjected to palm separation (column: Chiralpak AD-3 150 x 4.6 mm ID, 3 um mobile phase: A: carbon dioxide B: methanol (0.05% diethylamine)) to give isomeric Example 1 Example 2 (20.00 mg, 12.50% yield) (retention time: 4.221 min) and isomer 2 Example 3 (40 mg, 25.00% yield) (retention time: 6.466 min).

Example 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.18 (s, 1H), 7.94 (s, 1H), 7.62-7.50 (m, 2H), 7.37 (t, J = 7.4 Hz, 1H) ), 7.28-7.21 (m, 1H), 7.10 (s, 1H), 5.38 (dd, J = 3.5, 9.5 Hz, 1H), 3.19 (dd, J = 3.8, 12.5 Hz, 1H), 2.61 (t, J = 11.0Hz, 1H), 2.47-2.39 (m, 1H), 1.83 (d, J = 12.0Hz, 1H), 1.73 (d, J = 9.8Hz, 2H), 1.63 (d, J = 5.8Hz, 1H), 1.51 (d, J = 8.8 Hz, 1H), 1.35-1.06 (m, 5H).

Example 3: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.21 (br.s., 1H), 7.94 (br.s., 1H), 7.65-7.47 (m, 2H), 7.37 (t, J = 6.9 Hz, 1H), 7.29-7.19 (m, 1H), 7.11 (br.s., 1H), 5.39 (d, J = 6.3 Hz, 1H), 3.19 (d, J = 10.5 Hz, 1H) , 2.60 (t, J = 10.0 Hz, 1H), 2.47-2.37 (m, 1H), 1.83 (d, J = 10.0 Hz, 1H), 1.72 (br.s., 2H), 1.62 (br.s. , 1H), 1.51 (br.s., 1H), 1.33-1.07 (m, 5H).

Example 4-5: 5-((Cyclohexylthio)methyl)-5H-imidazo[5,1-a]-isoindole

To a solution of cyclohexyl mercaptan (1.1 g, 9.46 mmol) in DMF (15 mL) EtOAc. After stirring at 20 ° C for 0.5 h, the mixture was cooled to 0 ° C, and then a solution of &lt;RTI ID=0.0&gt;&gt; Gradually warmed to 20 ℃, after the completion of the reaction, saturated NH ₄ Cl solution (100 mL) quenched the reaction was diluted with EtOAc (80mL), (80mL × 3) extracted with EtOAc. Washed, Na dried organic phase was washed with brine (150mL) ₂ SO _4, filtered, and concentrated by column chromatography to give racemic compound (800mg, 2.63mmol, 33.36% yield). The racemate is separated by palmarity (SFC: "Column: AY (250mm*30mm, 10um) (250mm*30mm, 5um) Mobile phase: Base-ETOH in CO2 from 55% to 55% Flow rate: 80ML/MIN Injections : 110") gave yellow oil isomer 1 Example 4 (370.00 mg) and yellow oil isomer 2 Example 5 (390.00 mg).

Example 4: ¹ H NMR (400 MHz, METHANOL-d4): δ = 9.28 (s, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 7.0) Hz, 1H), 7.61-7.52 (m, 2H), 5.88 (t, J = 5.4 Hz, 1H), 3.56 (dd, J = 4.5, 14.3 Hz, 1H), 3.22 (dd, J = 6.7, 14.4 Hz) , 1H), 2.55 (br.s., 1H), 1.96 (br.s., 1H), 1.84 (d, J = 8.3 Hz, 1H), 1.72 (d, J = 10.0 Hz, 2H), 1.60 ( Br.s., 1H), 1.32-1.19 (m, 5H). SFC (RT = 4.635 min). LCMS (ESI) m/z: 285 (M+1).

Example 5: ¹ H NMR (400 MHz, METHANOL-d4): δ = 9.28 (s, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 7.0) Hz, 1H), 7.61-7.52 (m, 2H), 5.88 (t, J = 5.4 Hz, 1H), 3.56 (dd, J = 4.5, 14.6 Hz, 1H), 3.22 (dd, J = 6.8, 14.3 Hz) , 1H), 2.56 (br.s., 1H), 1.96 (br.s., 1H), 1.84 (d, J = 7.8 Hz, 1H), 1.72 (d, J = 10.0 Hz, 2H), 1.60 ( Br.s., 1H), 1.32-1.19 (m, 5H). SFC (RT = 6.391 min). LCMS (ESI) m/z: 285 (M+1).

Example 6: 5-((cyclohexylfluorenyl)methyl)-5H-imidazo[5,1-a]-isoindole

Example 8: 5-((cyclohexylfluorenyl)methyl)-5H-imidazo[5,1-a]-isoindole

m-CPBA (545.75 mg, 2.53 mmol) was added to a solution of EtOAc (EtOAc). The reaction was warmed to 20 ° C in 1 hour. Saturated Na ₂ SO ₃ solution (40 mL) to quench the reaction, after DCM (30mL) was diluted, DCM (30mL × 3) and extracted. The organic phase was washed with brine (80 mL), dried Na ₂ SO _4, filtered and concentrated, Column chromatography afforded Example 6 (300mg, 44.93% yield) and the embodiment 8 (180mg, 33.36% yield) Example.

Example 6: ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.14 (s, 1H), 7.62 (dd, J = 7.7, 14.7 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.40 -7.33 (m, 1H), 7.17 (s, 1H), 5.86 (d, J = 9.0 Hz, 1H), 3.95 (dd, J = 2.5, 14.6 Hz, 1H), 3.57 (dd, J = 9.3, 14.6) Hz, 1H), 3.20-3.12 (m, 1H), 2.22 (t, J = 15.6 Hz, 2H), 1.98-1.90 (m, 2H), 1.75 (d, J = 12.3 Hz, 1H), 1.62-1.50 (m, 2H), 1.43-1.26 (m, 3H). LCMS (ESI) m/z: 317 (M+1).

Example 8: ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.01 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.45 (t , J = 7.5 Hz, 1H), 7.38-7.33 (m, 1H), 7.19 (s, 1H), 5.80-5.72 (m, 1H), 3.65 (dd, J = 3.0, 13.8 Hz, 1H), 3.30- 3.23(m,1H),2.88-2.78(m,1H), 2.12(d,J=12.5Hz,1H),1.96-1.82(m,3H),1.71(d,J=12.3Hz,1H),1.55 - 1.28 (m, 5H). LCMS (ESI) m/z: 301 (M+1).

Example 7: 5-((Cyclohexylfluorenyl)methyl)-5H-imidazo[5,1-a]-isoindole

Example 9-10: 5-((cyclohexylfluorenyl)methyl)-5H-imidazo[5,1-a]-isoindole

m-CPBA (545.75 mg, 2.53 mmol) was added to a solution of EtOAc (EtOAc). The reaction was warmed to 20 ° C in 1 hour. Saturated Na ₂ SO ₃ solution (40 mL) to quench the reaction, after DCM (30mL) was diluted, DCM (30mL × 3) and extracted. Washed, Na dried organic phase was washed with brine (80mL) ₂ SO _4, filtered and concentrated to give the racemic sulfoxide compound (300mg) and Example 7 (190mg, 28% yield) embodiment.

Example 7: ¹ H NMR (400 MHz, METHANOL-d4): δ = 8.18 (s, 1H), 7.62 (dd, J = 7.7, 16.2 Hz, 2H), 7.48-7.43 (m, 1H), 7.39-7. (m, 1H), 7.19 (s, 1H), 5.87 (d, J = 7.5 Hz, 1H), 3.95 (dd, J = 2.5, 14.6 Hz, 1H), 3.58 (dd, J = 9.0, 14.6 Hz, 1H), 3.16 (tt, J=3.4, 12.0 Hz, 1H), 2.21 (t, J = 16.1 Hz, 2H), 1.97-1.90 (m, 2H), 1.74 (d, J = 12.5 Hz, 1H), 1.62-1.51 (m, 2H), 1.41-1.25 (m, 3H). LCMS (ESI) m/z: 317 (M+1).

The racemic sulfhydryl compound (300 mg, 1 mmol) was subjected to palm separation ("Column: AY (250 mm * 30 mm, 10 um) Mobile phase: Base-ETOH in CO2 from 55% to 55% Flow rate: 80ML/MIN Injections: 110") gave isomer 1 Example 9 (220 mg, 0.7 mmol, 73.33% yield) and isomer 2 Example 10 (40 mg, 0.13 mmol, 13.33% yield).

Example 9: ¹ H NMR (400 MHz, METHANOL-d4): δ = 8.01 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.45 (t, J) = 7.4 Hz, 1H), 7.38-7.33 (m, 1H), 7.19 (s, 1H), 5.76 (dd, J = 2.9, 8.9 Hz, 1H), 3.64 (dd, J = 3.0, 13.8 Hz, 1H) , 3.30-3.24(m,1H), 2.83(tt,J=3.7,11.3Hz,1H), 2.12(d,J=12.8Hz,1H),1.96-1.81(m,3H),1.74-1.68(m , 1H), 1.55-1.27 (m, 5H). LCMS (ESI) m/z: 301 (M+1). SFC ( RT = 3.931 min).

Example 10: ¹ H NMR (400 MHz, METHANOL-d4): δ = 8.08 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.38- 7.32 (m, 1H), 7.18 (s, 1H), 5.81 (t, J = 5.6 Hz, 1H), 3.62-3.55 (m, 1H), 3.49-3.42 (m, 1H), 2.78-2.70 (m, 1H), 2.07 (d, J = 12.5 Hz, 1H), 1.95-1.83 (m, 3H), 1.71 (d, J = 12.3 Hz, 1H), 1.52-1.29 (m, 5H). LCMS (ESI) m /z: 301 (M+1). SFC (RT = 6.436 min).

Example 11: 1,1-Dicyclohexyl-3-(5H-imidazo[1,5-b]isoindol-5-ylmethyl)urea

Example 11A: 1-(2-azido-1-(2-iodophenyl)ethyl)-1H-imidazole

To a solution of 2-imidazol-1-yl-2-(2-iodophenyl)ethanol (1.00 g, 3.18 mmol) in dichloromethane (10 mL) was added triethylamine (386.14 mg, 3.82 mmol) p-Toluenesulfonium chloride (636.58 mg, 3.34 mmol), and the mixture was stirred at 15 ° C for 16 hours. The reaction mixture was dissolved in dichloromethane (50 mL), EtOAc (EtOAc) (2-Iodophenyl)ethyl]4-toluenesulfonate crude (yellow liquid, 1.49 g). Add NaN ₃ (227.40 mg, in a solution of [2-imidazol-1-yl-2-(2-iodophenyl)ethyl] 4-toluenesulfonate (1.49 g, 3.18 mmol) in DMF (15.00 mL) 3.50 mmol), the mixture was stirred at 60 ° C for 16 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc EtOAc. LCMS (ESI) m/z: 340 (M+1).

Example 11B: 2-(1H-imidazol-1-yl)-2-(2-iodophenyl)ethylamine

Triphenylphosphine (1.08 g, 4.12 mmol) was added to a solution of <RTI ID=0.0>#</RTI></RTI><RTIgt;</RTI><RTIgt; The reaction mixture was quenched with EtOAc EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc EtOAc. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ = 7.89 (d, J = 8.0Hz, 1H), 7.70 (s, 1H), 7.37-7.29 (m, 1H), 7.13-7.07 (m, 2H), 7.05 -6.97 (m, 2H), 5.46 (t, J = 6.9 Hz, 1H), 3.40 (d, J = 7.0 Hz, 2H).

Example 11C: tert-Butyl (2-(1H-imidazol-1-yl)-2-(2-iodophenyl)ethyl)carbamate

To a solution of EXAMPLE 11B (7.5 g, 23.95 mmol) in dichloromethane <RTI ID=0.0>(</RTI> <RTIgt; <RTIgt; <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 16 hours. The reaction mixture was dissolved in dichloromethane (100 mL) EtOAc (EtOAc) Shape, 7g, 70.73% yield). LCMS (ESI) m/z: 414 (M+1).

Example 11D: tert-Butyl ((5H-imidazo[5,1-a]isoindol-5-yl)methyl)carbamate

Mixture Example 11C (7 g, 16.94 mmol), palladium acetate (760.59 mg, 3.39 mmol), triphenylphosphine (1.78 g, 6.78 mmol) and N-cyclohexyl-N-methyl-cyclohexylamine (5.29 g, A solution of 27.10 mmol, 5.75 mL of DMF (70 mL) was replaced with nitrogen three times and then stirred at 95 ° C for 48 hours. The reaction mixture was dissolved in ethyl acetate (200 mL), EtOAc (EtOAc) (Brown oil, 3.60 g, 68.97% yield). LCMS (ESI) m/z: 286 (M+1).

Example 11E: (5H-imidazo[5,1-a]isoindol-5-yl)methylamine

A solution of 4N hydrochloric acid/methanol (3.15 mL) was added to a solution of EtOAc (EtOAc, EtOAc. The solvent was evaporated to dryness crystals crystals crystals crystals

Preparation of the title compound (Example 11): 1,1-dicyclohexyl-3-(5H-imidazo[1,5-b]isoindol-5-ylmethyl)urea

A solution of Example 11E (30 mg, 135.32 μmol) and CDI (24.14 mg, 148.85 μmol) in acetonitrile (1 mL) and DMF (1 mL) was stirred at 10 ° C for 2 hr. After completion of the reaction, DIEA (34.98 mg, 270.64 μmol) and dicyclohexylamine (135.32 μmol) were added, and stirring was continued at 10 ° C for 14 hours. The reaction mixture was purified by preparative HPLC to afford the title compound. The yield was 56.97%. ¹ H NMR (400 MHz, METHANOL-d4) δ = 8.98 (s, 1H), 7.85 (dd, J = 3.4, 5.1 Hz, 1H), 7.75 (s, 1H), 7.73-7.66 (m, 1H), 7.59 (dd, J=3.3, 5.5 Hz, 2H), 5.81 (br.s., 1H), 4.31 (dd, J=3.3, 14.8 Hz, 1H), 3.71 (dd, J=4.5, 14.8 Hz, 1H) , 3.02 (t, J = 11.5 Hz, 2H), 1.78-1.55 (m, 10H), 1.44-1.19 (m, 8H), 1.14-1.03 (m, 2H).

The preparation of Examples 12-22 can be carried out by referring to the preparation method of Example 11, using different amines to obtain:

Example 23: N-((5H-imidazo[5,1-a]isoindol-5-yl)methyl)-2-cyclohexylacetamide

Example 11E (50 mg, 225.54 μmol) in DMF (1 mL) was added 2-cyclohexylacetic acid (225.54 μmol), HATU (85.76 mg, 225.54 μmol) and DIEA (58.30 mg, 451.08 μmol), at 12 ° C Stir for 30 minutes. The reaction mixture was purified by preparative HPLC to afford the title compound. The yield was 59.83%. ^{1 H NMR (400MHz, DMSO-} d6) δ = 9.32 (s, 1H), 7.92-7.80 (m, 3H), 7.67 (d, J = 7.0Hz, 1H), 7.58-7.47 (m, 2H), 5.80 (br.s., 1H), 4.12-4.08 (m, 1H), 3.95 (ddd, J = 4.5, 6.5, 14.6 Hz, 1H), 1.80-1.69 (m, 2H), 1.52 (d, J = 7.0) Hz, 3H), 1.33-1.11 (m, 4H), 1.02 (br.s., 2H), 0.67-0.50 (m, 2H).

Examples 24-46 were prepared according to the procedure of Example 23 using different amines:

Experimental Example 1: In vitro enzyme activity test of hIDO1

Purpose:

The NFK green ^TM fluorescent molecule was used to detect the change in the NFK production of the IDO1 enzyme metabolite, and the inhibitory effect of the compound on the recombinant human IDO1 enzyme was evaluated based on the IC50 value of the compound.

Experimental Materials:

IDO1 Enzyme Activity Assay Kit, NTRC # NTRC-hIDO-10K; 384-well Enzyme Reaction Plate, PerkinElmer # 6007279; 384-well Compound Plate, Greiner # 781280; Sealing Plate, PerkinElmer # 6050185; Envision Multi-Plate Reader, PerkinElmer ; Bravo automatic liquid handling platform, Agilent.

Experimental steps and methods:

Compound loading:

Dilute the compound to 1 mM with DMSO, 3 fold dilution, 10 gradients, double Double hole. 48 μL of 50 mM phosphate buffer pH 6.5 was transferred to the compound plate via a Bravo automated liquid handling platform. Then, 2 μL of the diluted compound DMSO solution was added, and after mixing, 10 μL was transferred to the enzyme reaction plate.

IDO1 enzyme activity detection experiment:

Dilute the IDO1 enzyme to 20 nM in reaction buffer (50 mM phosphate buffer pH 6.5, 0.1% Tween-20, 2% glycerol, 20 mM ascorbic acid, 20 μg/ml catalase and 20 μM methylene blue) and transfer 20 μL to Incubate for 30 minutes at 23 ° C in the enzyme reaction plate. The reaction was started by adding 10 μL of 400 μM L-type tryptophan substrate and incubated at 23 ° C for 90 minutes. 10 μL of NFK green ^TM fluorescent dye was added, sealed with a sealing plate, and placed at 37 ° C for 4 hours, and then read on an Envision multi-function plate reader (Ex 400 nm / Em 510 nm).

Analysis data:

The reference well to which the IDO1 enzyme was added but no compound was added was determined to have a 0% inhibition rate, and the reference well to which the IDO1 enzyme was not added was determined to be 100% inhibition rate, and the IC50 value of the compound was calculated by analyzing the data using XLFit5.

Experimental Example 2: hIDO1 cytological activity test

Purpose:

The change of kynurenine in Hela cells was detected by LC-MS method, and the inhibitory effect of the compound on IDO1 enzyme was evaluated by the IC50 value of the compound.

Experimental Materials:

Cell line: Hela cells; medium: RPMI 1640 phenol red free, Invitrogen #11835030 10% fetal bovine serum, Gibco #10099141 1X streptomycin, Gibco #15140-122; precipitant: 4 μM L-kynurenine-d4 Soluble in 100% acetonitrile, CacheSyn #CSTK008002; Trypsin, Invitrogen #25200-072; DPBS, Hyclone #SH30028.01B; recombinant human γ-interferon, Invitrogen #PHC4033; 5% (w/v) trichloroacetic acid, Alfa Aesar # A11156; 96-well cell plate, Corning #3357; 96-well compound plate, Greiner # 781280; 96-well V-bottom plate, Axygen #WIPP02280; CO ₂ incubator, Thermo #371; centrifuge, Eppendorf #5810R; Vi- Cell cytometer, Beckman Coulter; Labcyte FLIPR, Molecular Device.

Experimental steps and methods:

Hela cell inoculation:

Pre-heated medium, trypsin, DPBS in a 37 ° C water bath. Aspirate the culture medium and wash it with 10 mL of DPBS. Add the pre-warmed trypsin to the flask, rotate the flask to cover the flask evenly, and place it in a 37 ° C, 5% CO ₂ incubator. 2 minutes; each T150 was suspended with 10-15 mL of medium, centrifuged at 800 rpm for 5 minutes, resuspended in 10 mL of medium, and 1 mL of cell suspension was aspirated and counted with Vi-cell; Hela cells were diluted with medium to 5×10 ⁵ /mL, 80 μL was added to a 96-cell plate, and cultured at 37 ° C for 5-6 hours in a 5% CO ₂ incubator.

Compound loading:

The compound was diluted to 1 mM with DMSO, diluted 3 fold, 9 gradients, double duplicate wells. 5 μL of the diluted compound DMSO solution was added to a compound plate containing 95 μL of the medium. After mixing, transfer 10 μL to the cell plate.

Cytological activity test:

10 μL of recombinant human γ-type interferon was added to a final concentration of 100 ng/ml to induce expression of IDO1. The cells were cultured in a 5% CO ₂ incubator at 37 ° C for 20 hours. Add 4 μL of 5% (w/v) trichloroacetic acid, mix and incubate at 50 ° C for 30 minutes. After centrifugation at 2400 rpm for 10 minutes, 40 μL of the supernatant was taken into a 96-well V-bottom plate, and a precipitant was added. After mixing, centrifuge at 4000 rpm for 10 minutes. Transfer 100 μL of supernatant to a new 96-well V-bottom plate. The content of kynurenine was measured by LC-MS.

Analysis data:

The reference well to which γ-type interferon was added but no compound was added was determined to have a 0% inhibition rate, and the reference well to which Hela cells were not added was determined to have a 100% inhibition rate, and the IC50 value of the compound was calculated by analyzing the data using XLFit 5 .

The experimental results are shown in Table 1:

Claims (29)

a compound of formula I or a pharmaceutically acceptable salt thereof, Wherein D ^{41 is} selected from the group consisting of NH, N(OH), O, S, -NHC(=O)NH-, -NHC(=O)CH ₂ -, -NHC(=O)CH(CH ₃ )-, - NHC(=O)-, S(=O) and S(=O) ₂ ; R ^{41 is} selected from C _5-6 cycloalkyl, 5- to 12-membered heterocyclic ring optionally substituted by 1, 2 or 3 R An alkyl group, a 6 to 12 membered aryl group, a 5 to 12 membered heteroaryl group, N(R ⁴² R ⁴³ ), and R ⁴⁴ —LR ⁴⁵ ; R ⁴² and R ⁴³ are each independently selected from the group consisting of 1, 2 or 3 R substituted C _1-3 alkyl, C _3-6 cycloalkyl and 5-6 membered aryl C _1-3 alkyl; R ^{44 is} selected from 5~ optionally substituted by 1, 2 or 3 R 6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl and 5-9 membered heteroaryl; R ^{45 is} selected from C _1-6 optionally substituted by 1, 2 or 3 R Alkyl, 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl and 5-9 membered heteroaryl; L is selected from the group consisting of a single bond, O, S, C (=O) And C(=O)O; R is selected from the group consisting of OH, NH ₂ , F, Cl, Br, I, CN, COOH, oxo, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , NHCH ₃ , N (CH ₃ ) ₂ and . The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^{41 is} selected from C _5-6 cycloalkyl, 5- to 6-membered heterocycloalkyl optionally substituted by 1, 2 or 3 R, 5~ 12-membered aryl, 5- to 12-membered heteroaryl, N(R ⁴² R ⁴³ ), and R ⁴⁴ -LR ⁴⁵ . The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^{45 is} selected from 5 to 6 membered cycloalkyl, 5 to 6 membered heterocycloalkyl optionally substituted by 1, 2 or 3 R; 5 to 6 member aryl groups and 5 to 9 member heteroaryl groups. A compound according to any one of claims 1 to 3, wherein L is selected from the group consisting of a single bond, O, S and C (=O), or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of OH, NH ₂ , F, Cl, Br, I, CN, COOH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , NHCH ₃ , N(CH ₃ ) ₂ and . The compound of any one of claims 1 to 5, wherein D ^{41 is} selected from the group consisting of N(OH), S, -NHC(=O)NH-, -NHC(=O)CH ₂ -, -NHC(=O)CH(CH ₃ )-, -NHC(=O)-, S(=O) and S(=O) ₂ . The compound of any one of claims 1 to 6, wherein R ^{41 is} selected from cyclopentyl, cyclohexyl, optionally substituted by 1, 2 or 3 R, or a pharmaceutically acceptable salt thereof. , , , , , , , Losing a hydrogen atom at any position , Preferably, R ^{41 is} selected from the group consisting of optionally substituted by 1, 2 or 3 R , , , , Further preferably, R ^{41 is} selected from , , , , , , The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ^{41 is} selected from the group consisting of optionally substituted by 1, 2 or 3 R , , , , Preferably, R ^{41 is} selected from , , , , , The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R ⁴² and R ⁴³ are each independently selected from methyl, ethyl, propyl optionally substituted by 1, 2 or 3 R , isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl CH ₂ , phenyl CH ₂ CH ₂ , phenyl CH ₂ CH ₂ CH ₂ and phenyl CH(CH ₃ )CH ₂ . The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R ⁴² and R ⁴³ are each independently selected from Me, optionally substituted by 1, 2 or 3 R, , , with Preferably, R ⁴² and R ⁴³ are each independently selected from Me, , , with . The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, N(R ⁴² R ⁴³ ) is selected from , , , , The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R ^{44 is} selected from any of the positions optionally substituted by 1, 2 or 3 R to lose 2 hydrogen atoms. , , , , , And benzene; preferably, R ^{44 is} selected from the group consisting of phenylene and acridinyl optionally substituted by 1, 2 or 3 R; further preferably, R ^{44 is} selected from , , with . The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ^{44 is} selected from phenylene and acridinyl optionally substituted by 1, 2 or 3 R; preferably, R ₄₄ Selected from , with . The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R ^{45 is} selected from methyl, ethyl, propyl, isopropyl, butyl optionally substituted by 1, 2 or 3 R Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, pyridazinyl, phenyl, pyrimidinyl, pyrazolyl, which loses 1 hydrogen atom at any position , imidazolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl and [1,2,4]triazolo[4,3-a]pyridinyl; preferably, R ^{45 is} selected from the group consisting of 2 or 3 R-substituted tert-butyl, cyclohexyl, phenyl, pyrimidinyl, pyrazolyl and [1,2,4]triazolo[4,3-a]pyridines which lose 1 hydrogen atom at any position Further preferably, R ^{45 is} selected from t-butyl groups optionally substituted by 1, 2 or 3 R, , , Still more preferably, R ^{45 is} selected from , , , , , The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R ^{45 is} selected from cyclohexyl, pyridazinyl, phenyl, pyrimidinyl, pyridyl optionally substituted by 1, 2 or 3 R An azolyl, imidazolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl and [1,2,4]triazolo[4,3-a]pyridine; preferably, R _{45 is} selected from the group consisting of 1, 2 or 3 R substituted , , , More preferably, R _{45 is} selected , , , , , The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a single bond, O, C(=O), and C(=O)O. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R ⁴⁴ -LR ^{45 is} selected from , , , , The compound of any one of claims 1 to 17, wherein R is selected from the group consisting of F, Cl, CN, oxo, Me, CF ₃ and . The compound of any one of claims 1 to 18, which is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: The compound of any one of claims 1 to 18, which is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: A pharmaceutical composition comprising the compound of any one of claims 1 to 20 or a pharmaceutical thereof An acceptable salt and one or more pharmaceutically acceptable carriers or excipients. A method of treating an immunosuppressive disease mediated by guanidine 2,3-dioxygenase (IDO), the method comprising administering to a subject in need thereof a compound of any one of items 1-20, or a pharmaceutically acceptable thereof Salt or the pharmaceutical composition of claim 21. The method of claim 22, wherein the immunosuppressive disease is associated with an infectious disease or cancer. The method of claim 22 or 23, wherein the infectious disease is selected from the group consisting of influenza, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), poliovirus , herpes zoster virus, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV) or Coxsackie virus. The method of claim 22 or 23, wherein the cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head or neck cancer, lymphatic Tumor, leukemia or melanoma. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, prepared for the treatment of mediated by 吲哚2,3-dioxygenase (IDO) Use in drugs for immunosuppressive diseases. The use of claim 26, wherein the immunosuppressive disease is associated with an infectious disease or cancer. The use of claim 26 or 27, wherein the infectious disease is selected from the group consisting of influenza, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), poliovirus , herpes zoster virus, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV) or Coxsackie virus. The use of claim 26 or 27, wherein the cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head or neck cancer, lymphatic Tumor, leukemia or melanoma.