WO2021136464A1

WO2021136464A1 - Novel amide compounds and uses thereof

Info

Publication number: WO2021136464A1
Application number: PCT/CN2020/141883
Authority: WO
Inventors: Guangxiu Dai; Kun Xiao; Zheng Zhang
Original assignee: Hutchison Medipharma Limited
Priority date: 2020-01-02
Filing date: 2020-12-31
Publication date: 2021-07-08
Also published as: AR120935A1; TW202128647A

Abstract

The present invention relates to novel amide compounds, pharmaceutical compositions comprising the same, methods for preparing the same, and uses thereof.

Description

Novel amide compounds and uses thereof

Field of the Invention

The present invention relates to novel amide compounds, pharmaceutical compositions thereof, methods for preparing thereof, and uses thereof.

Background of the Invention

In mammalian cells, the amino acid L-tryptophan (L-Trp) is mainly catabolized via the so-called “kynurenine pathway” , i.e., the metabolic cascade that converts it into L-kynurenine. The first step, from L-tryptophan to N-formyl-L-kynurenine is the rate-limiting step of the kynurenine metabolic pathway. The present study suggests that there are mainly three enzymes, namely, IDO1 (indoleamine 2, 3-dioxygenase 1) , IDO2 (indoleamine 2, 3-dioxygenase 2) , and TDO (tryptophan 2, 3-dioxygenase) , participated in the L-tryptophan metabolic reactions as shown in the figure below.

IDO1, as a 45Kd monomer, is a cytosolic haem enzyme encoded by the INDO gene on human chromosome 8p22. It is expressed ubiquitously in various tissues and cells throughout the body, including immune cells, endothelial cells, and fibroblasts. The expression of IDO1 is mainly regulated by inflammatory cues, such as IFNγ, CpG-DNA, and LPS. IDO2 is encoded by the INDOL1 gene, and is structurally very similar to IDO1 with about 42%similarity at the amino acid level, but is of very low enzymatic activity based on in vitro studies. In addition, the high incidence of genetic polymorphisms exist for human IDO2, abolishing the enzyme’s function. At present, the research on the biological function of IDO2 is still insufficient. TDO is encoded by the TDO2 gene, and expressed in high levels in the liver, and is functionally related to IDO1 and IDO2, but structural similarities at the amino acid level are only 10%. TDO was thought to be mainly responsible for L-tryptophan homoeostasis in the body. More recently, studies have found that certain tumors mediate the tolerance of tumor cells to the host's immune system by highly expressing TDO. No TDO expression in host immune cells has been documented so far.

IDO1 expression is closely related to the occurrence and development of cancers. The studies found that in a variety of primary and metastatic human tumors, such as acute myeloid leukemia, lung cancer, melanoma, the high expression of IDO1 is correlated with tumor malignancy, metastasis and prognosis, suggesting that IDO1 may be a potential therapeutic target. In the tumor microenvironment, some pro-inflammatory mediators such as IFNγ can induce the expression of IDO1 in tumor cells or host immune cells (mainly antigen presenting cells, such as dendritic cells, macrophages, etc. ) . These induced expression of IDO1 catalyze the metabolic reaction of L-tryptophan, through simultaneously reducing the concentration of L-tryptophan and increasing the production of L-kynurenine and its further metabolites (such as 3-hydroxykynurenine and 3-hydroxy-2-aminobenzoic acid, etc. ) to inhibit the proliferation of effector lymphocytes, such as T cells and NK cells, and induce their entry into cell cycle arrest and apoptosis. At the same time, the immunosuppressive regulatory T cells are up-regulated, thereby helping the tumor cells to escape the host's immune surveillance and obtain a chance of malignant growth.

Preclinical animal experiments have shown the effectiveness of targeting IDO1. For example, using the gene knockout IDO1 protein, or using IDO1 small molecule inhibitors such as INCB024360 (Epacadostat) and NLG919 to inhibit IDO1 protein activity, can effectively reduce the level of kynurenine in animals, thereby relieves IDO1-mediated tumor tolerant to the host's immune system, activates effector cells such as T cells and NK cells, and thus acts to inhibit tumor growth. Now, some IDO1 inhibitors (such as INCB024360, BMS-986205, and Pf-06840003) or IDO1/TDO small molecule inhibitors (such as NLG919) have entered early clinical trials. Early clinical trials have shown that targeting IDO1 is a safe treatment and patients who participated in the trials showed good tolerance. In addition, after treatment with IDO1 small molecule inhibitors for a period of time, the decreasing kynurenine levels with varying degrees were observed in both patient plasma and tumor. Moreover, early efficacy data showed that IDO1 inhibitors combined with immune checkpoint CTLA4 or PD1 antibodies showed better efficacy in some tumors than single agents, for example, the phase 1/2 clinical trial of the IDO1 inhibitor INCB024360 combined PD-1 antibody Pembrolizumab in melanoma patients showed an objective response rate (ORR) of 58%, and was significantly better than the clinical trial data of Pembrolizumab alone (phase 3, ORR, 32.9%) . These results indicate that IDO1 is a potential target for the treatment of malignancies (ESMO, 2016, Abstract 1110PD; ASCO, 2017, Abstract 4503; JCO. 2017.35 (15 suppl) : Abstract 1103; JCO. 2017.35 (15 suppl) : Abstract 3003; Cancer Res., 2017, 77 (13 Suppl) : Abstract CT116; Analyst and Investor Day Meeting, NewLink Genetics Corporation, October 25, 2016) .

In addition to tumors, other diseases such as chronic infection, HIV, multiple sclerosis, and neurological depression are also associated with IDO1 activity. Therefore, IDO1 inhibitors may also be used to develop treatments for these diseases (Trends Immunol., 2013, 34 (3) : 137-143) . There is currently no approved targeting IDO1 drugs on the market, and IDO1 inhibitors currently entering clinical research have some drawbacks, and new IDO1 inhibitors are still needed to treat these diseases, especially cancer. The present invention addresses these needs.

Summary of the Invention

Provided is a compound of formula (I) :

or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is hydrogen, deuterium, -OH, C _1-6 alkyl, C _1-6 haloalkyl, -O (C _1-6 alkyl) , - (C _1-6 alkylene) _n-C _3-6 cycloalkyl or - (C _1-6 alkylene) _n-4-6 membered heterocyclyl, wherein C _1-6 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl, as a group or as part of a group, is each optionally substituted with one or more groups chosen from: deuterium, halogen, -CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, -O (C _1-6 alkyl) or -O (C _1-6 haloalkyl) ;

R ₂ is - (C _1-6 alkylene) _n-phenyl, - (C _1-6 alkylene) _n-4-6 membered heterocyclyl or - (C _1-6 alkylene) _n-5-12 membered heteroaryl; the phenyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl is each optionally substituted with one or more groups chosen from: deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, -O (C _1-6 alkyl) , -O (C _1-6 haloalkyl) or C _3-6 cycloalkyl;

R ₃ is hydrogen, deuterium, halogen or -OH;

R ₄ is halogen or C _1-6 haloalkyl;

X ₁, X ₂, X ₃ and X ₄ are each independently chosen from N or CR ₅; provided that at least one of X ₁, X ₂, X ₃ and X ₄ is N, and at least one of X ₁, X ₂, X ₃ and X ₄ is CR ₅;

R ₅ on X ₁, X ₂, X ₃ or X ₄, if present, is each independently chosen from: hydrogen, deuterium, halogen, -OH, -CN, -NH ₂, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, -O (C _1-6 alkyl) , -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, - (C _1-6 alkylene) _n-C _3-6 cycloalkyl or - (C _1-6 alkylene) _n-4-6 membered heterocyclyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl, as a group or as part of a group, is each optionally substituted with one or more groups chosen from: deuterium, halogen, -CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, -O (C _1-6 alkyl) or -O (C _1-6 haloalkyl) ; and

n is 0, 1 or 2.

The above compounds and the active compounds (including genus structural formula compounds and specific compounds) disclosed in the context of the present invention, including pharmaceutically acceptable salts thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof, which are covered by the above scope, are collectively referred to as "compounds of the present invention" .

Also provided is a pharmaceutical composition, comprising the compounds of the present invention, and optionally comprising a pharmaceutically acceptable excipient.

Also provided is a method of in vivo or in vitro inhibiting the activity of IDO1, comprising contacting IDO1 with an effective amount of the compounds of the present invention.

Also provided is a method of treating or preventing a disease mediated by IDO1 or at least in part by IDO1, comprising administering to the subject in need thereof an effective amount of the compounds of the present invention.

Also provided is a method of treating or preventing cancer, an autoimmune disease, obesity or an obesity-related disease, comprising administering to the subject in need thereof an effective amount of the compounds of the present invention.

Also provided is a use of the compounds of the present invention for treating or preventing a disease mediated by IDO1 or at least in part by IDO1.

Also provided is a use of the compounds of the present invention for treating or preventing cancer, an autoimmune disease, obesity or an obesity-related disease.

Also provided is a use of the compounds of the present invention in the manufacture of a medicament for treating or preventing a disease mediated by IDO1 or at least in part by IDO1.

Also provided is a use of the compounds of the present invention in the manufacture of a medicament for treating or preventing cancer, an autoimmune disease, obesity or an obesity-related disease.

Detailed Description of the Invention

Definitions

As used in the present application, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

A dash ( “-” ) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -OR ³ refers to the attachment of R ³ to the rest of the molecule through an oxygen atom.

The term “alkyl” as used herein refers to a straight or branched saturated hydrocarbon radical containing 1-18 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms, and further more preferably 1-4 carbon atoms. When the term "alkyl" is prefixed with "C" , it means the number of carbon atoms. For example, “C _1-6 alkyl” refers to an alkyl containing 1-6 carbon atoms. “C _1-4 alkyl” refers to an alkyl containing 1-4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (eg. n-propyl, i-propyl) , butyl (eg. n-butyl, i-butyl, s-butyl and t-butyl) , pentyl (eg. n-pentyl, i-pentyl, neo-pentyl) , and hexyl, and the like.

The term “alkenyl” as used herein refers to a straight or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2, or 3 carbon-carbon double bonds (C=C) and 2-18 carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms, and further more preferably 2-4 carbon atoms. When the term "alkenyl" is prefixed with "C" , it means the number of carbon atoms. For example, “C _2-6 alkenyl” refers to an alkenyl containing 2-6 carbon atoms. “C _2-4 alkenyl” refers to an alkenyl containing 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl (eg. 2-propenyl) , and butenyl (eg. 2-butenyl) , and the like. The point of attachment for the alkenyl can be on or not on the double bonds.

The term “alkynyl” as used herein refers to a straight or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2, or 3, carbon-carbon triple bonds (C≡C) and 2-18 carbon atoms, preferably 2-10 cabon atoms, more preferably 2-6 carbon atoms, and further more preferably 2-4 carbon atoms. When the term "alkynyl" is prefixed with "C" , it means the number of carbon atoms. For example, “C _2-6 alkynyl” refers to an alkynyl containing 2-6 carbon atoms. “C _2-4 alkynyl” refers to an alkynyl containing 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl (eg. 2-propynyl) , and butynyl (eg. 2-butynyl) , and the like. The point of attachment for the alkynyl can be on or not on the triple bonds.

The term “alkylene” as used herein refers to a straight or branched saturated bivalent hydrocarbon radical containing 1-18 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms, and further more preferably 1-4 carbon atoms. When the term "alkylene " is prefixed with "C" , it means the number of carbon atoms. For example, “C _1-6 alkylene” refers to an alkylene containing 1-6 carbon atoms. “C _1-4 alkylene” refers to an alkylene containing 1-4 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH ₂-) , ethylene (-CH ₂CH ₂-) , propylene (-CH2CH2CH2-or-CH (CH3) CH2-) , butylene (eg. n-butylene, sec-butylene, iso-butylene, and t-butylene) , pentylene (eg. n-pentylene, i-pentylene, neo-pentylene) , and hexylene, and the like.

The term “halogen” or “halo” as used herein means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro.

The term “haloalkyl” as used herein refers to an alkyl radical, as defined herein, in which one or more, for example 1, 2, 3, 4, or 5, hydrogen atoms are replaced with halogen atom, and when more than one hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other. In certain embodiment, the term “haloalkyl” as used herein refers to an alkyl radical, as defined herein, in which two or more, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are identical to each other. In another embodiment, the term “haloalkyl” as used herein refers to an alkyl radical, as defined herein, in which two or more hydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are different from each other. When the term "haloalkyl" is prefixed with "C" , it means the number of carbon atoms. For example, “C _2- ₆ haloalkyl” refers to a haloalkyl as defined herein containing 2-6 carbon atoms. “C _2-4 haloalkyl” refers to a haloalkyl as defined herein containing 2-4 carbon atoms. Examples of haloalkyl groups include, but are not limited to, -CF ₃, -CHF ₂, -CH ₂F, -CH ₂CF ₃, -CH (CF ₃) ₂, and the like.

The term “cycloalkyl” as used herein refers to saturated or partially unsaturated cyclic hydrocarbon radical having 3-12 ring carbon atoms, such as 3-8 ring carbon atoms, 5-7 ring carbon atoms, 4-7 ring carbon atoms or 3-6 ring carbon atoms, which may have one or more rings, such as 1, 2, or 3 rings, preferably 1 or 2 rings. When the term "cycloalkyl" is prefixed with "C" , it means the number of carbon atoms. For example, “C _3-12 cycloalkyl” refers to a cycloalkyl containing 3-12 carbon atoms in the ring, “C _3-8 cycloalkyl” refers to a cycloalkyl containing 3-8 carbon atoms in the ring, “C _3-6 cycloalkyl” refers to a cycloalkyl containing 3-6 carbon atoms in the ring. “Cycloalkyl” also includes a fused or bridged ring, or a spirocyclic ring. The rings of the cycle group may be saturated or has one or more, for example, one or two double bonds (i.e. partially unsaturated) , but not fully conjugated, and not an aryl as defined herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [4.1.0] heptyl, bicyclo [3.1.1] heptyl, spiro [3.3] heptyl, spiro [2.2] pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and bicyclo [3.1.1] hepta-2-ene.

The term “heterocycle” , “heterocyclyl” or “heterocyclic” as used herein can be used interchangeably and each refers to saturated or partially unsaturated cyclic radicals having 3-12 ring atoms, such as 3-8 ring atoms, 5-7 ring atoms, 4-7 ring atoms, 4-6 ring atoms or 3-6 ring atoms, and containing one or more, for example 1, 2 or 3, preferably 1 or 2 heteroatoms independently chosen from N, O and S in the rings, with the remaining ring atoms being carbon; it may have one or more rings, for example 1, 2 or 3, preferably 1 or 2 rings. The heterocycle group also includes those wherein the N or S heteroatom are optionally oxidized to various oxidation states. The point of attachment of heterocyclyl can be on the N heteroatom or carbon. For example, “3-12 membered heterocyclyl” refers to a heterocyclyl containing 3-12 ring atoms and containing at least one heteroatom independently chosen from N, O and S, “4-6 membered heterocyclyl” refers to a heterocyclyl containing 4-6 ring atoms and containing at least one heteroatom independently chosen from N, O and S. The heterocycle group also includes a fused or bridged ring, or a spirocyclic ring. The rings of the heterocycle group may be saturated or has one or more, for example, one or two double bonds (i.e. partially unsaturated) , but not fully conjugated, and not a heteroaryl as defined herein. Examples of heterocyclyl groups include, but are not limited to, 4-6 membered heterocyclyl, for example oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, pyrazolidinyl, and oxaspiro [3.3] heptanyl.

The term “aryl” or “aromatic ring” as used herein can be used interchangeably and each refers to carbocyclic hydrocarbon radical of 6 to 14 carbon atoms consisting of one ring or more fused rings, wherein at least one ring is an aromatic ring, for example phenyl, naphthalenyl, 1, 2, 3, 4-tetrahydronaphthalenyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthalenyl.

The term “heteroaryl” or “heteroaromatic ring” as used herein can be used interchangeably and each refers to: mono-, bi-, or tri-ring system having 5-15 ring atoms, preferably 5-12 ring atoms, more preferably 5-10 ring atoms, and most preferably 5-6 or 9-10 ring atoms, wherein at least one ring is 5-or 6-aromatic ring containing one or more, for example 1 to 4, heteroatoms independently chosen from N, O, and S. Preferably, heteroaryl is 5-12 membered heteroaryl. For example, said heteroaryl includes:

- 5-7 membered heteroaryl, preferably 5-6 membered heteroaryl, i.e. monocyclic aromatic hydrocarbon radical having 5, 6 or 7 ring atoms, preferably having 5 or 6 ring atoms, and containing one or more, for example 1, 2, 3 or 4, preferably 1, 2 or 3 heteroatoms independently chosen from N, O, and S (preferably N and O) in the ring, with the remaining ring atoms being carbon; and

- 8-12 membered heteroaryl, preferably 9-10 membered heteroaryl, i.e. bicyclic aromatic hydrocarbon radical having 8-12 ring atoms, preferably having 9 or 10 ring atoms, and containing one or more, for example, 1, 2, 3 or 4, preferably 1, 2 or 3 heteroatoms independently chosen from N, O, and S (preferably N) in the rings, with the remaining ring atoms being carbon, wherein both of the two rings are aromatic.

When the total number of S and O atoms in the heteroaryl group exceeds 1, said S and O heteroatoms are not adjacent to one another.

Examples of the heteroaryl group include, but are not limited to, 5-6 membered heteroaryl, for example pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, triazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (such as 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, and 1, 3, 4-oxadiazolyl) , thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl; and the bicyclic heteroaryl, for example benzooxazolyl, benzoisoxazolyl, benzothienyl, benzoisothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl (such as imidazo [1, 2-a] pyridyl) , imidazopyridazinyl (such as imidazo [1, 2-b] pyridazinyl) , indazolyl, pyrrolopyridyl (such as 1H-pyrrolo [2, 3-b] pyridyl) , pyrrolopyrimidinyl (such as pyrrolo [3, 4-d] pyrimidinyl) , pyrazolopyridyl (such as 1H-pyrazolo [3, 4-b] pyridyl) , pyrazolopyrimidinyl (such as pyrazolo [1, 5-a] pyrimidinyl) , triazolopyridyl (such as [1, 2, 4] triazolo [4, 3-a] pyridyl and [1, 2, 4] triazolo [1, 5-a] pyridyl) , tetrazolopyridyl (such as tetrazolo [1, 5-a] pyridyl) , benzofuryl, indolyl, indazolyl, purinyl, quinolinyl, and isoquinolinyl.

Term “–OH” as used herein refers to hydroxyl radical.

Term “–CN” as used herein refers cyano radical.

Any asymmetric atom (e.g. carbon, etc. ) of a compound of formula (I) may exist in an racemic or enantiomeric rich form, for example in (R) -, (s) -or (RS) -configuration. In some embodiments, asymmetric atoms have at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%enantiomeric excess in (R) -or (s) configurations, respectively.

When a structural formula or chemical name herein contains " (RS) " , it means any mixture of (R) configuration and (s) configuration of the compound.

When a structure herein contains an asterisk “*” , it means that the chiral center of the compound marked by “*” is in either R-configuration or S-configuration, and the content of the compound with single configuration marked by “*” is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between those enumerated values) .

The term “optional” or “optionally” as used herein means that the subsequently described event or circumstance may or may not occur, and the description includes instances wherein the event or circumstance occur and instances in which it does not occur. For example, “optionally substituted alkyl” encompasses both “unsubstituted” and “substituted” alkyl as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, chemically incorrect, synthetically non-feasible and/or inherently unstable.

The term “substituted” or “substituted with…” , as used herein, means that one or more (such as, 1, 2, 3 or 4) hydrogens on the designated atom or group are replaced with one or more (such as 1, 2, 3 or 4) substituents, preferably the substituents chosen from the indicated group of substituents or radicals, provided that the designated atom's normal valence is not exceeded. The said substituents may be the same or different from each other. The term “substituted with one or more substituents” as used herein means that one or more hydrogens on the designated atom or group are independently replaced with one or more radicals from the indicated group of substituents or radicals, wherein the said radicals may be the same or different from each other. In some embodiments, “substituted with one or more substituents” means that the designated atom or group is substituted with 1, 2, 3, or 4 radicals independently chosen from the indicated group of substituents or radicals, wherein the said radicals may be the same or different from each other. In some embodiments, when a substituent is oxo (i.e., =O) , then 2 hydrogens on a single atom are replaced by the oxo. An optional substituent can be any radicals, provided that combinations of substituents and/or variables result in a chemically correct and stable compound. A chemically correct and stable compound is meant to imply a compound that is sufficiently robust to survive sufficient isolation from a reaction mixture to be able to identify the chemical structure of the compound, and also sufficiently robust to allow subsequent formulation as an agent having at least one practical utility. Preferably, substituents are those exemplified in the compounds of the embodiment of the present application.

Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl) alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.

It will be appreciated by the person of ordinary skill in the art ( “POSITA” ) that some of the compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms. The racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers when there are two chiral centers, and mixtures partially enriched with specific diastereomers are within the scope of the present invention. It will be further appreciated by the POSITA that the present invention includes all the individual stereoisomers (e.g. enantiomers) , racemic mixtures or partially resolved mixtures of the compounds of formula (I) and, where appropriate, the individual tautomeric forms thereof.

The racemates can be used as such or can be resolved into their individual isomers. The resolution can afford stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separation of isomers are well known (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry" , Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using a chiral adsorbent. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, individual isomers can be separated chemically from a mixture by: forming diastereomeric salts with a chiral acid (such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like) , fractionally crystallizing the salts, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of >95%. Alternatively, the racemates can be covalently linked to a chiral compound (auxiliary) to produce diastereomers which can be separated by chromatography or by fractional crystallization after which time the chiral auxiliary is chemically removed to afford the pure enantiomers, as is known to the POSITA.

The term “tautomer” as used herein refers to constitutional isomers of compounds generated by rapid movement of an atom in two positions in a molecule. Tautomers readily interconvert into each other, e.g., enol form and ketone form are tipical tautomers.

A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound of Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. For example, an acid addition salt includes such as a salt derived from an inorganic acid and an organic acid. Said inorganic acid includes such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid; said organic acid includes such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. For examples, see, generally, S. M. Berge, et al., “Pharmaceutical Salts” , J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.

In addition, if a compound of the present invention herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. The POSITA will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts.

The term "deuterated compound" or “deuterates” refers to a compound in which one or more hydrogen atoms, such as 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by deuterium atoms (d) .

The term “solvates” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water, or less than one molecule of water, with one molecule of the substances in which the water retains its molecular state as H ₂O, such combination being able to form one or more hydrates, for example, hemihydrate, monohydrate, and dihydrate.

As used herein, the terms “group (s) ” and “radical (s) ” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to other fragments of molecules.

The term “active ingredient” is used to indicate a chemical substance which has biological activity. In some embodiments, an “active ingredient” is a chemical substance having pharmaceutical utility.

The terms “treating” or “treatment” or “prevention” of a disease or disorder, in the context of achieving therapeutic benefit, refer to administering one or more pharmaceutical substances, especially a compound of formula (I) described herein to a subject that has the disease or disorder, or has a symptom of a disease or disorder, or has a predisposition toward a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition toward the disease or disorder. In some embodiments, the disease or disorder is cancer. In another embodiment, the disease or disorder is an autoimmune disease. In another embodiment, the disease or disorder is obesity or an obesity-related disease.

The terms “treating” , “contacting” and “reacting, ” in the context of a chemical reaction, mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately lead to the formation of the indicated and/or the desired product.

The term “effective amount” as used herein refers to an amount or dose of an IDO1 inhibiting agent sufficient to generally bring about a therapeutic benefit in patients in need of treatment for a disease or disorder mediated by IDO1 or at least in part by IDO1. Effective amounts or doses of the active ingredient of the present disclosure may be ascertained by methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the attending physician.

An exemplary dose is in the range of from about 0.0001 to about 200 mg of active agent per kg of subject's body weight per day, such as from about 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID) . For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 5 g/day. Once improvement of the patient's disease or disorder has occurred, the dose may be adjusted for maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

The term “inhibition” or “inhibiting” indicates a decrease in the baseline activity of a biological activity or process. The term “inhibition of IDO1 activity” is a practical pharmaceutical activity for purposes of this disclosure and refers to a decrease in the activity of IDO1 as a direct or indirect response to the presence of the compound of the present invention, relative to the activity of IDO1 in the absence of the compound of the present invention. The decrease in activity may be due to the direct interaction of the compound of the present invention with IDO1, or due to the interaction of the compound of the present invention, with one or more other factors that in turn affect the IDO1 activity. For example, the presence of the compound of the present invention may decrease the IDO1 activity by directly binding to the IDO1, by causing (directly or indirectly) another factor to decrease the IDO1 activity, or by (directly or indirectly) decreasing the amount of IDO1 present in the cell or organism.

The term “subject” as used herein means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “subject” does not denote a particular age or sex. In some embodiments, the subject is a human.

In general, the term “about” is used herein to modify a numerical value above or below the stated value by a variance of 20%.

Technical and scientific terms used herein and not specifically defined have the meaning commonly understood by the POSITA to which the present disclosure pertains.

Detailed Description of Embodiments

Embodiment 1. A compound of formula (I) :

R ₃ is hydrogen, deuterium, halogen or -OH;

R ₄ is halogen or C _1-6 haloalkyl;

n is 0, 1 or 2.

Embodiment 2. The compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁ is hydrogen, deuterium, -OH, C _1-6 alkyl, C _1-6 haloalkyl or -O (C _1-6 alkyl) .

Embodiment 3. The compound of formula (I) according to embodiment 2, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁ is C _1-6 alkyl.

Embodiment 4. The compound of formula (I) according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is phenyl or 5-12 membered heteroaryl (e.g., 5-6 membered heteroaryl or a 9-10 membered heteroaryl) , each of which is optionally substituted with one or more groups chosen from: deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, -O (C _1-6 alkyl) , -O (C _1-6 haloalkyl) or C _3-6 cycloalkyl.

Embodiment 5. The compound of formula (I) according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is phenyl, which is optionally substituted with one or more groups chosen from halogen, C _1- ₆ alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl; or R ₂ is 5-6 membered heteroaryl or 9-10 membered heteroaryl, each of which is optionally substituted with one or more groups chosen from: halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl.

Embodiment 6. The compound of formula (I) according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is

wherein X, Y and Z are each independently N or CH, and R _a is chosen from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl.

Embodiment 7. The compound of formula (I) according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is

wherein R _a is chosen from hydrogen, deuterium, halogen, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl; or R ₂ is

wherein X, Y and Z are each independently N or CH, provided that at least one of X, Y and Z is N, and wherein R _a is chosen from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl.

Embodiment 8. The compound of formula (I) according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₃ is hydrogen.

Embodiment 9. The compound of formula (I) according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein at least one of X ₁, X ₂, X ₃ and X ₄ is C-NH ₂.

Embodiment 10. The compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is C _1-6 alkyl;

R ₂ is phenyl, 5-12 membered heteroaryl (e.g., 5-6 membered heteroaryl or 9-10 membered heteroaryl) , each of which is optionally substituted with one or more groups chosen from: halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl;

R ₃ is hydrogen or deuterium;

R ₄ is halogen or C _1-6 haloalkyl; and

X ₁, X ₂, X ₃ and X ₄ are each independently chosen from N or CR ₅; provided that at least one of X ₁, X ₂, X ₃ and X ₄ is N, and at least one of X ₁, X ₂, X ₃ and X ₄ is CR ₅; R ₅ on X ₁, X ₂, X ₃ or X ₄, if present, is each independently chosen from hydrogen, deuterium or -NH ₂.

Embodiment 11. The compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is C _1-6 alkyl;

R ₂ is

wherein X, Y and Z are each independently N or CH, and R _a is chosen from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl;

R ₃ is hydrogen or deuterium;

R ₄ is halogen or C _1-6 haloalkyl; and

Embodiment 12. The compound of formula (I) according to embodiment 11, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is C _1-6 alkyl;

R ₂ is

wherein X, Y and Z are each independently N or CH, provided that at least one of X, Y and Z is N, and wherein R _a is chosen from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl;

R ₃ is hydrogen or deuterium;

R ₄ is halogen or C _1-6 haloalkyl; and

Embodiment 13. The compound of formula (I) according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein the compound of formula (I) is a compound of formula (I-1) , formula (I-2) or formula (I-3) :

wherein R ₁₁, R ₁₃, R ₁₄, R ₂₁, R ₂₃, R ₂₄, R ₃₁ and R ₃₃ are each independently chosen from hydrogen, deuterium or -NH ₂; and R ₁₂, R ₂₂ and R ₃₂ are chosen from halogen or C _1-6 haloalkyl.

Embodiment 14. The compound of formula (I) according to embodiment 13, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁₂, R ₂₂ and R ₃₂ are each independently chosen from F, Cl, Br or CF ₃.

Embodiment 15. The compound of formula (I) according to embodiment 13, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁₄ is -NH ₂; one of R ₂₁ and R ₂₄ is -NH ₂, and the other is hydrogen; and one of R ₃₁ and R ₃₃ is -NH ₂, and the other is hydrogen.

Embodiment 16. The compound of formula (I) according to embodiment 13, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁₁, R ₁₃ and R ₂₃ are each hydrogen.

Embodiment 17. The compound of formula (I) according to embodiment 13, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein the compound of formula (I) is a compound of formula (I-1) :

wherein R ₁₁, R ₁₃ and R ₁₄ are each independently chosen from hydrogen or -NH ₂; R ₁₂ is halogen or C _1-6 haloalkyl.

Embodiment 18. The compound of formula (I) according to embodiment 17, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein both R ₁₁ and R ₁₃ are hydrogen.

Embodiment 19. The compound of formula (I) according to embodiment 17, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁₂ is F, Cl or -CF ₃.

Embodiment 20. The compound of formula (I) according to embodiment 17, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁₄ is -NH ₂.

Embodiment 21. The compound of formula (I) according to embodiment 17, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is C _1-6 alkyl;

R ₂ is:

wherein X, Y and Z are each independently N or CH, and R _a is chosen from hydrogen, halogen, -CN, C _2-6 alkynyl or -O (C _1-6 alkyl) ;

R ₃ is hydrogen.

Embodiment 22. The compound of formula (I) according to embodiment 21, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is:

and R _a is chosen from halogen, C _2-6 alkynyl or -O (C _1-6 alkyl) .

Embodiment 23. The compound of formula (I) according to embodiment 13, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein the compound of formula (I) is a compound of formula (I-2) :

wherein R ₂₁, R ₂₃ and R ₂₄ are each independently chosen from hydrogen or -NH ₂; R ₂₂ is C _1-6 haloalkyl.

Embodiment 24. The compound of formula (I) according to embodiment 23, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂₁ and R ₂₄ are each independently chosen from hydrogen or -NH ₂.

Embodiment 25. The compound of formula (I) according to embodiment 23, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein one of R ₂₁ and R ₂₄ is -NH ₂, and the other is hydrogen.

Embodiment 26. The compound of formula (I) according to embodiment 23, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂₂ is -CF ₃.

Embodiment 27. The compound of formula (I) according to embodiment 23, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂₃ is hydrogen.

Embodiment 28. The compound of formula (I) according to embodiment 23, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is C _1-6 alkyl;

R ₂ is:

R ₃ is hydrogen.

Embodiment 29. The compound of formula (I) according to embodiment 28, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is

wherein R _a is chosen from C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl; or R ₂ is

and R _a is chosen from C _2-6 alkynyl.

Embodiment 30. The compound of formula (I) according to embodiment 13, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein the compound of formula (I) is a compound of formula (I-3) :

wherein R ₃₁ and R ₃₃ are each independently chosen from hydrogen or -NH ₂; R ₃₂ is C _1-6 haloalkyl.

Embodiment 31. The compound of formula (I) according to embodiment 30, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₃₂ is -CF ₃.

Embodiment 32. The compound of formula (I) according to embodiment 30, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₃₁ and R ₃₃ are each independently chosen from hydrogen or -NH ₂.

Embodiment 33. The compound of formula (I) according to embodiment 30, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is C _1-6 alkyl;

R ₂ is:

wherein X, Y and Z are each independently N or CH, and R _a is chosen from hydrogen, halogen, -CN or C _2-6 alkynyl;

R ₃ is hydrogen.

Embodiment 34. The compound of formula (I) according to embodiment 33, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is:

and R _a is chosen from halogen, -CN or C _2-6 alkynyl.

Embodiment 35. The compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein the compound is chosen from:

Embodiment 36. The compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is chosen from the compounds of the present invention prepared in the examples of the present invention.

Embodiment 37. A pharmaceutical composition, comprising the compound of formula (I) (e.g., any of those described herein) according to any one of embodiments 1 to 36, and/or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .

Embodiment 38. A method of in vivo or in vitro inhibiting the activity of IDO1, comprising contacting IDO1 with an effective amount of the compound of formula (I) (e.g., any of those described herein) according to any one of embodiments 1 to 36, and/or a pharmaceutically acceptable salt thereof.

Embodiment 39. Use of the compound of formula (I) (e.g., any of those described herein) according to any one of embodiments 1 to 36, and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease mediated by IDO1 or at least in part by IDO1.

Embodiment 40. The use according to embodiment 39, wherein the medicament is used for treating or preventing cancer, an autoimmune disease, obesity or an obesity-related disease.

Embodiment 41. The use according to embodiment 40, wherein the cancer is solid tumor or hematologic malignancy, such as leukemia, lymphoma or myeloma.

Embodiment 42. The use according to embodiment 40, wherein the cancer is chosen from skin cancer (such as melanoma and basal cancer) , lung cancer (such as non-small cell lung cancer) , kidney cancer (such as renal cell carcinoma) , head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer (such as hepatocellular carcinoma) , endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, brain tumors (such as including glioma and glioblastoma (GBM) ) , thyroid cancer, mesothelial endometrial carcinoma, choriocarcinoma, adrenal carcinoma, sarcoma (such as Kaposi’s sarcoma) , leukemia (such as acute myeloid leukemia (AML) , human acute monocytic leukemia (M (5) ) , acute lymphoblastic leukemia (ALL) ) , lymphoma (such as diffuse large B-cell lymphoma (DLBCL) ) or myeloma; the autoimmune disease is chosen from arthritis, such as rheumatoid arthritis, and collagen-induced arthritis; the obesity-related disease is chosen from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythms, arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, and angina pectoris) , cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and the like.

Embodiment 43. A method of treating or preventing a disease mediated by IDO1 or at least in part by IDO1 in a subject, comprising administering to the subject in need thereof an effective amount of the compound of formula (I) (e.g., any of those described herein) according to any one of embodiments 1 to 36, and/or a pharmaceutically acceptable salt thereof.

Embodiment 44. A method of treating or preventing cancer, an autoimmune disease, obesity or an obesity-related disease in a subject, comprising administering to the subject in need thereof an effective amount of the compound of formula (I) (e.g., any of those described herein) according to any one of embodiments 1 to 36, and/or a pharmaceutically acceptable salt thereof.

Embodiment 45. The compound of formula (I) according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof for use as a medicament.

Embodiment 46. The compound of formula (I) according to embodiment 45, or a pharmaceutically acceptable salt thereof for use as a medicament for treating or preventing a disease mediated by IDO1 or at least in part by IDO1 in a subject.

Embodiment 47. The compound of formula (I) according to embodiment 45, or a pharmaceutically acceptable salt thereof for use as a medicament for treating or preventing cancer, an autoimmune disease, obesity or an obesity-related disease.

Embodiment 48. The compound of formula (I) according to embodiment 47, or a pharmaceutically acceptable salt thereof, wherein the cancer is solid tumor or hematologic malignancy, such as leukemia, lymphoma or myeloma.

Embodiment 49. The compound of formula (I) according to embodiment 47, or a pharmaceutically acceptable salt thereof, wherein the cancer is chosen from skin cancer (such as melanoma and basal cancer) , lung cancer (such as non-small cell lung cancer) , kidney cancer (such as renal cell carcinoma) , head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer (such as hepatocellular carcinoma) , endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, brain tumors (such as including glioma and glioblastoma (GBM) ) , thyroid cancer, mesothelial endometrial carcinoma, choriocarcinoma, adrenal carcinoma, sarcoma (such as Kaposi’s sarcoma) , leukemia (such as acute myeloid leukemia (AML) , human acute monocytic leukemia (M (5) ) , acute lymphoblastic leukemia (ALL) ) , lymphoma (such as diffuse large B-cell lymphoma (DLBCL) ) or myeloma; the autoimmune disease is chosen from arthritis, such as rheumatoid arthritis, and collagen-induced arthritis; the obesity-related disease is chosen from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythms, arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, and angina pectoris) , cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and the like.

Embodiment 50. A combination, comprising the compound of formula (I) (e.g., any of those described herein) according to any one of embodiments 1 to 36, and/or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

Embodiment 51. The combination according to embodiment 50, wherein the additional therapeutic agent is chosen from an anti-neoplastic agent such as a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

Embodiment 52. The combination according to embodiment 51, wherein the immune checkpoint inhibitor or agonist is chosen from PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor or OX-40 agonist.

Embodiment 53. The combination according to embodiment 51, wherein the immune checkpoint inhibitor is chosen from pembrolizumab, nivolumab and ipilimumab.

Embodiment 54. A method of treating or preventing a disease mediated by IDO1 or at least in part by IDO1 in a subject, comprising administering to the subject in need thereof an effective amount of the compound of formula (I) (e.g., any of those described herein) according to any one of embodiments 1 to 36, and/or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent.

Embodiment 55. The method according to embodiment 54, wherein the disease mediated by IDO1 or at least in part by IDO1 is cancer, an autoimmune disease, obesity or an obesity-related disease.

Embodiment 56. The method according to embodiment 55, wherein the cancer is solid tumor or hematologic malignancy, such as leukemia, lymphoma or myeloma.

Embodiment 57. The method according to embodiment 55, wherein the cancer is chosen from skin cancer (such as melanoma and basal cancer) , lung cancer (such as non-small cell lung cancer) , kidney cancer (such as renal cell carcinoma) , head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer (such as hepatocellular carcinoma) , endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, brain tumors (such as including glioma and glioblastoma (GBM) ) , thyroid cancer, mesothelial endometrial carcinoma, choriocarcinoma, adrenal carcinoma, sarcoma (such as Kaposi’s sarcoma) , leukemia (such as acute myeloid leukemia (AML) , human acute monocytic leukemia (M (5) ) , acute lymphoblastic leukemia (ALL) ) , lymphoma (such as diffuse large B-cell lymphoma (DLBCL) ) or myeloma; the autoimmune disease is chosen from arthritis, such as rheumatoid arthritis, and collagen-induced arthritis; the obesity-related disease is chosen from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythms, arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, and angina pectoris) , cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and the like.

Embodiment 58. The method according to embodiment 54, wherein the additional therapeutic agent is an anti-neoplastic agent such as a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

Embodiment 59. The method according to embodiment 58, wherein the immune checkpoint inhibitor or agonist is chosen from PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor or OX-40 agonist.

Embodiment 60. The method according to embodiment 58, wherein the immune checkpoint inhibitor is chosen from pembrolizumab, nivolumab and ipilimumab.

Embodiment 61. Use of the compound of formula (I) (e.g., any of those described herein) according to any one of embodiments 1 to 36, and/or a pharmaceutically acceptable salt thereof in the manufacture of a product for in vivo or in vitro inhibiting the activity of IDO1.

General synthetic methods

The compound of the present invention can be synthesized using commercially available raw materials, by methods known in the art, or methods disclosed in the patent application. The synthetic routes shown in Scheme 1 and Scheme 2 illustrate the general synthetic methods for preparing the compounds of the present invention.

Method 1:

Scheme 1

As shown in Scheme 1, a compound of formula (1-1) is subjected to the coupling reaction with a compound of formula (1-2) in the presence of a palladium catalyst (such as, but not limited to Pd (PPh ₃) ₄) to obtain a compound of formula (1-3) ; the compound of formula (1-3) is hydrogenated in the presence of a palladium catalyst (e.g., Pd-C) to obtain a compound of formula (1-4) ; the compound of formula (1-4) is deprotected under acidic conditions (e.g., p-TSA) to obtain a compound of formula (1-5) ; then, the compound of formula (1-5) is subjected to the Wittig-Horner reaction with an organophosphine reagent (1-6) to obtain a compound of formula (1-7) ; the compound of formula (1-7) is subjected to the amine transesterification with a compound of formula (1-8) under alkaline conditions to obtain a compound of formula (1-9) ; finally, the compound of formula (1-9) is subjected to chiral resolution to obtain compounds of formula (1-10) and formula (1-11) . The compound of formula (1-7) can also be hydrolyzed to obtain a compound of formula (1-12) , and then the compound of formula (1-12) is subjected to the condensation reaction with the compound of formula (1-8) to obtain the compound of formula (1-9) ; or the compound of formula (1-12) is subjected to an acyl chloride reaction to obtain a compound of formula (1-13) , and then the compound of formula (1-13) is subjected to the ammonolysis reaction with the compound of formula (1-8) to obtain the compound of formula (1-9) .

Method 2:

Scheme 2

As shown in Scheme 2, the compound of formula (1-7) is subjected to chiral resolution to obtain a compound of formula (2-1) ; then the compound of formula (2-1) is subjected to the amine transesterification reaction with the compound of the formula (1-8) under alkaline conditions to obtain a compound of formula (2-2) .

The substituents of the compounds thus obtained can be further modified to provide other desired compounds. Synthetic chemistry transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989) ; L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994) ; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

Before use, the compound (s) of the present invention can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

Pharmceutical Compositions and Practical Utility

The compound of the present invention herein (e.g., any of those described herein) is used, alone or in combination with one or more additional therapeutic agent, to formulate pharmaceutical compositions. A pharmaceutical composition comprises: (a) an effective amount of one or more compounds of the present invention; (b) one or more pharmaceutically acceptable excipients (e.g., one or more pharmaceutically acceptable carriers) ; and optional (c) at least one additional therapeutic agent.

A pharmaceutically acceptable excipient refers to an excipient that is compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated. For example, solubilizing agents, such as cyclodextrins (which form specific, more soluble complexes with the compounds of the present invention) , can be utilized as pharmaceutical excipients for delivery of the active ingredients. Examples of other excipients or carries include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the art.

A pharmaceutical composition comprising a compound of the present invention herein can be administered in various known manners, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

A pharmaceutical composition described herein can be prepared in the form of tablet, capsule, sachet, dragee, powder, granule, lozenge, powder for reconstitution, liquid preparation, or suppository. In some embodiments, a pharmaceutical composition comprising a compound of the present invention herein is formulated for intravenous infusion, topical administration, or oral administration.

An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added to tablets. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

In some embodiments, the compound of the present invention can be present in an amount of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg in a tablet. In some embodiments, the compound of the present invention can be present in an amount of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg in a capsule.

A sterile injectable composition (e.g., aqueous or oleaginous suspension) can be formulated according to techniques known in the art using suitable dispersing or wetting agents (for example, Tween 80) and suspending agents. The sterile injectable medium can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono-or di-glycerides) . Fatty acids, such as oleic acid and its glyceride derivatives, and natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions, can be used as sterile injectable medium. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.

An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

A topical composition can be formulated in form of oil, cream, lotion, ointment, and the like. Suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin) , branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C12) . In some embodiments, the pharmaceutically acceptable carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in those topical formulations. Examples of such enhancers can be found in U.S. Patents 3,989,816 and 4,444,762.

Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. An example of such a cream is one which includes, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. An example of such an ointment is one which includes about 30%by weight almond oil and about 70%by weight white soft paraffin.

Suitable in vitro assays can be used to evaluate the practical utility of the compound of the present invention, in inhibiting the IDO1 activity. The compound of the present invention can further be examined for additional practical utility in treating cancer by in vivo assays. For example, the compound of the present invention can be administered to an animal (e.g., a mouse model) having cancer and its therapeutic effects can be accessed. If the pre-clinical results are successful, the dosage range and administration route for animals, such as humans, can be projected.

The compound of the present invention can be shown to have sufficient pre-clinical practical utility to merit clinical trials hoped to demonstrate a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.

As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies, such as leukemia, lymphoma or myeloma. The term "cancer" encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term "cancer" further encompasses primary and metastatic cancers.

Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC) , bronchioloalveolar carcinoma (BAC) , and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; endometrial cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; skin cancer, including, e.g., melanoma and basal carcinoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; sarcoma, including, e.g., Kaposi's sarcoma; adrenal carcinoma; mesothelial carcinoma; choriocarcinoma; muscle carcinoma; connective tissue carcinoma; and thyroid carcinoma.

Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML) ; chronic myelogenous leukemia (CML) , including accelerated CML and CML blast phase (CML-BP) ; acute lymphoblastic leukemia (ALL) ; chronic lymphocytic leukemia (CLL) ; Hodgkin's lymphoma; non-Hodgkin's lymphoma (NHL) ; follicular lymphoma; mantle cell lymphoma (MCL) ; B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL) ; multiple myeloma (MM) ; Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS) , including refractory anemia (RA) , refractory anemia with ringed siderblasts (RARS) , refractory anemia with excess blasts (RAEB) , and RAEB in transformation (RAEB-T) ; and myeloproliferative syndrome.

In some embodiments, solid tumors include melanoma, lung cancer (such as non-small cell lung cancer) , renal cell carcinoma, head and neck cancer (such as squamous cell carcinoma of the head and neck) , urothelial carcinoma, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular cancer, endometrial cancer, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, glioma, and glioblastoma (GBM) .

In some embodiments, exemplary hematologic malignancies include leukemia, such as acute lymphocytic leukemia (ALL) , acute myeloid leukemia (AML) , chronic lymphocytic leukemia (CLL) , and chronic myelogenous leukemia (CML) ; multiple myeloma (MM) ; and lymphoma, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL) , mantle cell lymphoma (MCL) , follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL) .

In some embodiments, cancer is chosen from skin cancer (such as melanoma and basal cancer) , lung cancer (such as non-small cell lung cancer) , kidney cancer (such as renal cell carcinoma) , head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer (such as hepatocellular carcinoma) , endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, brain tumors (such as including glioma and glioblastoma (GBM) ) , thyroid cancer, mesothelial endometrial carcinoma, choriocarcinoma, adrenal carcinoma, sarcoma (such as Kaposi’s sarcoma) , leukemia (such as acute myeloid leukemia (AML) , human acute monocytic leukemia (M (5) ) , acute lymphoblastic leukemia (ALL) ) , lymphoma (such as diffuse large B-cell lymphoma (DLBCL) ) or myeloma.

The compound of the present invention can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.

The compound of the present invention can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with an autoimmune disease, or in subjects with obesity or obesity-related disease.

The term “autoimmune disease” refers to a disease or disorder arising from and/or directed against an individual's own tissues or organs, or a co-segregate or manifestation thereof, or resulting condition therefrom. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD) , allergic rhinitis, lupus, myasthenia gravis, multiple sclerosis (MS) , arthritis (such as, rheumatoid arthritis (RA) , collagen induced arthritis) , psoriasis, inflammatory bowel disease (IBD) , asthma and idiopathic thrombocytopenic purpura, and myeloproliferative disease, such as myelofibrosis, post-Polycythemia vera/Essential Thrombocythemia myelofibrosis (post-PV/ET myelofibrosis) . In some embodiment, autoimmune disease is chosen from arthritis, such as, rheumatoid arthritis (RA) , collagen induced arthritis, and the like.

The term “obesity” refers to a condition caused by excessive accumulation of fat, especially triglycerides, in the body. Although for adults, "obesity" is generally defined as a body mass index (BMI) of 30 or higher, for the purposes of this patent application, any individual who needs or wishes to lose weight, including those with a body mass index below 30, is also included in the scope of "obesity" .

The term “obesity-related disease” refers to a disease or disorder that is associated with, caused by, or resulted from obesity. Examples of obesity-related diseases include, but are not limited to, diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythms, arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, angina pectoris) , cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and the like.

In addition, the compound of the present invention invention (e.g., any of those described herein) may be used in combination with additional active ingredients in the treatment of diseases or disorders as described herein, for example, cancer, autoimmune disease, obesity or obesity-related disease. The additional active ingredients may be coadministered separately with the compound of the present invention or included with such an ingredient in a pharmaceutical composition according to the disclosure, such as a fixed-dose combination drug product. In some embodiments, additional active ingredients are those that are known or discovered to be effective in the treatment of diseases mediated by IDO1 or at least in part by IDO1, such as another IDO1 inhibitor or a compound active against another target associated with the particular disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of the compound of the present invention) , decrease one or more side effects, or decrease the required dose of the compound of the present invention.

In some embodiments, the compound of the present invention (e.g., any of those described herein) is administered in conjunction with an anti-neoplastic agent. As used herein, the term "anti-neoplastic agent" refers to any agent that is administered to a subject with cancer for purposes of treating the cancer. The anti-neoplastic agents include, but are not limited to: radiotherapeutic agents, chemotherapeutic agents, immunotherapeutic agents, targeted therapeutic agents.

In some embodiments, the compound of the present invention (e.g., any of those described herein) is administered in conjunction with an immune checkpoint inhibitor, a targeted therapeutic agent, or a chemotherapeutic agent.

Non-limiting examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors, for example, anti-PD-1 antibodies, such as pembrolizumab and nivolumab; PD-L1 inhibitors, for example, anti-PD-L1 antibodies, such as atezolizumab, durvalumab, and avelumab; CTLA-4 inhibitors, for example, anti-CTLA-4 antibodies, such as ipilimumab; and BTLA inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors.

Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin) ; topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin) ; alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide) ; DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin) ; and free radical generators such as bleomycin; nucleoside mimetics (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea) ; paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047) .

Non-limiting examples of targeted therapeutic agents include protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib) ; proteasome inhibitors (e.g., bortezomib) ; NF-kappa B inhibitors, including inhibitors of I kappa B kinase; antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab) ; and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication.

EXAMPLES

The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc. ) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, ratio between solvents in a mobile phase is volume/volume, temperature is in degrees Centigrade, and pressure is at or near atmospheric. All MS data were determined by Agilent 6120 or Agilent 1100. All NMR data were generated using a Varian 400-MR machine. All reagents, except intermediates, used in this invention are commercially available. All compound names except the reagents were generated by Chemdraw 16.0.

If there is any atom with empty valence (s) in any one of the structures disclosed herein, the empty balance (s) is (are) the hydrogen atom (s) which is (are) omitted for convenience purpose.

In the present application, in the case of inconsistency of the structure and name of a compound, when the two of which are both given for the compound, it is subject to the structure of the compound, unless the context shows that the structure of the compound is incorrect and the name is correct.

The abbreviations used herein have meanings generally recognized by those skilled in the art. In the following examples, the abbreviations below are used:

AcOK Potassium acetate

CD ₃OD Deuterated methanol

DCM Dichloromethane

DIEA N, N-diisopropylethylamine

DMF N, N-dimethylformamide

DMSO-d ₆ Deuterated dimethyl sulfoxide

DTBPPS 3- (bis-tert-butylphosphine) propane sulfonate

EA/EtOAc Ethyl acetate

Et ₃N Triethylamine

EtOH Ethanol

g Gram

HATU 2- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethylurea hexafluorophosphate

L Liter

M Mole/liter

MeOH Methanol

MeCN Acetonitrile

mg Milligram

mL Milliliter

mmol Millimole

mol Mole

Na ₂PdCl ₄ Sodium tetrachloropalladate

Pd-C Palladium carbon

Pd (PPh ₃) ₂Cl ₂ Bis (triphenylphosphine) palladium dichloride

PE Petroleum ether

i-PrMgCl Isopropylmagnesium chloride

SOCl ₂ Thionyl chloride

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TMS Trimethylsilane

p-TSA·H ₂O p-toluenesulfonic acid monohydrate

Example 1: Preparation of intermediates

Intermediate I-1

5- ( (Trimethylsilyl) ethynyl) pyrazin-2-amine

5-bromopyrazin-2-amine (1.0 g, 5.74 mmol) , ethynyltrimethylsilane (3.0 mL) , Pd (PPh ₃) ₂Cl ₂ (201 mg, 0.28 mmol) , CuI (108 mg, 0.57 mol) , Et ₃N (1.5 mL) and DMF (5.0 mL) were added to a reaction flask. The reactants were stirred at 80℃ for 5 hours under nitrogen protection. The reaction mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (water/methanol = 100: 0 to 0: 100, gradient elution) to obtain a yellow solid product (600 mg, yield 55%) . MS (m/z) : 192.1 [M+H] ⁺

The compound in the following table was prepared with corresponding reagents with reference to the preparation processes of intermediate I-1.

Example 2: Synthesis of the compounds of the present invention

Compounds 1 and 2

Optically pure enantiomers of (R) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridin-3-yl) butanamide and (S) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridin-3-yl) butanamide

(A) 3- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -6- (trifluoromethyl) pyridin-2-amine

3-bromo-6- (trifluoromethyl) pyridin-2-amine (2.41 g, 10.0 mmol) , 8- (4, 4, 5, 5-tetramethyl-1, 3-dioxolan-2-yl) -1, 4-dioxaspiro [4.5] dec-7-ene (3.22 g, 12.0 mmol) , Na ₂PdCl ₄ (147 mg, 0.50 mmol) , DTBPPS (268 mg, 1.0 mmol) , K ₂CO ₃ (3.46 g, 25.0 mmol) , MeCN (45 mL) and H ₂O (15 mL) were added to a reaction flask. The reactants were stirred at 60℃ for 2 hours under nitrogen protection. After the reaction was completed, a saturated sodium chloride solution was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was concentrated, and purified by flash column chromatography (petroleum ether/ethyl acetate = 100: 0 to 0: 100, gradient elution) to obtain a white solid product (3.00 g, yield 100%) . MS (m/z) : 301.1 [M+H] ⁺

(B) 3- (1, 4-Dioxaspiro [4.5] decane-8-yl) -6- (trifluoromethyl) pyridin-2-amine

3- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -6- (trifluoromethyl) pyridin-2-amine (3.00 g, 10.0 mmol) , HCO ₂NH ₄ (12.61 g, 200 mmol) , 10%Pd-C (50%wet, 1.20 g) and ethanol (40 mL) were added to a reaction flask. The reactants were stirred at 85℃ for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and then ethyl acetate and water were added. The organic phase was concentrated to obtain a white solid product, which was directly used in the next step (3.02 g, yield 100%) . MS (m/z) : 303.1 [M+H] ⁺

(C) 4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexan-1-one

3- (1, 4-dioxaspiro [4.5] decane-8-yl) -6- (trifluoromethyl) pyridin-2-amine (3.02 g, 10.0 mmol) , p-TSA·H ₂O (5.71 g, 30.0 mmol) , acetonitrile (40 mL) and water (10 mL) were added to a reaction flask. The reactants were stirred at 60℃ for 16 hours under nitrogen protection. The reaction mixture was cooled, the pH was adjusted to 9 with saturated aqueous K ₂CO ₃ solution and extracted with ethyl acetate. The organic phase was concentrated, and purified by flash column chromatography (petroleum ether/ethyl acetate = 100: 0 to 0: 100, gradient elution) to obtain a white solid product (1.82 g, yield 71%) . MS (m/z) : 259.0 [M+H] ⁺

(D) Ethyl (RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyrate

60%NaH (366 mg, 9.16 mmol) and dry THF (40 mL) were added to a reaction flask under nitrogen protection, cooled to 0℃, and added with ethyl 2-(ethoxyphosphono) butyrate (2.31 g, 9.16 mmol) dropwise. The reactants were stirred at 0℃ for 20 minutes and at room temperature for 40 minutes. 4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexan-1-one (1.82 g, 7.05 mmol) was dissolved in dry THF (10 mL) , added dropwise to the above reaction mixture, and stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous NH ₄Cl solution and extracted with ethyl acetate. The organic phase was concentrated, and purified by flash column chromatography (petroleum ether/ethyl acetate = 100: 0 to 0: 100, gradient elution) to obtain a white solid product (1.82 g, yield 72%) . 357.0 [M+H] ⁺

(E) (RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6- ( (trimethylsilyl) ethynyl) pyridin-3-yl) butanamide

2 M i-PrMgCl/THF solution (4.0 mL, 8.0 mmol) was added dropwise to a solution of 6- ( (trimethylsilyl) ethynyl) pyridin-3-amine (952 mg, 5.0 mmol) in dry THF (10 mL) at 0℃ under nitrogen protection, and stirred at room temperature for 20 minutes. Ethyl (RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyrate (713 mg, 2.0 mmol) was dissolved in dry THF (10mL) , and added dropwise to the above reaction mixture, and refluxed and stirred for 2 hours. The reaction mixture was poured into saturated aqueous NH ₄Cl solution and extracted with ethyl acetate. The organic phase was concentrated and purified by flash column chromatography (water/methanol = 100: 0 to 0: 100, gradient elution) to obtain a white solid product (600 mg, yield 60%) . 501.1 [M+H] ⁺

(F) (RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridin-3-yl) butanamide

Solid K ₂CO ₃ (498 mg, 3.6 mmol) was added to a solution of (RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6- ( (trimethylsilyl) ethynyl) pyridin-3-yl) butyramide (600 mg, 1.2 mmol) in methanol (5 mL) , and stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and washed with water. The organic phase was concentrated and purified by thin layer chromatography (DCM/methanol = 40/1) to obtain the title compound.

(G) Optically pure enantiomers of (R) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridin-3-yl) butanamide and (S) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridin-3-yl) butanamide

(RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridin-3-yl) butanamide was resolved by chiral HPLC to obtain a pair of optically pure enantiomers, (R) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridin-3-yl) butanamide and (S) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridin-3-yl) butanamide. Chiral HPLC resolution conditions: column: IG (2 × 25 cm) ; mobile phase: n-heptane/isopropanol = 80: 20; flow rate: 15 mL/min; detector wavelength: UV 254 nm) .

Under the above conditions, the compound obtained after removing the solvent from the first eluent obtained was named compound 1 (154 mg, yield 30%) , ee%= 98.21%, MS (m/z) : 429.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) : δ 8.80-8.66 (m, 1H) , 8.25-8.12 (m, 1H) , 7.58-7.51 (m, 1H) , 7.51-7.43 (m, 1H) , 7.00-6.89 (m, 1H) , 3.68 (s, 1H) , 2.91-2.74 (m, 2H) , 2.67-2.56 (m, 1H) , 2.48-2.35 (m, 2H) , 2.28-2.19 (m, 1H) , 2.17-2.06 (m, 2H) , 2.04-1.96 (m, 1H) , 1.59-1.41 (m, 2H) , 1.15-1.02 (m, 3H) .

Under the above conditions, the compound obtained after removing the solvent from the second eluent obtained was named compound 2 (146 mg, yield 28%) , ee%= 95.14%, MS (m/z) : 429.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) : δ 8.77-8.66 (m, 1H) , 8.25-8.12 (m, 1H) , 7.58-7.51 (m, 1H) , 7.51-7.44 (m, 1H) , 6.99-6.89 (m, 1H) , 3.68 (s, 1H) , 2.90-2.74 (m, 2H) , 2.67-2.56 (m, 1H) , 2.46-2.35 (m, 2H) , 2.28-2.19 (m, 1H) , 2.16-2.06 (m, 2H) , 2.04-1.96 (m, 1H) , 1.59-1.42 (m, 2H) , 1.14-1.03 (m, 3H) .

The compounds in the following table were prepared with corresponding intermediates and reagents with reference to the preparation processes of compound 1.

The optically pure enantiomeric compounds in the above table were obtained by chiral HPLC resolution. The resolution conditions were: flow rate: 15 mL/min, detector wavelength: UV 254 nm; the chiral column and mobile phase used, and the ee values of the obtained compounds were shown in the table below (wherein in each pair of enantiomeric compounds, the earlier numbered compounds were the compounds obtained after removing the solvent from the first eluent obtained from the chiral column, and the later numbered compounds were the compounds obtained after removing the solvent from the second eluent obtained from the chiral column) :

Compound 45

(*) -2- (4- (2-Amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (4-cyanophenyl) butanamide

(A) Optically pure enantiomers of ethyl 2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyrate

Ethyl (RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyrate (4.0 g) was resolved by chiral HPLC to obtain a pair of optically pure enantiomers, ethyl (*) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyrate (intermediate I-5) (1.8 g, yield 45%) and ethyl (*) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyrate (intermediate I-6) (1.8 g, 45%yield) . Chiral HPLC conditions: column: OD-H (0.46 cm I.D. × 15 cm L) ; mobile phase: n-heptane/ethanol = 70: 30; flow rate: 0.5 mL/min; detector wavelength: UV 254 nm) . The compound obtained after removing the solvent from the first eluent obtained from the chiral column was intermediate I-5, ee%= 100%. The compound obtained after removing the solvent from the second eluent obtained from the chiral column was intermediate I-6, ee%= 99.70%.

(B) (*) -2- (4- (2-Amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (4-cyanophenyl) butanamide

Ethyl (*) -2- (4- (2-Amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyrate (intermediate I-6) and 4-cyanobenzylamine were used to obtain compound 45 (yield 82%) by referring to the synthetic step E of compounds 1 and 2. ee%= 97.86%, MS (m/z) : 429.1 [M+H] ⁺

¹H NMR (400 MHz, CD ₃OD) : δ 7.87-7.75 (m, 2H) , 7.72-7.63 (m, 2H) , 7.51-7.43 (m, 1H) , 6.99-6.88 (m, 1H) , 2.87-2.74 (m, 2H) , 2.64-2.54 (m, 1H) , 2.45-2.33 (m, 2H) , 2.27-2.18 (m, 1H) , 2.15-2.05 (m, 2H) , 2.02-1.94 (m, 1H) , 1.58-1.41 (m, 2H) , 1.13-1.02 (t, J =7.5 Hz, 3H) .

Compounds 46 and 47:

Optically pure enantiomers of (R) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridazin-3-yl) butanamide and (S) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridazin-3-yl) butanamide

(A) (RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyric acid

Ethyl (RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyrate (1.01 g, 2.83 mmol) , LiOH·H ₂O (1.19 g, 28.3 mmol) , ethanol (10 mL) and water (10 mL) were added to a reaction flask. The reactants were stirred at 100℃ for 16 hours. The reaction mixture was concentrated, and the residue was dissolved in water, and extracted with DCM. The aqueous phase was collected, adjusted to pH 4 with acetic acid, and extracted with EtOAc. The organic phase was collected and distilled under reduced pressure to obtain a white solid product (0.89 g, yield 96%) . MS (m/z) : 329.0 [M+H] ⁺

(B) (RS) -2- (4- (2-Amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6- ( (trimethylsilyl) ethynyl) pyridazin-3-yl) butanamide

(RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyric acid (890 mg, 2.7 mmol) and SOCl ₂ (6.46 g, 54 mmol) were added to a reaction flask. The reactants were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in MeCN. 6- ( (Trimethylsilyl) ethynyl) pyridazin-3-amine (1.04 g, 5.42 mmol) and DIEA (1.05 g, 8.1 mmol) were added sequentially, and stirred at room temperature for 0.5 hour. The reaction mixture was diluted with DCM, and washed with water. The organic phase was concentrated and purified by thin layer chromatography (DCM/MeOH = 20/1) to obtain a yellow solid product (213 mg, yield 16%) .

(C) (R) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridazin-3-yl) butyramide and (S) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6-ethynylpyridazin-3-yl) butanamide

(RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (6- ( (trimethylsilyl) ethynyl) pyridazin-3-yl) butyramide was used to obtain compounds 46 and 47 by referring to the synthesis and resolution steps F and G of compounds 1 and 2.

Chiral HPLC resolution conditions: column: IG (2 × 25 cm) ; Mobile phase: n-heptane/ethanol = 80/20; flow rate: 15 mL/min; detector wavelength: UV 254 nm.

Under the above conditions, the compound obtained after removing the solvent from the first eluent obtained was named compound 46 (70 mg, yield 39%) , ee%= 100%, MS (m/z) : 430.0 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) : δ 8.56-8.46 (m, 1H) , 7.82-7.74 (m, 1H) , 7.51-7.44 (m, 1H) , 6.97-6.91 (m, 1H) , 3.33 (s, 1H) , 2.89-2.75 (m, 2H) , 2.68-2.58 (m, 1H) , 2.47-2.36 (m, 2H) , 2.29-2.19 (m, 1H) , 2.17-2.05 (m, 2H) , 2.02-1.94 (m, 1H) , 1.61-1.44 (m, 2H) , 1.12-1.04 (m, 3H) .

Under the above conditions, the compound obtained after removing the solvent from the second eluent obtained was named compound 47 (70 mg, yield 39%) , ee%= 96.17%, MS (m/z) : 430.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) : δ 8.56-8.46 (m, 1H) , 7.82-7.74 (m, 1H) , 7.51-7.44 (m, 1H) , 6.97-6.91 (m, 1H) , 3.32 (s, 1H) , 2.89-2.75 (m, 2H) , 2.68-2.58 (m, 1H) , 2.47-2.36 (m, 2H) , 2.29-2.19 (m, 1H) , 2.17-2.05 (m, 2H) , 2.02-1.94 (m, 1H) , 1.61-1.44 (m, 2H) , 1.13-1.04 (m, 3H) .

The compounds in the following table were prepared with corresponding intermediates and reagents with reference to the preparation processes of compounds 46 and 47.

Compounds 48 and 49 were obtained by chiral HPLC resolution. The resolution conditions were: column: IG (2 × 25 cm) , mobile phase: n-heptane/ethanol (0.1%NH ₃) =85/15, flow rate: 15 mL/min, detector wavelength: UV 254 nm. The compound obtained after removing the solvent from the first eluent obtained from the chiral column was compound 48 (ee%= 100%) , and the compound obtained after removing the solvent from the second eluent obtained from the chiral column was compound 49 (ee%= 100%) .

Compounds 53 and 54:

Optically pure enantiomers of (R) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (4-chlorophenyl) butanamide and (S) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) -N- (4-chlorophenyl) butanamide

(RS) -2- (4- (2-amino-6- (trifluoromethyl) pyridin-3-yl) cyclohexylidene) butyric acid (328 mg, 1.0 mmol) , 4-chloroaniline (127 mg, 1.0 mmol) , HATU (570 mg, 1.5 mmol) , DMF (4 mL) and DIEA (387 mg, 3.0 mmol) were added sequentially to a reaction flask. The reactants were stirred at room temperature for 16 hours. The reaction mixture was concentrated, purified by flash column chromatography (water/methanol = 90 : 10 to 0 : 100, gradient elution) , and then resolved by chiral HPLC.

Chiral HPLC conditions: column: IG (2 × 25 cm) ; Mobile phase: n-heptane/ethanol (0.1%NH ₃) = 80/20; Flow rate: 15 mL/min; detector wavelength: UV 254 nm.

Under the above conditions, the compound obtained after removing the solvent from the first eluent obtained was named compound 53 (55 mg, yield 13%) , ee%= 98.17%, MS (m/z) : 438.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) : δ 9.95 (s, 1H) , 7.67 (d, J = 8.9 Hz, 2H) , 7.40 (d, J = 7.5 Hz, 1H) , 7.32 (d, J = 8.8 Hz, 2H) , 6.88 (d, J = 7.6 Hz, 1H) , 6.44 (s, 2H) , 2.77 (t, J = 11.5 Hz, 1H) , 2.67 (d, J = 12.6 Hz, 1H) , 2.43 (s, 1H) , 2.26 (q, J = 7.6 Hz, 2H) , 2.15-1.93 (m, 3H) , 1.82 (d, J = 12.2 Hz, 1H) , 1.45-1.25 (m, 2H) , 0.97 (t, J = 7.5 Hz, 3H) .

Under the above conditions, the compound obtained after removing the solvent from the second eluent obtained was named compound 54 (65 mg, yield 15%) , ee%= 97.92%, MS (m/z) : 438.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) : δ 9.95 (s, 1H) , 7.67 (d, J = 8.8 Hz, 2H) , 7.40 (d, J = 7.5 Hz, 1H) , 7.32 (d, J = 8.8 Hz, 2H) , 6.88 (d, J = 7.6 Hz, 1H) , 6.44 (s, 2H) , 2.77 (t, J = 12.3 Hz, 1H) , 2.67 (d, J = 12.8 Hz, 1H) , 2.43 (s, 1H) , 2.26 (q, J = 7.4 Hz, 2H) , 2.15-1.90 (m, 3H) , 1.82 (d, J = 11.0 Hz, 1H) , 1.50-1.27 (m, 2H) , 0.97 (t, J = 7.4 Hz, 3H) .

The compounds in the following table were prepared with corresponding intermediates and reagents with reference to the preparation processes of compounds 53 and 54.

Compounds 55 and 56 were obtained by chiral HPLC resolution. The resolution conditions were: column: IG (2 × 25 cm) , mobile phase: n-heptane/ethanol (0.1%NH ₃) = 80/20, flow rate: 15 mL/min, detector wavelength: UV 254 nm. The compound obtained after removing the solvent from the first eluent obtained from the chiral column was compound 55 (ee%= 100%) , and the compound obtained after removing the solvent from the second eluent obtained from the chiral column was compound 56 (ee%=99.22%) .

Example 3 Determination of IDO1 activity in SKOV-3 cells

1. Reagents and materials

SKOV-3 cells: SKOV-3 cells were purchased from American Standard Biological Collection Center ATCC Cell Bank, and were cultured at 37℃ in a cell culture incubator supplied with 5%CO ₂ with DMEM medium containing 3.7 g/L sodium bicarbonate and 4.5 g/L glucose, and supplemented 2 mM L-glutamine and 10 %fetal bovine serum (FBS) ;

DMEM: GIBCO, Catalog number: 31053028;

Glutamine: GIBCO, Catalog number: 35050061;

Fetal bovine serum (FBS) : GIBCO, Catalog number: 10099-141;

Human IFNγ: R&D Systems, Catalog number: 285-IF-100;

L-tryptophan (L-Trp) : Sigma-Aldrich, Catalog number: T0254;

trichloroacetic acid (6.1N) : Sigma-Aldrich, Catalog number: T0699;

p-dimethylaminobenzaldehyde: Sigma-Aldrich, Catalog number: 156477;

L-Kynurenine: Sigma-Aldrich, Catalog number: K8625;

Microplate reader: SpectraMax M2, Molecular Devices;

96-well plate: Beckman Dickinson, Catalog number: 353072.

2. Solution preparation

Standard curve stock solution: was prepared by diluting a series of concentrations of L-Kynurenine with cell culture media DMEM. The final concentration is 240, 120, 60, 30, 15, 7.5, 3.75, and 1.87 μM, respectively.

3. Method

When the inhibitor activity of compounds were determined, SKOV-3 cells were seeded in a 96 well culture plate at a density of 1.0 x 10 ⁴ per well, i.e. 180 μL per well, and incubated in a cell culture incubator at 5%CO ₂ and 37℃. After the cell adherence, the test compound was diluted 3 times in serum-free DMEM medium to the corresponding concentration on the same day, and then 10 μL/well of different concentrations of the diluted compound (the final concentration: 1.0, 0.33, 0.11, 0.037, 0.012, 0.0041, 0.0014, and 0.00046 μM, DMSO final concentration: 0.5%) or 10 μL/well control solution (0.5%DMSO) were added to the 180 μL/well cell culture system, then 10 μL/well of mixture of human IFNγ (final concentration of 50 ng/mL) and L-Trp (final concentration of 50 μmol/L) diluted in serum-free DMEM medium were added into cells. The cells were incubated in a cell culture incubator at 5%CO ₂ and 37℃ for 48 hours.

140 μL of the supernatant per well of the 96 well plate was transferred to a new 96 well plate. Then 10 μL of trichloroacetic acid was mixed into each well and incubated at 65℃ for 20 min in water bath. The reaction mixture was then centrifuged at 1200 g for 10min, 100 μL of the supernatant per well was transferred to another new 96 well plate and mixed with 100 μL of 20 g/L of p-dimethylaminobenzaldehyde in glacial acetic acid per well.

4. Detection

After mixing for 1 minute, the absorbance optical density signal was detected at a wavelength of 480 nm using a SpectraMax M2 microplate reader. Serial concentrations of kynurenine standards were diluted in cell culture medium and the optical density values at each concentration point were measured after treatment as described above. Then, the optical density signal is taken as the ordinate, the kynurenine concentration is plotted on the abscissa, and the kynurenine standard curve is plotted using the EXCEL software. The linear regression equation is fitted, and the concentration of kynurenine in test compound treated wells and human IFN-γ control treated wells are calculated according to the equation. The inhibition rate (%) of each concentration of compounds was calculated according to the concentration of kynurenine in each well, and then calculated by the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited) to obtain an IC ₅₀ value.

The inhibition rate is calculated as follows:

wherein:

●[kynurenine] _Compound : represents the concentration of kynurenine in the cell well containing human IFN-γ and the test compound.

●[kynurenine] _IFN-γ: represents the concentration of kynurenine in the cell well containing only human IFN-γ.

5. Results

Example 4 Determination of IDO1 activity in human whole blood

1. Reagents and materials

Human peripheral blood: routinely incubated at 37℃ in cell incubator supplied with 5%CO ₂

RPMI -1640: GIBCO, catalog number 11875-093

Human IFNγ: R&D Systems, catalog number 285-IF-100

Salmonella typhimurium (LPS) : Calbiochem, catalog number 437650

Tryptophan (L-Trp) : Sigma-Aldrich, catalog number T0254

Kynurenine (L-Kynurenine) : Sigma-Aldrich, catalog number K8625

96-well plate: Beckman Dickinson, Catalog number: 353072

Dimethyl sulfoxide (DMSO) : Sigma-Aldrich, catalog number 34869-4L.

2. Solution preparation

Preparation of Standard Curve Solution: 5 μL of the standard curve working solution was added to 45 μL of blank plasma from which endogenous canine urine amino acid was removed via activated carbon, and the Standard Curve Solution was obtained after vortex. The final gradient concentration is 50, 20, 5.0, 2.0, 1.0, 0.50, 0.20, 0.10 and 0.050 μ M.

3. Method

When the activity of compounds were determined, the whole blood was seeded in a 96 well plates at 180 μL/well, and incubated in a cell incubator at 5%CO ₂ and 37 ℃. Half an hour later, the test compound was diluted 3 times in serum-free RPMI-1640 medium to the corresponding concentration, and then 10 μL/well of different concentrations of the diluted compound (the final concentration: 0.30, 0.10, 0.033, 0.011, 0.0037 and 0.0012 μM, and the final concentration of DMSO was 0.25%) or 10 μL/well control solution (0.25%DMSO) were added to the 180 μL/well human whole blood culture system, then 10 μL/well of mixture of human IFNγ (final concentration of 150 ng/mL) , LPS (final concentration of 150 μmol/L) and L-Trp (final concentration of 50 μmol/L) diluted in serum-free DMEM medium were added into cells. The cells were incubated in a cell culture incubator at 5%CO ₂ and 37℃ for 24 hours.

After the 96 well plate was centrifuged for 10min, 70 μL of the plasma supernatant per well was transferred to a new 1.5mL of tube, and then was detected.

4. Detection

LC-MS/MS was used to determine the concentration of Kynurenine in the sample. The peak area of Kynurenine and internal standard compound is automatically collected and integrated by Software Analyst 1.6.2. The standard curve for quantification is obtained by fitting the theoretical concentration of kynurenine to the peak area ratio of Kynurenine and internal standard compound using linear regression equation. The inhibition rate (%) of each of the concentration of test compounds was calculated according to the concentration of kynurenine in each well, and then calculated by the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited) to obtain an IC ₅₀ value.

The inhibition rate is calculated as follows:

Inhibition rate (%) = 100%- { (test compound well–control solution well) / (human IFN-γ control well –control solution well) } ×100%, wherein:

Test compound well: represents the concertration of Kynurenine in human whole blood containing human IFN-γ and the test compound.

Human IFN-γ control well: represents the concertration of Kynurenine in human whole blood containing only human IFN-γ.

Control solution well: represents the concertration of Kynurenine in uncultured human whole blood plasma.

The above test showed that the compounds of the present invention exemplified in the examples effectively inhibit IDO1 activity in human whole blood, IC ₅₀ < 0.1 μ M.

Example 5: Metabolic Stability test in liver microsomes

1. Experiment materials:

Both male CD-1 mouse liver microsomes (pooled) and male SD rat liver microsomes (pooled) were purchased from BioreclamationIVT Corporation, USA.

Phenacetin, glucose-6-phosphate (G-6-P) , glucose-6-phosphate dehydrogenase (G-6-PDH) and nicotinamide adenine dinucleotide phosphate (NADP) were all purchased from Sigma-Aldrich Corporation, USA.

2. Solution preparation:

10 mM test compound stock solution: a certain amount of test compound was weighed, and dissolved with an appropriate volume of DMSO to prepare a stock solution with a concentration of 10mM for use.

Reaction stopping solution: an appropriate amount of internal standard compound phenacetin was dissolved in acetonitrile to prepare a reaction stopping solution with a concentration of 1000 ng/mL for use at room temperature.

3. Experiment method:

The test compound stock solution was diluted with an organic solvent (usually a mixture of acetonitrile, methanol and water with various ratios, depending on the solubility of the compound) to the target concentration to make the final concentration of the reaction system be 1 μM and the concentration percentage of the organic solvents in the incubation system no more than 1% (wherein the percentage of DMSO was required to be no more than 0.1%) . 100 mM NADP, 500 mM G-6-P and 100 Unit/mL G-6-PDH were mixed and diluted with ultrapure water to make the final system contain 1 mM NADP, 5 mM G-6-P and 1 Unit/mL G-6-PDH, pre-incubated in a 37℃ water bath for 10 minutes and then placed on ice for use as a NADPH regeneration solution. 20 mg/mL liver microsome solution and 200 mM phosphate buffer was mixed, and diluted with ultrapure water to make the final concentration in the reaction system be 0.5 mg/mL for liver microsomes and 50 mM for phosphate buffer. The diluted liver microsome solution and the prepared NADPH regeneration solution were mixed, added with an appropriate volume of 100 mM EDTA and 300 mM MgCl ₂ solution (3 mM MgCl ₂ and 1 mM EDTA in the final incubation system) and placed in a 37℃ water bath. The reaction was started by adding the test compound, and the reaction time was 30 minutes. The reaction was terminated by adding the ice-cold reaction stopping solution containing the internal standard. 0 minute samples were obtained when the reaction was terminated just after the test compound was added (without incubation in the water bath) . All the samples were vortexed, and then centrifuged at 4400 rpm for 10 minutes. The supernatant was taken for LC-MS/MS analysis.

4. Analysis results:

LC-MS/MS was used to determine the concentration of the compound in the sample. The peak area ratio of the compound to the internal standard was used as an indicator, and the remaining percentage of the compound for the 30-minute incubation sample was obtained by comparing the peak area ratio with that in 0-minute sample, to evaluate the metabolic stability of the compound.

The results indicated that the metabolic stability of the example compounds of the present invention was relative good. Specifically, the following table lists the stability data obtained in this test for some compounds of the present invention. It can be seen that those compounds with amino groups, such as the example compounds 1, 5, 9, 11, 14, 40, 41, 45, 46, 48 and 55, have particularly good metabolic stability in rat and mouse liver microsomes.

Claims

A compound of formula (I) :

or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is hydrogen, deuterium, -OH, C _1-6 alkyl, C _1-6 haloalkyl, -O (C _1-6 alkyl) , - (C _1-6 alkylene) _n-C _3-6 cycloalkyl or - (C _1-6 alkylene) _n-4-6 membered heterocyclyl, wherein C _1-6 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl, as a group or as part of a group, is each optionally substituted with one or more groups chosen from: deuterium, halogen, -CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, -O (C _1-6 alkyl) or -O (C _1-6 haloalkyl) ;

R ₂ is - (C _1-6 alkylene) _n-phenyl, - (C _1-6 alkylene) _n-4-6 membered heterocyclyl or - (C _1-6 alkylene) _n-5-12 membered heteroaryl; the phenyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl is each optionally substituted with one or more groups chosen from: deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, -O (C _1-6 alkyl) , -O (C _1-6 haloalkyl) or C _3-6 cycloalkyl;

R ₃ is hydrogen, deuterium, halogen or -OH;

R ₄ is halogen or C _1-6 haloalkyl;

X ₁, X ₂, X ₃ and X ₄ are each independently chosen from N or CR ₅; provided that at least one of X ₁, X ₂, X ₃ and X ₄ is N, and at least one of X ₁, X ₂, X ₃ and X ₄ is CR ₅;

R ₅ on X ₁, X ₂, X ₃ or X ₄, if present, is each independently chosen from: hydrogen, deuterium, halogen, -OH, -CN, -NH ₂, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, -O (C _1-6 alkyl) , -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, - (C _1-6 alkylene) _n-C _3-6 cycloalkyl or - (C _1-6 alkylene) _n-4-6 membered heterocyclyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl, as a group or as part of a group, is each optionally substituted with one or more groups chosen from: deuterium, halogen, -CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, -O (C _1-6 alkyl) or -O (C _1-6 haloalkyl) ; and

n is 0, 1 or 2.
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁ is hydrogen, deuterium, -OH, C _1-6 alkyl, C _1-6 haloalkyl or -O (C _1-6 alkyl) ; preferably, R ₁ is C _1-6 alkyl.
The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is phenyl or 5-12 membered heteroaryl (e.g., 5-6 membered heteroaryl or a 9-10 membered heteroaryl) , each of which is optionally substituted with one or more groups chosen from: deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) ₂, -O (C _1-6 alkyl) , -O (C _1-6 haloalkyl) or C _3-6 cycloalkyl.
The compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is phenyl, which is optionally substituted with one or more groups chosen from halogen, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl; or R ₂ is 5-6 membered heteroaryl or 9-10 membered heteroaryl, each of which is optionally substituted with one or more groups chosen from: halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl.
The compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₂ is
wherein X, Y and Z are each independently N or CH, and R _a is chosen from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl;

preferably, R ₂ is
wherein R _a is chosen from hydrogen, deuterium, halogen, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl; or R ₂ is
wherein X, Y and Z are each independently N or CH, provided that at least one of X, Y and Z is N, and wherein R _a is chosen from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl.
The compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₃ is hydrogen.
The compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein at least one of X ₁, X ₂, X ₃ and X ₄ is C-NH ₂.
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is C _1-6 alkyl;

R ₂ is phenyl or 5-12 membered heteroaryl (e.g., 5-6 membered heteroaryl or 9-10 membered heteroaryl) , each of which is optionally substituted with one or more groups chosen from: halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl;

R ₃ is hydrogen or deuterium;

R ₄ is halogen or C _1-6 haloalkyl; and

X ₁, X ₂, X ₃ and X ₄ are each independently chosen from N or CR ₅; provided that at least one of X ₁, X ₂, X ₃ and X ₄ is N, and at least one of X ₁, X ₂, X ₃ and X ₄ is CR ₅; R ₅ on X ₁, X ₂, X ₃ or X ₄, if present, is each independently chosen from hydrogen, deuterium or -NH ₂.
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein

R ₁ is C _1-6 alkyl;

R ₂ is
wherein X, Y and Z are each independently N or CH, and R _a is chosen from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl; preferably, R ₂ is
wherein R _a is chosen from hydrogen, deuterium, halogen, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl, or R ₂ is
wherein X, Y and Z are each independently N or CH, provided that at least one of X, Y and Z is N, and wherein R _a is chosen from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _2-6 alkynyl, -O (C _1-6 alkyl) , C _1-6 haloalkyl or C _3-6 cycloalkyl;

R ₃ is hydrogen or deuterium;

R ₄ is halogen or C _1-6 haloalkyl; and

X ₁, X ₂, X ₃ and X ₄ are each independently chosen from N or CR ₅; provided that at least one of X ₁, X ₂, X ₃ and X ₄ is N, and at least one of X ₁, X ₂, X ₃ and X ₄ is CR ₅; R ₅ on X ₁, X ₂, X ₃ or X ₄, if present, is each independently chosen from hydrogen, deuterium or -NH ₂.
The compound of formula (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein the compound of formula (I) is a compound of formula (I-1) , formula (I-2) or formula (I-3) :

wherein R ₁₁, R ₁₃, R ₁₄, R ₂₁, R ₂₃, R ₂₄, R ₃₁ and R ₃₃ are each independently chosen from hydrogen, deuterium or -NH ₂; and R ₁₂, R ₂₂ and R ₃₂ are chosen from halogen or C _1-6 haloalkyl.
The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁₂, R ₂₂ and R ₃₂ are each independently chosen from F, Cl, Br or CF ₃.
The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁₄ is -NH ₂; one of R ₂₁ and R ₂₄ is -NH ₂, and the other is hydrogen; and one of R ₃₁ and R ₃₃ is -NH ₂, and the other is hydrogen.
The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein R ₁₁, R ₁₃ and R ₂₃ are each hydrogen.
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein the compound is chosen from:
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, wherein the compound of formula (I) is chosen from:
A pharmaceutical composition, comprising the compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, and optionally comprising a pharmaceutically acceptable excipient.
Use of the compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof in the manufacture of a medicament for treating or preventing a disease mediated by IDO1 or at least in part by IDO1.
Use according to claim 17, wherein the medicament is used for treating or preventing cancer, an autoimmune disease, obesity or an obesity-related disease.
Use according to claim 18, wherein the cancer is solid tumor or hematologic malignancy, such as leukemia, lymphoma or myeloma.
Use according to claim 18, wherein the cancer is chosen from skin cancer (such as melanoma and basal cancer) , lung cancer (such as non-small cell lung cancer) , kidney cancer (such as renal cell carcinoma) , head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer (such as hepatocellular carcinoma) , endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, brain tumors (such as including glioma and glioblastoma (GBM) ) , thyroid cancer, mesothelial endometrial carcinoma, choriocarcinoma, adrenal carcinoma, sarcoma (such as Kaposi’s sarcoma) , leukemia (such as acute myeloid leukemia (AML) , human acute monocytic leukemia (M (5) ) , acute lymphoblastic leukemia (ALL) ) , lymphoma (such as diffuse large B-cell lymphoma (DLBCL) ) or myeloma; the autoimmune disease is chosen from arthritis, such as rheumatoid arthritis, and collagen-induced arthritis; the obesity-related disease is chosen from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythms, arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, and angina pectoris) , cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
A combination comprising the compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof and/or a deuterate, a solvate, a racemic mixture, an enantiomer, a diastereomer and a tautomer thereof, and at least one additional therapeutic agent.
The combination according to claim 21, wherein the additional therapeutic agent is chosen from an anti-neoplastic agent such as a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.