CN112047877A - Novel amide compound and use thereof - Google Patents

Novel amide compound and use thereof Download PDF

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Publication number
CN112047877A
CN112047877A CN201910409909.5A CN201910409909A CN112047877A CN 112047877 A CN112047877 A CN 112047877A CN 201910409909 A CN201910409909 A CN 201910409909A CN 112047877 A CN112047877 A CN 112047877A
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China
Prior art keywords
alkyl
haloalkyl
compound
pharmaceutically acceptable
acceptable salt
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CN201910409909.5A
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Chinese (zh)
Inventor
苏慰国
戴广袖
张维汉
贾红
杨海彬
蔡华庆
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Hutchmed Ltd
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Hutchison Medipharma Ltd
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Priority to CN201910409909.5A priority Critical patent/CN112047877A/en
Priority to PCT/CN2020/090598 priority patent/WO2020228823A1/en
Priority to TW109116218A priority patent/TW202110801A/en
Priority to ARP200101388A priority patent/AR118940A1/en
Publication of CN112047877A publication Critical patent/CN112047877A/en
Pending legal-status Critical Current

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

The invention relates to novel amides of formula (I), pharmaceutical compositions containing them, and processes for their preparation and their use, wherein the symbols are as defined in the specification.

Description

Novel amide compound and use thereof
Technical Field
The invention relates to novel amide compounds, pharmaceutical compositions containing them, and methods for their preparation and use.
Background
In mammalian cells, L-tryptophan (L-Trp) is degraded to L-Kynurenine (L-Kynurenine) mainly via the "Kynurenine pathway", wherein the first step in the production of N-formyl-L-Kynurenine by L-tryptophan is the rate-limiting step in the Kynurenine metabolic pathway. The current research shows that three major enzymes, i.e., IDO1 (indoleamine-2, 3-dioxygenase 1), IDO2 (indoleamine-2, 3-dioxygenase 2) and TDO (tryptophan 2, 3-dioxygenase), participate in the L-tryptophan metabolic reaction shown in the following formula.
Figure BDA0002062489860000011
IDO1 is a cytoplasmic heme enzyme with a size of about 45Kd encoded by the indoo gene located on human chromosome 8p22 and is ubiquitously expressed in a variety of tissues and cells in vivo, including immune cells, endothelial cells, fibroblasts, and the like. The expression of IDO1 is primarily regulated by inflammatory signals such as IFN γ, CpG-DNA, and LPS, among others. IDO2 is encoded by the INDOL1 gene and has about 42% amino acid sequence identity and very similar structure compared to IDO1, but in vitro studies show that human IDO2 has very low enzymatic activity and a high proportion of genetic polymorphisms are present which result in loss of enzymatic activity. The biological function of IDO2 is currently under investigation. TDO is encoded by the TDO2 gene, is functionally related to IDO1 and IDO2, but has only 10% amino acid sequence identity, is constitutively highly expressed in liver, and functions mainly to maintain L-tryptophan stability in the human body. Recent studies found that some tumors mediated tolerance of tumor cells to the host's immune system by highly expressing TDO, but to date, there has been no report of TDO expression in immune cells.
IDO1 expression is closely related to the generation and development of tumors. The research finds that the high expression of IDO1 in various primary and metastatic human tumors, such as acute myelogenous leukemia, lung cancer, melanoma and the like, is related to the malignancy, metastasis and prognosis of the tumors, and suggests that IDO1 can be a potential therapeutic target. In the tumor microenvironment, some pro-inflammatory factors such as IFN γ and the like can induce the expression of IDO1 by tumor cells or host immune cells (mainly antigen presenting cells such as dendritic cells, macrophages and the like). The IDO1 which is induced to express catalyzes the metabolic reaction of L-tryptophan, and inhibits the proliferation of effector lymphocytes such as T cells and NK cells and induces the proliferation of effector lymphocytes such as T cells and NK cells to enter into cycle arrest and apoptosis by simultaneously reducing the concentration of L-tryptophan and increasing the concentration of the generated L-kynurenine and further metabolites thereof (such as 3-hydroxykynurenine, 3-hydroxy-2-aminobenzoic acid and the like) in a tumor microenvironment. And simultaneously up-regulate the immunosuppressive regulatory T cells, thereby helping tumor cells escape from the immune surveillance of the host and obtaining the opportunity of malignant growth.
Preclinical animal experiments have shown the effectiveness of targeting IDO 1. For example, by knocking out IDO1 protein or inhibiting IDO1 protein activity by using IDO1 small molecule inhibitors such as INCB024360(Epacadostat) and NLG919, the level of kynurenine in an animal body can be effectively reduced, so that the tolerance of IDO1 mediated tumor to an organism immune system is relieved, corresponding cells such as T cells and NK cells are activated, and the effect of inhibiting tumor growth is further achieved. Small molecule inhibitors of IDO1 (e.g., INCB024360, BMS-986205, and Pf-06840003) or IDO1/TDO (e.g., NLG919) have now entered early clinical trials. Early clinical trial results indicated that targeting IDO1 was a safe treatment and that the patients involved in the trial showed good tolerability. In addition, after a period of treatment with the small molecule IDO1 inhibitor, different reductions in kynurenine levels were observed in patients, both in plasma and in tumors. Moreover, early efficacy data showed that IDO1 inhibitor in combination with immune checkpoint CTLA4 or PD1 antibody showed better efficacy in some tumors than single drug, e.g., the Objective Remission Rate (ORR) reached 58% as shown by stage 1/2 clinical trial results for IDO1 inhibitor INCB024360 in combination with PD-1 antibody Pembrolizumab in melanoma patients, and was significantly better than that for Pembrolizumab alone (stage 3, ORR, 32.9%). These results show that IDO1 is a potential target for treating malignancies (ESMO,2016, abstract 1110 PD; ASCO,2017, abstract 4503; jco.2017.35(15_ supl): abstract 1103; jco.2017.35(15_ supl): abstract 3003; Cancer res.,2017,77(13Suppl): abstract CT 116; analysis and investigator Day Meeting, new link Genetics Corporation,2016 10/25).
In addition to tumors, other diseases, such as chronic infections, HIV virus, multiple sclerosis, neuro-depression, etc., are also associated with IDO1 activity. Therefore, IDO1 inhibitors may also be useful in the development of treatments for these diseases (Trends immunol.,2013,34(3): 137-143). There is currently no drug targeting IDO1 approved for the market, and there are certain drawbacks to the IDO1 inhibitors currently entering clinical research, and there is still a need for new IDO1 inhibitors for the treatment of these diseases, particularly cancer. The present invention addresses these needs.
Brief description of the invention
The present invention provides compounds of formula (I):
Figure BDA0002062489860000031
or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein:
x is N or CR3(ii) a Y is N or CR4；
R1、R2、R3And R4Each independently selected from: hydrogen, halogen, -OH, -CN, -NH2、 C1-6Alkyl radical, C1-6Haloalkyl, -O (C)1-6Alkyl), -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2；
Z is O, NR5Or CR6R7；
R5Selected from: hydrogen, C1-6Alkyl or C3-6A cycloalkyl group;
R6and R7Each independently selected from: hydrogen, halogen, -CN, C1-6Haloalkyl, -O (C)1-6Haloalkyl), -OH, C)1-6Alkyl radical, C3-6Cycloalkyl or-O (C)1-6Alkyl groups);
Figure BDA0002062489860000041
is phenyl, 5-6 membered heteroaryl or indazolyl; each of which is optionally substituted with one or more groups selected from: halogen, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-O(C1-6Alkyl) or-O (C)1-6Haloalkyl);
Figure BDA0002062489860000042
is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, each of which is optionally substituted with one or more groups selected from: halogen, - (C)1-6Alkyl radical)n-CN、-NO2、 C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, - (C)1-6Alkyl radical)n-C3-6Cycloalkyl, - (C)1-6Alkyl radical)n-phenyl, - (C)1-6Alkyl radical)n-4-6 membered heterocyclyl, - (C)1-6Alkyl radical)n-5-6 membered heteroaryl, - (C)1-6Alkyl radical)n-NR1’R2’、-(C1-6Alkyl radical)n-CONR1’R2’、-(C1-6Alkyl radical)n-NR1’R2’C(O)R3’、-(C1-6Alkyl radical)n-C(O)R3’-、-(C1-6Alkyl radical)n-C(O)OR4’、 -(C1-6Alkyl radical)n-OR5’、-(C1-6Alkyl radical)n-S(O)mNR1’R2’、-(C1-6Alkyl radical)n- NR1’R2’S(O)mR6’、-(C1-6Alkyl radical)n-S(O)mR6' and- (C)1-6Alkyl radical)n-SR7'; wherein, said phenyl, C3-6Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with one or more groups selected from: halogen, -CN, -OH, -NH2、C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6Alkyl, -O (C)1-6Alkyl), -NH (C)1-6Alkyl), -N (C)1-6Alkyl radical)2、C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group;
n is 0 or 1;
m is 1 or 2;
p is 0 or 1;
R1’、R2’、R3’、R4’、R5’、R6' and R7' independently from each other are selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, - (C)1-6Alkyl) -O- (C1-6Alkyl), - (C)1-6Alkyl) -OH, - (C)1-6Alkyl) -CN, - (C)1-6Alkyl) -NH2Or C3-6A cycloalkyl group; or R1’、R2' together with the N atom to which they are attached form a 4-6 membered heterocyclic ring.
The above-mentioned compounds and the active compounds covered by this range disclosed in the context of the present invention are collectively referred to as "compounds of the present invention".
The invention also provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
The present invention also provides a method of inhibiting IDO activity in vivo or in vitro comprising contacting an effective amount of a compound of the present invention with IDO.
The present invention also provides a method of treating a disease mediated by IDO or mediated at least in part by IDO, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.
The present invention also provides a method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound of the present invention.
The invention also provides the use of a compound of the invention in the treatment of a disease mediated by IDO or mediated at least in part by IDO.
The invention also provides the use of a compound of the invention in the treatment of cancer or an autoimmune disease.
The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease mediated by IDO or mediated at least in part by IDO.
The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of cancer or an autoimmune disease.
Detailed Description
Definition of
As used in this application, the following words, phrases and symbols have the meanings as set forth below, unless the context indicates otherwise.
A dash ("-") that is not between two letters or symbols indicates a point of attachment for a substituent. For example, -OR3Refers to the attachment of R to the rest of the molecule through an oxygen atom3。
The term "alkyl" as used herein means a radical containing from 1 to 18 carbon atoms, preferably from 1 to 10 carbon atoms, particularly preferably from 1 to 6 carbon atomsA straight or branched chain saturated hydrocarbon group of carbon atoms. For example, "C1-6Alkyl "means an alkyl group as described having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
The term "alkenyl" as used herein refers to a straight or branched chain unsaturated hydrocarbon group containing 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, containing one or more, e.g. 1,2 or3 carbon-carbon double bonds (C ═ C). For example, "C2-6Alkenyl "denotes said alkenyl having 2-6 carbon atoms, preferably" C2-4Alkenyl ", i.e. said alkenyl having 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, and 2-butenyl. The point of attachment of the alkenyl group may or may not be at the double bond.
The term "alkynyl" as used herein refers to a straight or branched chain unsaturated hydrocarbon radical containing from 2 to 10 carbon atoms, preferably from 2 to 6 carbon atoms, more preferably from 2 to 4 carbon atoms, containing one or more, e.g. 1,2 or3, carbon-carbon triple bonds (C ≡ C). For example, "C2-6Alkynyl "denotes an alkynyl group as described having 2 to 6 carbon atoms, preferably" C2-4Alkynyl ", i.e. said alkynyl having 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment of the alkynyl group may or may not be at the triple bond.
The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.
The term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein one or more hydrogen atoms, for example 1,2,3,4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein two or more hydrogen atoms, for example 2,3,4 or 5 hydrogen atoms, are replaced by a halogen atom, wherein the halogen atomAre identical to each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein two or more hydrogen atoms, for example 2,3,4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to, -CF3、-CHF2、-CH2CF3、-CH(CF3)2And the like.
The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3 to 12 ring carbon atoms (e.g., containing from 3 to 8 ring carbon atoms, 5 to 7 ring carbon atoms, 4 to 7 ring carbon atoms, or3 to 6 ring carbon atoms); it may have one or more rings, for example 1,2 or3, preferably 1 or 2 rings. For example, "C3-12Cycloalkyl "denotes said cycloalkyl having 3 to 12 ring carbon atoms," C3-8Cycloalkyl "means a cycloalkyl group as defined having 3 to 8 ring carbon atoms. Cycloalkyl groups may include fused or bridged rings as well as spiro rings. The ring of the cycloalkyl group may be saturated, or it may contain one or more, for example one or two, double bonds in the ring (i.e. partially unsaturated), but it is not fully conjugated, nor "aryl" as defined in the present invention. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bis [4.1.0 ]]Heptylalkyl, bicyclo [3.1.1]Heptylalkyl, spiro [3.3]Heptylalkyl, spiro [2.2]Pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo [3.1.1]Hept-2-ene.
The term "heterocycloalkyl", "heterocyclyl" or "heterocycle" as used herein refers to: a saturated or partially unsaturated ring having 3 to 12 ring atoms (e.g., having 3 to 8 ring atoms, 5 to 7 ring atoms, 4 to 6 ring atoms, or3 to 6 ring atoms), containing one or more (e.g., 1,2 or3, preferably 1 or 2) ring heteroatoms independently selected from N, O and S in the ring, the remaining ring atoms being carbon atoms; it may have one or more rings, for example 1,2 or3, preferably 1 or 2 rings. Where N and S may optionally be oxidized to various oxidation states, the point of attachment of the heterocycloalkyl group may be at the N heteroatom or at a carbon atom. For example, "3-12 membered heterocycloalkyl" means said heterocycloalkyl having 3-12 ring atoms, which contains at least one heteroatom selected from N, O and S, "4-6 membered heterocycloalkyl" or "4-6 membered heterocyclyl" means said heterocycloalkyl having 4-6 ring atoms, which contains at least one heteroatom selected from N, O and S. Heterocycloalkyl groups may include fused or bridged rings as well as spiro rings. The heterocycloalkyl ring may be saturated or may contain one or more, for example one or two, double bonds (i.e. partially unsaturated) in the ring, but it is not fully conjugated or "heteroaryl" as defined in the present invention. Examples of heterocycloalkyl groups include, but are not limited to: 4-6 membered heterocyclic groups such as oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrazolidinyl, and oxaspiro [3.3] heptanyl.
The term "aryl" or "aromatic ring" as used herein refers to a carbocyclic hydrocarbon group containing 6 to 14 carbon atoms consisting of one or more fused rings, at least one of which is aromatic, such as phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl.
The term "heteroaryl" or "heteroaromatic ring" as used herein refers to: an aromatic ring having 5 to 12 ring atoms (e.g., having 5 to 10 ring atoms, 5 to 6 ring atoms, or 6 ring atoms), comprising one or more (e.g., 1,2,3, or 4, more preferably 1,2, or 3) ring heteroatoms independently selected from N, O and S in the ring, the remaining ring atoms being carbon atoms; it may have one or more rings, for example 1,2 or3, preferably 1 or 2 rings, for example, the heteroaryl group includes:
monocyclic aromatic hydrocarbon groups having 5, 6 or 7 ring atoms (preferably having 5 or 6 ring atoms, i.e. 5-6 membered heteroaryl) which contain in the ring one or more, for example 1,2,3 or 4, more preferably 1,2 or3 ring heteroatoms independently selected from N, O and S (preferably N and O), the remaining ring atoms being carbon atoms; and
bicyclic aromatic hydrocarbon radicals having 8 to 12 ring atoms, preferably having 9 or 10 ring atoms, which contain in the ring one or more, for example 1,2,3 or 4, preferably 1,2 or3, ring heteroatoms independently selected from N, O and S (preferably N), the remaining ring atoms being carbon atoms, wherein at least one ring is aromatic. For example, bicyclic heteroaryl includes a 5-6 membered heteroaryl ring fused to a 5-6 membered cycloalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.
Examples of heteroaryl groups include, but are not limited to: 5-to 6-membered heteroaryl, e.g. pyridyl, pyridyloxy, pyrazinyl, pyrimidinyl, triazinyl, pyrazolyl, imidazolyl,
Figure BDA0002062489860000081
Azolyl radical, iso
Figure BDA0002062489860000082
Azolyl group,
Figure BDA0002062489860000085
Oxadiazolyl (e.g. 1,2,4-
Figure BDA0002062489860000083
Oxadiazolyl, 1,2,5-
Figure BDA0002062489860000084
Oxadiazolyl and 1,3,4-
Figure BDA0002062489860000086
Oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl, and bicyclic heteroaryls such as benzodioxolyl, and benzothiazolyl
Figure BDA0002062489860000087
Azolyl, benzisoyl
Figure BDA0002062489860000088
Azolyl, benzothienyl, benzisothiazolyl, benzothiazolyl, benzisothiazolyl, imidazoPyridyl (e.g. imidazo [1, 2-a)]Pyridyl), imidazopyridazinyl (e.g. imidazo [1, 2-b)]Pyridazinyl), indazolyl, pyrrolopyridyl (e.g. 1H-pyrrolo [2, 3-b)]Pyridyl), pyrrolopyrimidyl (e.g. pyrrolo [3, 4-d)]Pyrimidinyl), pyrazolopyridinyl (e.g. 1H-pyrazolo [3, 4-b)]Pyridyl), pyrazolopyrimidyl (e.g. pyrazolo [1, 5-a)]Pyrimidinyl), triazolopyridinyl (e.g. [1,2, 4)]Triazolo [4,3-a]Pyridyl and [1,2,4 ]]Triazolo [1,5-a]Pyridyl group), tetrazolopyridyl group (e.g. tetrazolo [1, 5-a)]Pyridyl), benzofuranyl, benzimidazolinyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, and quinazolinyl.
The term "hydroxy" as used herein refers to an-OH group.
The term "oxo" as used herein refers to an ═ O group.
If a formula herein contains an asterisk, it indicates that the chiral center at the mark of the asterisk in the compound is in a single configuration, either the (R) configuration or the (S) configuration; wherein the single configuration of the label ". mark" is present in an amount of at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between these recited values).
The terms "optional," "optional," or "optionally" as used herein mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. It will be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any substitution patterns that are sterically impractical, chemically incorrect, synthetically infeasible and/or inherently unstable.
The term "substituted" or "substituted with … …" as used herein means that one or more hydrogen atoms on a given atom or group are replaced with one or more substituents selected from a given group of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., ═ O), then two hydrogen atoms on a single atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in chemically correct and stable compounds. A chemically correct and stable compound means that the compound is sufficiently stable to be isolated from the reaction mixture and subsequently formulated into a formulation that has at least practical utility.
Unless otherwise indicated, substituents are named into the core structure. For example, it is understood that when (cycloalkyl) alkyl is listed as one possible substituent, it means that the point of attachment of that substituent to the core structure is at the alkyl moiety.
The term "substituted with one or more substituents" as used herein means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from the given group. In some embodiments, "substituted with one or more substituents" means that a given atom or group is substituted with 1,2,3, or 4 substituents independently selected from a given group.
It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus exist as two or more stereoisomers. Racemic mixtures of these isomers, individual isomers and an enantiomerically enriched mixture, as well as diastereomeric and partially enriched mixtures of particular diastereomers when there are two chiral centers, are within the scope of the invention. It will also be understood by those skilled in the art that the present invention includes all individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I), and where appropriate, individual tautomers thereof.
Racemic mixtures can be used as such or can be resolved into their individual isomers. The resolution can result in a stereochemically pure compound or in an enriched mixture of one or more isomers. Methods for separating isomers are well known (see Allinger n.l. and Eliel e.l., "Topics in stereospecificity", volume 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. The individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers may be obtained by chemical separation of the mixture by forming diastereomeric salts with chiral acids (e.g. the individual enantiomers of 10-camphorsulfonate, camphorate, α -bromocamphorate, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of said salts, and then liberating one or both of the resolved bases, optionally repeating this process, to obtain one or both isomers substantially free of the other isomer, i.e. having an optical purity of > 95%. Alternatively, the racemate may be covalently attached to a chiral compound (the auxiliary) to give diastereomers, which may be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral auxiliary to give the pure enantiomers.
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions. Interconversions between tautomers are possible, for example enol and keto forms are typical tautomers.
"pharmaceutically acceptable salt" refers to a salt of the free acid or base of a compound of formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject to be treated. For example, acid addition salts include, for example, addition salts derived from inorganic acids including, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid, and organic acids including, for example, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. For a general description of pharmaceutically acceptable salts see, for example: berge et al, "Pharmaceutical Salts", J.pharm.Sci.,1977,66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, compiled by Stahl and Wermuth, Wiley-VCH and VHCA, Zurich, 2002.
Furthermore, if the compounds described herein are obtained in the form of an acid addition salt, the free base form thereof can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of the free base, its acid addition salts, in particular the pharmaceutically acceptable acid addition salts, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid, according to the usual procedures for preparing acid addition salts from basic compounds. Those skilled in the art will be able to ascertain without undue experimentation, various synthetic procedures which may be used to prepare non-toxic pharmaceutically acceptable acid or base addition salts.
The term "solvate" means a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to hold a fixed molar ratio of solvent molecules in the solid state, forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance, where the water retains its H2The molecular state of O, such combination being capable of forming one or more hydrates, such as hemihydrate, monohydrate and dihydrate.
As used herein, the terms "group" and "group" are synonymous and are used to refer to a functional group or molecular fragment that can be linked to other molecular fragments.
The term "active ingredient" is used to denote a chemical substance that has biological activity. In some embodiments, an "active ingredient" is a chemical substance having pharmaceutical use. In the united states, actual pharmaceutical activity can be determined by appropriate preclinical testing, whether in vitro or in vivo. But can be sufficiently active for regulatory authorities (e.g., FDA in the united states) to have higher standards than preclinical testing. The success of such a higher standard of pharmaceutical activity, which is generally not reasonably predictable from preclinical test results, can be established by appropriate and effective randomized, double-blind, controlled clinical trials in humans.
The terms "treat" or "treating" a disease or disorder refer to administering one or more pharmaceutical substances, particularly a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, to an individual suffering from, or having symptoms of, the disease or disorder, or having a predisposition toward the disease or disorder, for curing, healing, alleviating, altering, curing, ameliorating, improving, or affecting 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.
The terms "treating", "contacting", and "reacting" when referring to a chemical reaction mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction that produces the indicated and/or the desired product may not necessarily result directly from the combination of the two reagents that were initially charged, i.e., one or more intermediates that are formed may be present in the mixture that ultimately result in 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 IDO inhibitor that is generally sufficient to produce a beneficial therapeutic effect in a patient in need of treatment for a disease or disorder mediated by IDO activity or mediated at least in part by IDO. The effective amount or dose of the active ingredient of the present invention may be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., mode or route of administration or administration, pharmacokinetics of the pharmaceutical ingredient, severity and course of the disease or disorder, previous or ongoing treatment of the individual, health and response to drugs in the individual, and the judgment of the attending physician). In the united states, determination of effective dosages is generally difficult to predict from preclinical testing. In fact, the dosage is completely unpredictable and new unpredictable dosage regimens may develop after the original use in randomized, double-blind, controlled clinical trials.
Typical dosage ranges are from about 0.0001 to about 200 milligrams of active ingredient per kilogram of body weight of the subject per day, e.g., from about 0.001 to 100 milligrams/kilogram/day, or about 0.01 to 35 milligrams/kilogram/day, or about 0.1 to 10 milligrams/kilogram, administered once or in divided dosage units per day (e.g., twice daily, three times daily, four times daily). For a 70 kg human, suitable dosages illustratively range from about 0.05 to about 7 grams per day, or about 0.2 to about 5 grams per day. Once the patient's disease or disorder has improved, the dosage may be adjusted to maintain treatment. For example, the dosage or number of administrations, or both, may be reduced to a level that maintains the desired therapeutic effect, depending on the change in symptoms. Of course, if the symptoms are reduced to an appropriate level, treatment may be discontinued. However, for a recurrence of symptoms, the patient may require intermittent long-term treatment.
The term "inhibition" refers to a decrease in the baseline activity of a biological activity or process. The term "inhibiting IDO activity" is the actual pharmaceutical activity for the purposes of this invention and refers to a reduction in IDO activity in response, directly or indirectly, to the presence of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein relative to IDO activity in the absence of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof. The reduction in activity may be caused by a direct interaction of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein with IDO, or by a interaction of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein with one or more other factors that affect IDO activity. For example, the presence of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein may reduce the activity of IDO by binding directly to IDO, by affecting another factor directly or indirectly, or by reducing the amount of IDO present in a cell or body directly or indirectly.
The term "subject" as used herein refers to mammals and non-mammals. Mammal refers to any member of the mammalian family, including but not limited to: a human; non-human primates, such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; 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 "individual" does not limit a particular age or gender. In some embodiments, the subject is a human.
Generally, the term "about" is used herein to adjust a given value to 20% above or below that value.
Technical and scientific terms used herein that are not specifically defined have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
The present invention provides compounds of formula (I):
Figure BDA0002062489860000131
or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein:
x is N or CR3(ii) a Y is N or CR4；
R1、R2、R3And R4Each independently selected from: hydrogen, halogen, -OH, -CN, -NH2、 C1-6Alkyl radical, C1-6Haloalkyl, -O (C)1-6Alkyl), -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2；
Z is O, NR5Or CR6R7；
R5Selected from: hydrogen, C1-6Alkyl or C3-6A cycloalkyl group;
R6and R7Each independently selected from: hydrogen, halogen, -CN, C1-6Haloalkyl, -O (C)1-6Haloalkyl), -OH, C)1-6Alkyl radical, C3-6Cycloalkyl or-O (C)1-6Alkyl groups);
Figure BDA0002062489860000141
is phenyl, 5-6 membered heteroaryl or indazolyl; each of which is optionally substituted by one or more groups selected fromAnd (3) substitution: halogen, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-O(C1-6Alkyl) or-O (C)1-6Haloalkyl);
Figure BDA0002062489860000142
is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, each of which is optionally substituted with one or more groups selected from: halogen, - (C)1-6Alkyl radical)n-CN、-NO2、 C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, - (C)1-6Alkyl radical)n-C3-6Cycloalkyl, - (C)1-6Alkyl radical)n-phenyl, - (C)1-6Alkyl radical)n-4-6 membered heterocyclyl, - (C)1-6Alkyl radical)n-5-6 membered heteroaryl, - (C)1-6Alkyl radical)n-NR1’R2’、-(C1-6Alkyl radical)n-CONR1’R2’、-(C1-6Alkyl radical)n-NR1’R2’C(O)R3’、-(C1-6Alkyl radical)n-C(O)R3’-、-(C1-6Alkyl radical)n-C(O)OR4’、 -(C1-6Alkyl radical)n-OR5’、-(C1-6Alkyl radical)n-S(O)mNR1’R2’、-(C1-6Alkyl radical)n- NR1’R2’S(O)mR6’、-(C1-6Alkyl radical)n-S(O)mR6' and- (C)1-6Alkyl radical)n-SR7'; wherein, said phenyl, C3-6Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with one or more groups selected from: halogen, -CN, -OH, -NH2、C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6Alkyl, -O (C)1-6Alkyl), -NH (C)1-6Alkyl), -N (C)1-6Alkyl radical)2、C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group;
n is 0 or 1;
m is 1 or 2;
p is 0 or 1;
R1’、R2’、R3’、R4’、R5’、R6' and R7' independently from each other are selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, - (C)1-6Alkyl) -O- (C1-6Alkyl), - (C)1-6Alkyl) -OH, - (C)1-6Alkyl) -CN, - (C)1-6Alkyl) -NH2Or C3-6A cycloalkyl group; or R1’、R2' together with the N atom to which they are attached form a 4-6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I), X is CR3(ii) a Y is CR4。
In some embodiments of the compounds of formula (I), X is CH; y is CH.
In some embodiments of the compounds of formula (I), R1、R2、R3、R4、R6And R7Each independently selected from: hydrogen and halogen (e.g., F).
In some embodiments of the compounds of formula (I), R1、R2、R3、R4、R5、R6And R7Are all hydrogen.
In some embodiments of the compounds of formula (I), X is CH; y is N.
In some embodiments of the compounds of formula (I), X is N; y is N.
In some embodiments of the compounds of formula (I), p is 0 and Z is CR6R7；R6And R7Each independently selected from: hydrogen, halogen, -CN, C1-6Haloalkyl, -O (C)1-6Haloalkyl), -OH, C)1-6Alkyl radical, C3-6Cycloalkyl or-O (C)1-6Alkyl groups).
In the one part of the compound of formula (I)In some embodiments, p is 0 and Z is CHR6；R6Selected from: hydrogen, -OH, C1-6Alkyl or-O (C)1-6Alkyl groups).
In some embodiments of the compounds of formula (I), p is 0 and Z is CH2。
In some embodiments of the compounds of formula (I), p is 1 and Z is CR6R7；R6And R7Each independently selected from: hydrogen, halogen, -CN, C1-6Haloalkyl, -O (C)1-6Haloalkyl), -OH, C)1-6Alkyl radical, C3-6Cycloalkyl or-O (C)1-6Alkyl groups).
In some embodiments of the compounds of formula (I), p is 1 and Z is CHR6；R6Selected from: hydrogen, -OH, C1-6Alkyl or-O (C)1-6Alkyl groups).
In some embodiments of the compounds of formula (I), p is 1 and Z is NR5；R5Selected from: hydrogen, haloalkyl C1-6Alkyl or C3-6A cycloalkyl group.
In some embodiments of the compounds of formula (I), p is 1 and Z is NR5；R5Is hydrogen or C1-6An alkyl group.
In some embodiments of the compounds of formula (I), p is 1 and Z is O.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000151
is phenyl or 5-6 membered heteroaryl, optionally substituted with one or more groups selected from: halogen, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、 -O(C1-6Alkyl) or-O (C)1-6Haloalkyl).
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000161
is phenyl, pyridyl, pyrimidinyl, indolyl, pyrrolyl, pyrazolyl or thienyl, optionally substituted with one or more groups selected from: halogen, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-O(C1-6Alkyl) or-O (C)1-6Haloalkyl).
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000162
is phenyl, optionally substituted with one or more groups selected from: halogen, CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-OH、-O(C1-6Haloalkyl) or-O (C)1-6Alkyl groups).
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000163
is phenyl, optionally substituted with one or more groups selected from: halogen, CN, C1-6Alkyl radical, C2-6Alkynyl, C1-6Haloalkyl, -O (C)1-6Haloalkyl) or-O (C)1-6Alkyl groups).
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000164
is phenyl, optionally substituted with one or more groups selected from: F. cl, Br, CN, methyl, ethyl, ethynyl, trifluoromethyl, -O (trifluoromethyl), -OCHF2Or a methoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000165
is phenyl, substituted with one or more groups selected from: F. cl, Br, CNMethyl, ethyl, -CF3、-OCF3、-OCHF2Or a methoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000166
is phenyl substituted by ethynyl.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000167
is phenyl substituted by halogen.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000168
is a quilt-OCF3or-OCHF2A substituted phenyl group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000169
is phenyl substituted by CN.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000171
is a pyridyl group, optionally substituted with one or more groups selected from: c2-6Alkynyl or-O (C)1-6Alkyl groups).
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000172
is pyrrolyl or thienyl, optionally substituted by halogen or CN.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000173
is a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl group, optionally substituted with one or more groups selected from:
1) halogen;
2)-NO2；
3) oxo;
4)-(C1-6alkyl radical)n-CN；
5)C1-6An alkyl group;
6)C1-6a haloalkyl group;
7)C3-6a cycloalkyl group;
8)(C1-6alkyl radical)n-a 4-6 membered heterocyclyl group;
9)5-6 membered heteroaryl;
10)(C1-6alkyl radical)n-NR1’R2’；
11)-CONR1’R2’；
12)-NR1’R2’C(O)R3’；
13)-C(O)OR4’；
14)-(C1-6Alkyl radical)n-OR5’；
15)-S(O)2NR1’R2'; or
16)-NR1’R2’S(O)2R6’；
Wherein said 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more groups selected from: c1-6Alkyl, -O (C)1-6Alkyl) or-NH (C)1-6Alkyl groups);
n is 0 or 1;
R1’、R2’、R3’、R4’、R5' and R6' independently from each other are selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, - (C)1-6Alkyl) -O- (C1-6Alkyl), - (C)1-6Alkyl) -OH, - (C)1-6Alkyl) -CN, - (C)1-6Alkyl) -NH2Or C3-6A cycloalkyl group; or R1’、R2' together with the N atom to which they are attached form a 4-6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000181
is a pyridyl, pyrimidinyl or pyridazinyl group substituted by one, two or three groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000182
is pyridyl substituted by amino, pyrimidinyl substituted by amino or pyridazinyl substituted by amino, each of which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、 -(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000183
is a quilt- (C)1-6Pyridyl substituted by (C) alkyl) -OH1-6Pyrimidinyl substituted by alkyl) -OH or by- (C)1-6Alkyl) -OH substituted pyridazinyl, each of which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000184
is pyridyl or pyrimidinyl, optionally substituted by one or more groups selected fromSubstituted by the group:
1) halogen;
2)-NO2；
3) oxo;
4)-(C1-6alkyl radical)n-CN；
5)C1-6An alkyl group;
6)C1-6a haloalkyl group;
7)-C3-6a cycloalkyl group;
8)-(C1-6alkyl radical)n-a 4-6 membered heterocyclyl group;
9) -5-6 membered heteroaryl;
10)-(C1-6alkyl radical)n-NR1’R2’；
11)-CONR1’R2’；
12)-NR1’R2’C(O)R3’；
13)-C(O)OR4’；
14)-(C1-6Alkyl radical)n-OR5’；
15)-S(O)2NR1’R2'; or
16)-NR1’R2’S(O)2R6’；
Wherein said 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more groups selected from: c1-6Alkyl, -O (C)1-6Alkyl) or-NH (C)1-6Alkyl groups);
n is 0 or 1;
R1’、R2’、R3’、R4’、R5' and R6' independently from each other are selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, - (C)1-6Alkyl) -O- (C1-6Alkyl), - (C)1-6Alkyl) -CN or C3-6A cycloalkyl group; or R1’、R2' together with the N atom to which they are attached form a 4-6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000191
is pyridyl or pyrimidinyl, substituted with one, two or three groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group. In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000192
is pyridyl substituted by amino or pyrimidinyl substituted by amino, each of which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000193
is a quilt- (C)1-6Pyridyl substituted by- (C) alkyl) -OH1-6Alkyl) -OH substituted pyrimidinyl, each of which is substituted simultaneously with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、 -(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000201
is a pyridyl group, optionally substituted with one or more groups selected from:
1) halogen;
2)-NO2；
3) oxo;
4)-(C1-6alkyl radical)n-CN；
5)C1-6An alkyl group;
6)C1-6a haloalkyl group;
7)-C3-6a cycloalkyl group;
8)-(C1-6alkyl radical)n-a 4-6 membered heterocyclyl group;
9) -5-6 membered heteroaryl;
10)-(C1-6alkyl radical)n-NR1’R2’；
11)-CONR1’R2’；
12)-NR1’R2’C(O)R3’；
13)-C(O)OR4’；
14)-(C1-6Alkyl radical)n-OR5’；
15)-S(O)2NR1’R2'; or
16)-NR1’R2’S(O)2R6’；
Wherein said 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more groups selected from: c1-6Alkyl, -O (C)1-6Alkyl) or-NH (C)1-6Alkyl groups);
n is 0 or 1;
R1’、R2’、R3’、R4’、R5' and R6' independently from each other are selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, - (C)1-6Alkyl) -O- (C1-6Alkyl), - (C)1-6Alkyl) -CN or C3-6A cycloalkyl group; or R1’、R2' together with the N atom to which they are attached form a 4-6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000202
is a pyridyl group, which is substituted by one, two or three groups selected fromAnd (3) substitution: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000211
is pyridyl substituted by amino, which is simultaneously substituted by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group. In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000212
is a quilt- (C)1-6Alkyl) -OH substituted pyridyl, which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000213
is a quilt- (C)1-6Alkyl) -OH and C1-6Haloalkyl substituted pyridyl.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000214
is composed of
Figure BDA0002062489860000215
Optionally substituted with one or more groups selected from:
1) halogen;
2)-NO2；
3) oxo;
4)-(C1-6alkyl radical)n-CN；
5)C1-6An alkyl group;
6)C1-6a haloalkyl group;
7)-C3-6a cycloalkyl group;
8)-(C1-6alkyl radical)n-a 4-6 membered heterocyclyl group;
9) -5-6 membered heteroaryl;
10)-(C1-6alkyl radical)n-NR1’R2’；
11)-CONR1’R2’；
12)-NR1’R2’C(O)R3’；
13)-C(O)OR4’；
14)-(C1-6Alkyl radical)n-OR5’；
15)-S(O)2NR1’R2'; or
16)-NR1’R2’S(O)2R6’；
Wherein said 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more groups selected from: c1-6Alkyl, -O (C)1-6Alkyl) or-NH (C)1-6Alkyl groups);
n is 0 or 1;
R1’、R2’、R3’、R4’、R5' and R6' independently from each other are selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, - (C)1-6Alkyl) -O- (C1-6Alkyl), - (C)1-6Alkyl) -CN or C3-6A cycloalkyl group; or R1’、R2' together with the N atom to which they are attached form a 4-6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000221
is composed of
Figure BDA0002062489860000222
Optionally substituted with one or more groups selected from: CN, halogen, C1-6Alkyl radical, C1-6Haloalkyl, -O- (C)1-6Alkyl), -O- (C)1-6Haloalkyl), -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2or-NH (C)1-6Haloalkyl).
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000223
is composed of
Figure BDA0002062489860000224
Substituted with one, two or three groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000225
being substituted by amino groups
Figure BDA0002062489860000226
Figure BDA0002062489860000227
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group. In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000228
is a quilt- (C)1-6Alkyl) -OH substituted
Figure BDA0002062489860000229
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000231
is a quilt- (C)1-6Alkyl) -OH and C1-6Substituted by haloalkyl
Figure BDA0002062489860000232
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000233
is pyrimidinyl, optionally substituted with one or more groups selected from: halogen, -CN, C1-6Alkyl radical, C1-6Haloalkyl, 4-6-membered heterocyclyl, -NR1’R2' OR-OR5’；R1’、R2' and R5' independently from each other are selected from hydrogen, C1-6Alkyl or C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000234
is pyrimidinyl, which is substituted by one, two or three groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000235
is pyrimidinyl, which is substituted by one, two or three groups selected from: -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2And C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000236
is pyrimidinyl substituted with amino, which is substituted simultaneously with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group. In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000237
is pyrimidinyl substituted with amino, which is substituted simultaneously with one or two groups selected from: -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2And C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000238
is a quilt- (C)1-6Alkyl) -OH substituted pyrimidinyl, which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000241
is a quilt- (C)1-6Alkyl) -OH and C1-6A haloalkyl substituted pyrimidinyl group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000242
is composed of
Figure BDA0002062489860000243
Optionally substituted with one or more groups selected from: halogen, -CN, C1-6Alkyl radical, C1-6Haloalkyl, 4-6-membered heterocyclyl, -NR1’R2' OR-OR5’；R1’、R2' and R5' independently from each other are selected from hydrogen, C1-6Alkyl or C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000244
is composed of
Figure BDA0002062489860000245
Optionally substituted with one or more groups selected from: CN, halogen, C1-6Alkyl radical, C1-6Haloalkyl, -O- (C)1-6Alkyl), -O- (C)1-6Haloalkyl), -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2or-NH (C)1-6Haloalkyl).
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000246
is composed of
Figure BDA0002062489860000247
Substituted with one, two or three groups selected from: halogen, C1-6Alkyl, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group. In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000248
is composed of
Figure BDA0002062489860000249
Substituted with one, two or three groups selected from: -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2And C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I),
Figure BDA00020624898600002410
being substituted by amino groups
Figure BDA00020624898600002411
Which is substituted simultaneously by one or two groups selected from: halogen, C1-6Alkyl, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000251
being substituted by amino groups
Figure BDA0002062489860000252
Which is substituted simultaneously by one or two groups selected from: -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2And C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000253
is a quilt- (C)1-6Alkyl) -OH substituted
Figure BDA0002062489860000254
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I),
Figure BDA0002062489860000255
is a quilt- (C)1-6Alkyl) -OH and C1-6Substituted by haloalkyl
Figure BDA0002062489860000256
In some embodiments of the compounds of formula (I), the compounds of formula (I) have the structure of formula (I-1):
Figure BDA0002062489860000257
in some embodiments of the compounds of formula (I-1), X is N or CH; y is N or CH.
In some embodiments of the compounds of formula (I-1), X is CH; y is CH.
In some embodiments of the compounds of formula (I-1), X is CH; y is N.
In some embodiments of the compounds of formula (I-1), X is N; y is N.
In some embodiments of the compounds of formula (I), Z is NR5、CR6R7Or O; wherein R is6And R7Independently selected from: hydrogen, -OH, C1-6Alkyl or-O (C)1-6Alkyl groups); r5Is hydrogen or C1-6An alkyl group.
In some embodiments of the compounds of formula (I-1), Z is O.
In some embodiments of the compounds of formula (I-1), Z is CH2。
In some embodiments of the compounds of formula (I-1), Z is NH.
In some embodiments of the compounds of formula (I-1), RaSelected from: halogen, CN, C1-6Alkyl radical, C2-6Alkynyl, C1-6Haloalkyl, -O (C)1-6Haloalkyl) or-O (C)1-6Alkyl groups).
In some embodiments of the compounds of formula (I-1), RaSelected from: F. cl, Br, CN, methyl, ethyl, ethynyl, trifluoromethyl, -O (trifluoromethyl) or methoxy.
In some embodiments of the compounds of formula (I-1), RaSelected from: F. cl, Br, CN, methyl, ethyl, -CF3、-OCF3Or a methoxy group.
In some embodiments of the compounds of formula (I-1), RaIs an ethynyl group.
In some embodiments of the compounds of formula (I-1), RaIs halogen.
In some embodiments of the compounds of formula (I-1), Rais-OCF3or-OCHF2。
In some embodiments of the compounds of formula (I-1), RaIs CN.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000261
is pyridyl substituted by amino, pyrimidinyl substituted by amino or pyridazinyl substituted by amino, each of which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、 -(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000262
is pyridyl substituted by amino or pyrimidine substituted by aminoPyridyl, each of which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000263
is pyridyl substituted by amino, which is simultaneously substituted by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000264
being substituted by amino groups
Figure BDA0002062489860000265
Figure BDA0002062489860000266
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000271
is pyrimidinyl substituted with amino, which is substituted simultaneously with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH、C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000272
is pyrimidinyl substituted with amino, which is substituted simultaneously with one or two groups selected from: -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2And C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000273
being substituted by amino groups
Figure BDA0002062489860000274
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000275
being substituted by amino groups
Figure BDA0002062489860000276
Which is substituted simultaneously by one or two groups selected from: -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2And C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000277
is a quilt- (C)1-6Pyridyl substituted by (C) alkyl) -OH1-6Pyrimidinyl substituted by alkyl) -OH or by- (C)1-6Alkyl) -OH substituted pyridazinyl, each of which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000278
is a quilt- (C)1-6Pyridyl substituted by- (C) alkyl) -OH1-6Alkyl) -OH substituted pyrimidinyl, each of which is substituted simultaneously with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、 -(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000281
is a quilt- (C)1-6Alkyl) -OH substituted pyridyl, which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000282
is a quilt- (C)1-6Alkyl) -OH and C1-6Haloalkyl substituted pyridyl.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000283
is a quilt- (C)1-6Alkyl) -OH substitutionIs/are as follows
Figure BDA0002062489860000284
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000285
is a quilt- (C)1-6Alkyl) -OH and C1-6Substituted by haloalkyl
Figure BDA0002062489860000286
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000287
is a quilt- (C)1-6Alkyl) -OH substituted pyrimidinyl, which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000288
is a quilt- (C)1-6Alkyl) -OH and C1-6A haloalkyl substituted pyrimidinyl group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000291
is a quilt- (C)1-6Alkyl) -OH substituted
Figure BDA0002062489860000292
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000293
is a quilt- (C)1-6Alkyl) -OH and C1-6Substituted by haloalkyl
Figure BDA0002062489860000294
In some embodiments of the compounds of formula (I), the compounds of formula (I) have the structure of formula (I-2):
Figure BDA0002062489860000295
in some embodiments of the compounds of formula (I-2), X is N or CH; y is N or CH.
In some embodiments of the compounds of formula (I-2), X is CH; y is CH.
In some embodiments of the compounds of formula (I-2), X is CH; y is N.
In some embodiments of the compounds of formula (I-2), X is N; y is N.
In some embodiments of the compounds of formula (I-2), RaSelected from: halogen, CN, C1-6Alkyl radical, C2-6Alkynyl, C1-6Haloalkyl, -O (C)1-6Haloalkyl) or-O (C)1-6Alkyl groups).
In some embodiments of the compounds of formula (I-2), RaSelected from: F. cl, Br, CN, methyl, ethyl, ethynyl, trifluoromethyl, -O (trifluoromethyl) or methoxy.
In some embodiments of the compounds of formula (I-2), RaSelected from: F. cl, Br, CN, methyl,Ethyl group, -CF3、-OCF3Or a methoxy group.
In some embodiments of the compounds of formula (I-2), RaIs an ethynyl group.
In some embodiments of the compounds of formula (I-2), RaIs halogen.
In some embodiments of the compounds of formula (I-2), Rais-OCF3or-OCHF2。
In some embodiments of the compounds of formula (I-2), RaIs CN.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000301
is pyridyl substituted by amino, pyrimidinyl substituted by amino or pyridazinyl substituted by amino, each of which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、 -(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000302
is pyridyl substituted by amino or pyrimidinyl substituted by amino, each of which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000303
is pyridyl substituted by amino, which is simultaneously substituted by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000304
being substituted by amino groups
Figure BDA0002062489860000305
Figure BDA0002062489860000306
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000307
is pyrimidinyl substituted with amino, which is substituted simultaneously with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000308
is pyrimidinyl substituted with amino, which is substituted simultaneously with one or two groups selected from: -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2And C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000311
being substituted by amino groups
Figure BDA0002062489860000312
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000313
being substituted by amino groups
Figure BDA0002062489860000314
Which is substituted simultaneously by one or two groups selected from: -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2And C1-6A haloalkyl group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000315
is a quilt- (C)1-6Pyridyl substituted by (C) alkyl) -OH1-6Pyrimidinyl substituted by alkyl) -OH or by- (C)1-6Alkyl) -OH substituted pyridazinyl, each of which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000316
is a quilt- (C)1-6Pyridyl substituted by- (C) alkyl) -OH1-6Alkyl) -OH-substituted pyrimidinyl radicals, each of themIndependently of the substitution by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、 -(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000317
is a quilt- (C)1-6Alkyl) -OH substituted pyridyl, which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000318
is a quilt- (C)1-6Alkyl) -OH and C1-6Haloalkyl substituted pyridyl.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000321
is a quilt- (C)1-6Alkyl) -OH substituted
Figure BDA0002062489860000322
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000323
is a quilt- (C)1-6Alkyl radical) -OH and C1-6Substituted by haloalkyl
Figure BDA0002062489860000324
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000325
is a quilt- (C)1-6Alkyl) -OH substituted pyrimidinyl, which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000326
is a quilt- (C)1-6Alkyl) -OH and C1-6A haloalkyl substituted pyrimidinyl group.
In some embodiments of the compounds of formula (I-2),
Figure BDA0002062489860000327
is a quilt- (C)1-6Alkyl) -OH substituted
Figure BDA0002062489860000328
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、 -NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
In some embodiments of the compounds of formula (I-1),
Figure BDA0002062489860000329
is a quilt- (C)1-6Alkyl) -OH and C1-6Substituted by haloalkyl
Figure BDA00020624898600003210
The present invention also provides a compound selected from compounds numbered 1-327 in the experimental section, and/or a pharmaceutically acceptable salt thereof.
In another aspect, the invention also provides a pharmaceutical composition comprising a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
In another aspect, the invention also provides a method of inhibiting IDO activity in vivo or in vitro comprising contacting an effective amount of a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof with IDO.
In another aspect, the present invention also provides a method of inhibiting IDO activity in vivo or in vitro comprising contacting an effective amount of a pharmaceutical composition comprising a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) with IDO.
In another aspect, the present invention also provides a method of treating a disease mediated by IDO or mediated at least in part by IDO in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention also provides a method of treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention also provides a method of treating a disease mediated by IDO or at least partially mediated by IDO in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
In another aspect, the present invention also provides a method of treating cancer or an autoimmune disease in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
In another aspect, the invention also provides a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof as described herein for use in treating a disease mediated by IDO or mediated at least in part by IDO.
In another aspect, the invention also provides a compound of formula (I) (e.g., any of the compounds herein) and/or a pharmaceutically acceptable salt thereof as described herein for use in treating cancer or an autoimmune disease.
In another aspect, the present invention also provides the use of a compound of formula (I) as described herein (e.g. any compound herein) and/or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease mediated by IDO or mediated at least in part by IDO.
In another aspect, the present invention also provides the use of a compound of formula (I) as described herein (e.g., any of the compounds herein) and/or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, an autoimmune disease, obesity, or an obesity-related disease.
In another aspect, the invention also provides a combination comprising a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
In some embodiments, the additional therapeutic agent is an anti-neoplastic agent.
In some embodiments, the additional therapeutic agent is a chemotherapeutic agent.
In some embodiments, the additional therapeutic agent is an immune checkpoint inhibitor.
In another aspect, the present invention also provides a method of treating a disease mediated by IDO or at least partially mediated by IDO in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and an anti-neoplastic agent.
In another aspect, the invention also provides a method of treating cancer in an individual comprising administering to the individual in need thereof an effective amount of a compound of formula (I) (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, a targeted therapeutic, or a chemotherapeutic agent.
In another aspect, the present invention also provides the use of a compound of formula (I) (e.g. any of the compounds herein) and/or a pharmaceutically acceptable salt thereof as described herein, together with an anti-neoplastic agent in the manufacture of a combination for the treatment of a disease mediated by, or at least partially mediated by, IDO.
In another aspect, the invention also provides the use of a compound of formula (I) as described herein (e.g. any of the compounds herein) and/or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, a targeted therapeutic or a chemotherapeutic agent in the manufacture of a combination for the treatment of cancer or an autoimmune disease.
In some embodiments, the immune checkpoint inhibitor is selected from an anti-PD-1 inhibitor, a CTLA-4 inhibitor, or an OX-40 inhibitor.
In some embodiments, the immune checkpoint inhibitor is selected from palivizumab (pembrolizumab), nivolumab (nivolumab), and plemarumab (ipilimumab).
In some embodiments, the disease mediated by IDO or at least partially mediated by IDO is cancer or an autoimmune disease.
In some embodiments, the cancer is a solid tumor or a hematologic malignancy, such as: leukemia, lymphoma, or myeloma.
In some embodiments, the cancer is selected from skin cancer (e.g., melanoma and basal carcinoma), lung cancer, non-small cell lung cancer, kidney cancer, head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer, endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, stomach cancer, esophageal cancer, brain tumors including glioma and Glioblastoma (GBM), thyroid cancer, mesothelial intimal cancer, choriocarcinoma, adrenal cancer, sarcomas (e.g., Kaposi's sarcoma), leukemia, lymphoma, or myeloma.
In some embodiments, the cancer is selected from melanoma, lung cancer, renal cell carcinoma, head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular cancer, endometrial cancer, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, glioma, Glioblastoma (GBM), Acute Myelogenous Leukemia (AML), human acute monocytic leukemia (M (5)), Acute Lymphocytic Leukemia (ALL), and diffuse large B-cell lymphoma (DLBCL).
In some embodiments, the autoimmune disease is selected from arthritis, such as rheumatoid arthritis, collagen-induced arthritis, and the like.
In some embodiments, the obesity-related disorder is selected from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, cardiac arrhythmia, 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.
General synthetic methods for the disclosed embodiments
The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein can be synthesized using commercially available starting materials, by methods known in the art, or as disclosed in the present patent application. The synthetic routes shown in schemes 1-3 illustrate general synthetic methods for the compounds of the present invention.
The method comprises the following steps:
Figure BDA0002062489860000361
scheme 1
As shown in scheme 1, compounds of formula (1-1) are prepared in the presence of a palladium reagent (e.g., but not limited to Pd (PPh)3)4) Carrying out coupling reaction with the compound (1-2) under catalysis to obtain a compound represented by a molecular formula (1-3); then, removing the protecting group under acidic conditions (such as, but not limited to, TFA, etc.) to obtain a compound represented by the formula (1-4); finally, the compound represented by the formula (1-5) is subjected to a condensation reaction in the presence of a condensing agent (for example, but not limited to HATU, etc.) to obtain a compound represented by the formula (1-6). Wherein R is1、R2、X、Y、p、
Figure BDA0002062489860000362
As defined herein; raAnd RbAre each one or more substituents; w is a leaving group.
The method 2 comprises the following steps:
Figure BDA0002062489860000371
scheme 2
As shown in scheme 2, a compound represented by formula (2-1) is subjected to a condensation reaction with a compound represented by formula (2-2) in the presence of a condensing agent (for example, but not limited to, HATU, etc.) to obtain a compound represented by formula (2-3); then, in a palladium reagent (such as, but not limited to, Pd (PPh)3)4) Carrying out coupling reaction under catalysis to obtain a compound represented by a molecular formula (2-4); finally, in a palladium reagent (such as, but not limited to, Pd (PPh)3)4) Catalytically with moleculesThe compound represented by the formula (2-5) is further subjected to a condensation reaction to obtain a compound represented by the formula (2-6). Wherein R is1、R2、X、Y、p、
Figure BDA0002062489860000372
As defined herein; raAnd RbAre each one or more substituents; w is a leaving group.
The method 3 comprises the following steps:
Figure BDA0002062489860000373
scheme 3
As shown in scheme 3, a compound represented by the formula (3-1) is subjected to a coupling reaction with a compound represented by the formula (3-2) to obtain a compound represented by the formula (3-3); then, removing the protecting group under acidic conditions (such as, but not limited to, TFA, etc.) to obtain a compound represented by the formula (3-4); finally, the compound represented by the formula (3-6) is obtained by condensation reaction with a compound represented by the formula (3-5) in the presence of a condensing agent (for example, but not limited to HATU, etc.). Wherein R is1、R2、X、Y、p、
Figure BDA0002062489860000381
As defined herein; raAnd RbAre each one or more substituents; w is a leaving group; m is C1-6Alkyl substituted tin, boric acid or borate.
The substituents of the compounds obtained by the above-described methods may be further modified to give other desired compounds. Synthetic chemical conversion methods can be referred to, for example: larock, Comprehensive Organic Transformations, VCH Publishers (1989); fieser and m.fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.Patquette, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its successors.
Prior to use, the compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.
Pharmaceutical composition and practical application
A compound of formula (I) as described herein (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof can be formulated alone or in combination with one or more additional active ingredients into a pharmaceutical composition. The pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein; and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
A pharmaceutically acceptable carrier refers to a carrier that is compatible with (in some embodiments, stabilizes) the active ingredient in the composition and is not deleterious to the subject being treated. For example, solubilizing agents such as cyclodextrins (which form specific, more soluble complexes with the compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein) can be used as pharmaceutical excipients to deliver the active ingredient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D & C Yellow No. 10 (D & C Yellow # 10). Suitable pharmaceutically acceptable carriers are disclosed in the reference book of one of the standards in the art (Remington's Pharmaceutical Sciences, a.osol).
Pharmaceutical compositions comprising a compound of formula (I) described herein (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof can be administered in a variety of known ways, e.g., orally, topically, rectally, parenterally, by inhalation or implantation, and the like. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.
The pharmaceutical composition described herein can be prepared in the form of tablets, capsules, sachets, dragees, powders, granules, troches, powder injections, liquid preparations or suppositories. In some embodiments, the pharmaceutical composition comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof may be formulated for intravenous drip, topical administration, or oral administration.
The composition for oral administration may be any orally acceptable dosage form including, but not limited to: tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added to tablets. When administered orally in capsule form, useful diluents include lactose and dried corn starch. When administered orally in the form of an aqueous suspension or emulsion, the active ingredient may be suspended or dissolved in the oily phase by emulsifying or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
In some embodiments, the amount of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof in the tablet can be 1,5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 milligrams. In some embodiments, the amount of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof in the capsule can be 1,5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg.
Sterile injectable compositions, such as aqueous or oleaginous suspensions, can be formulated according to the techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable intermediate medium may 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 carriers and solvents that may be used are mannitol, water, ringer's solution and physiological saline. In addition, sterile, non-volatile oils, such as synthetic mono-or diglycerides, are conventionally employed as a solvent or suspending medium. Fatty acids such as oleic acid and its glyceride derivatives are useful as injectable intermediates, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
Inhalation compositions may be prepared according to techniques well known in the art of pharmaceutical formulation, using benzyl alcohol or other suitable preservatives, using absorption promoters to enhance bioavailability, using fluorocarbons and/or other solubilizing or dispersing agents known in the art, or may be prepared as solutions in saline.
Topical compositions may be formulated in the form of oils, creams, lotions, ointments and the like. Suitable carriers for use in the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (i.e., alcohols having greater than 12 carbon atoms). In some embodiments, a pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble. If desired, the composition may also contain emulsifiers, stabilizers, humectants and antioxidants, as well as substances which impart color or fragrance thereto. In addition, transdermal penetration enhancers may also be added to the topical formulations. Examples of such accelerators can be found in U.S. patent nos. 3,989,816 and 4,444,762.
Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water, with the active ingredient dissolved in a small amount of oil, such as almond oil, mixed therein. One example of a cream comprises, 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, for example almond oil, with warm soft paraffin and cooling the mixture. An example of an ointment comprises about 30% almond oil and about 70% white soft paraffin by weight.
Suitable in vitro assays may be used to assess the practical use of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein for inhibiting IDO activity. Further practical uses of the compounds of formula (I) and/or pharmaceutically acceptable salts thereof as described herein in the treatment of cancer may be further tested by in vivo assays. For example, a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein can be administered to an animal (e.g., a mouse model) having cancer and then its therapeutic effect evaluated. If the results of the preclinical testing are successful, the dosage range and route of administration to an animal, e.g., a human, can also be predicted.
The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may exhibit sufficient preclinical utility to merit clinical testing and are expected to exhibit beneficial therapeutic or prophylactic effects, for example, in individuals with cancer.
The term "cancer" as used herein refers to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new foci of growth elsewhere. The term "cancer" includes, but is not limited to: solid tumors and hematological malignancies. The term "cancer" includes cancers of the skin, tissues, organs, bone, cartilage, blood and blood vessels. The term "cancer" includes both 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; kidney cancers, including, for example, metastatic renal cell carcinoma; urothelial cancer; liver cancer; hepatocellular carcinoma; lung cancer including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer; endometrial cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; skin cancers, including, for example, malignant melanoma and basal cancers; neuroendocrine cancers, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; sarcomas, including, for example, Kaposi's sarcoma; adrenal cancer; mesothelial intimal cancer; choriocarcinoma; muscle cancer; connective tissue cancer; and thyroid cancer.
Non-limiting examples of hematological malignancies include Acute Myeloid Leukemia (AML); chronic Myelogenous Leukemia (CML), including accelerated phase CML and CML catastrophe phase (CML-BP); acute Lymphocytic Leukemia (ALL); chronic Lymphocytic Leukemia (CLL); hodgkin lymphoma; non-hodgkin 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 syndromes (MDS) including Refractory Anemia (RA), refractory anemia of cricothyroid granulocytes (RARS), refractory anemia of excess granulocytes (RAEB) and refractory anemia of excess granulocytes combined with acute transformation (RAEB-T); and myeloproliferative syndrome (myeloproliferative syndrome).
In some embodiments, the solid tumor comprises melanoma, lung cancer (e.g., non-small cell lung cancer), renal cell carcinoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), urothelial cancer, 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, typical hematological malignancies include leukemias, such as Acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), and Chronic Myelogenous Leukemia (CML); multiple Myeloma (MM); and lymphomas 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).
The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject having cancer.
The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein may be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject suffering from an autoimmune disease.
The term "autoimmune disease" refers to a disease or condition caused by an immune response to a self-antigen in a body resulting in damage to a self-tissue or organ. Examples of autoimmune diseases include, but are not limited to: chronic Obstructive Pulmonary Disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), collagen-induced arthritis, psoriasis, inflammatory bowel disease (inflmatous bowel disease), asthma and idiopathic thrombocytopenic purpura (idiopathetic thrombotic purpura), and myeloproliferative diseases (myeloproliferative diseases), such as myelofibrosis (myelofibrosis), polycythemia vera/essential thrombocytosis myelofibrosis (post-PV/myelofibrosis).
The term "obesity-related disease" refers to a disease or disorder associated with, caused by, or caused by obesity. Examples of obesity-related diseases include, but are not limited to: the obesity related diseases are selected from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular diseases (including atherosclerosis, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease and angina pectoris), cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and the like.
In addition, a compound of formula (I) described herein (e.g., any of the compounds herein) and/or a pharmaceutically acceptable salt thereof can be administered in combination with an additional therapeutic agent for the treatment of cancer. The additional therapeutic agent may be administered separately from the compound of formula (I) and/or pharmaceutically acceptable salts thereof described herein, or it may be included in a pharmaceutical composition according to the present disclosure, e.g., a fixed dose combination. In some embodiments, the additional therapeutic agent is an agent known or found to be effective for treating a disease mediated by IDO or mediated at least in part by IDO, such as another IDO inhibitor or a compound effective to antagonize another target associated with the particular disease. The combination may be used to improve the therapeutic effect (e.g., by including in the combination a compound that enhances the efficacy or effectiveness of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein), reduce one or more side effects, or reduce the required dosage of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein.
In some embodiments, a compound of formula (I) described herein (e.g., any of the compounds herein) and/or a pharmaceutically acceptable salt thereof can be administered in combination with an anti-tumor agent. The term "anti-neoplastic agent" as used herein refers to any agent administered to a subject having cancer for the purpose of treating cancer, including, but not limited to, radiotherapeutic agents, chemotherapeutic agents, immunotherapeutic agents, targeted therapeutic agents, and the like.
In some embodiments, a compound of formula (I) described herein (e.g., any of the compounds herein) and/or a pharmaceutically acceptable salt thereof can be administered in combination with an immune checkpoint inhibitor, a targeted therapeutic, or a chemotherapeutic agent.
Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 antibodies, such as palivizumab (pembrolizumab) and nivolumab (nivolumab); anti-PD-L1 antibodies, such as atilizumab (atezolizumab), dolvacizumab (durvalumab), and avizumab (avelumab); anti-CTLA-4 antibodies, such as, for example, Yipimima (ipilimumab); and BTLA antibodies, LAG-3 antibodies, TIM3 antibodies, TIGIT antibodies, VISTA antibodies, and the like.
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, demethoxydaunorubicin, and daunomycin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea mustard, lomustine, methylcyclohexylnitrosourea, streptozotocin, dacarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea), paclitaxel, docetaxel, and related analogs; vincristine, vinblastine and related analogs; sedatives and related analogs (e.g., CC-5013 and CC-4047).
Non-limiting examples of targeted therapeutics include: protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF- κ B inhibitors, including Iκ B kinase inhibitors; antibodies that bind to proteins that are overexpressed in cancer, thereby down-regulating cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be up-regulated, over-expressed or activated in cancer, and their inhibition down-regulates cell replication.
Examples
The following examples are illustrative of the invention and are not intended to limit the invention in any way. The data presented (e.g., amounts, temperatures, etc.) strives to ensure their accuracy, but those skilled in the art will appreciate that they may have some experimental error and offset. Unless otherwise indicated, all parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. All mass spectral data were measured by Agilent 6120 and 1100. All NMR data were measured by a Varian 400 MR. All reagents used in the present invention, except for synthetic intermediates, are commercially available. All compound names except reagents were generated by Chemdraw 16.0.
In any of the structural formulae herein, if there is a free valence on any atom, the free valence is actually a hydrogen atom not specifically depicted for the sake of simplicity.
In the present application, if a compound is referred to by its name and structural formula, in the case where the name and structural formula are not identical, the structure of the compound is used as the standard unless the context indicates that the structure of the compound is incorrect and the name is correct.
List of abbreviations used in the following examples:
KOAc potassium acetate
DIEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
dppf 1,1' -bis (diphenylphosphino) ferrocene
EDTA ethylene diamine tetraacetic acid
EtMgBr Ethyl magnesium bromide
HATU 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
MgCl2Magnesium chloride
MsCl methanesulfonyl chloride
Pd(dppf)Cl2·CH2Cl2[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex
Pd(PPh3)4Tetrakis (triphenylphosphine) palladium
TEA Triethylamine
TFA trifluoroacetic acid
Ti(OiPr)4Titanium tetraisopropoxide
Example 1
Compound 1
N- (1- (4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) phenyl) cyclopropyl) -4-chlorobenzamide
Figure BDA0002062489860000461
a) (1- (4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) phenyl) cyclopropyl) carbamic acid tert-butyl ester
Tert-butyl (1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) carbamate (359mg, 1.0mmol), 2-bromo-5- (trifluoromethyl) pyridin-3-amine (241mg, 1.0mmol), KOAc (276mg, 2.0mmol) and Pd (dppf) Cl2·CH2Cl2(82mg, 0.1mmol) was dissolved in 10mL of dioxahexazineThe ring was replaced with 3mL of water, and the solution was purged with nitrogen and refluxed overnight. After the reaction mixture was evaporated to dryness, the reaction mixture was separated by column chromatography (mobile phase: ethyl acetate/petroleum ether: 0 to 100%) to obtain the target compound (230mg) as a white solid, yield: 58.5 percent. MS (M/z): 394.2(M +1)+。1H NMR(399MHz,DMSO-d6)8.14(d,J＝0.8Hz,1H), 7.74(s,1H),7.59-7.56(m,2H),7.37(d,J＝1.6Hz,1H),7.21-7.18(m, 2H),5.54(s,2H),1.37(s,9H),1.15(brs,4H)。
b) N- (1- (4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) phenyl) cyclopropyl) -4-chlorobenzamide
Tert-butyl (1- (4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) phenyl) cyclopropyl) carbamate (230mg, 0.58mmol) was dissolved in 5mL TFA, concentrated to dryness, the resulting residue was dissolved in 3mL DMF, and 4-chlorobenzoic acid (92mg, 0.58mmol), HATU (222mg, 0.58mmol), and DIEA (151mg, 1.16mmol) were added to the solution in this order, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was separated by column chromatography (mobile phase: methanol/water 0 to 100%) to obtain the objective compound (170mg) as a white solid in yield: 67.5 percent. MS (M/z) 432.1 (M +1)+。1H NMR(399MHz,DMSO-d6)9.31(s,1H),8.14-8.13(m,1H), 7.92–7.88(m,2H),7.59–7.50(m,4H),7.36(d,J＝2.0Hz,1H),7.28– 7.24(m,2H),5.55(s,2H),1.29(brs,4H)。
The following compounds were prepared following the procedure for compound 1 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.
Figure BDA0002062489860000471
Figure BDA0002062489860000481
Figure BDA0002062489860000491
Figure BDA0002062489860000501
Figure BDA0002062489860000511
Figure BDA0002062489860000521
Figure BDA0002062489860000531
Figure BDA0002062489860000541
Figure BDA0002062489860000551
Figure BDA0002062489860000561
Figure BDA0002062489860000571
Figure BDA0002062489860000581
Figure BDA0002062489860000591
Figure BDA0002062489860000601
Figure BDA0002062489860000611
Figure BDA0002062489860000621
Figure BDA0002062489860000631
Figure BDA0002062489860000641
Figure BDA0002062489860000651
Figure BDA0002062489860000661
Figure BDA0002062489860000671
Figure BDA0002062489860000681
Figure BDA0002062489860000691
Figure BDA0002062489860000701
Figure BDA0002062489860000711
Figure BDA0002062489860000721
Figure BDA0002062489860000731
Figure BDA0002062489860000741
Figure BDA0002062489860000751
Figure BDA0002062489860000761
Figure BDA0002062489860000771
Figure BDA0002062489860000781
Figure BDA0002062489860000791
Figure BDA0002062489860000801
Figure BDA0002062489860000811
Figure BDA0002062489860000821
Figure BDA0002062489860000831
Figure BDA0002062489860000841
Figure BDA0002062489860000851
Figure BDA0002062489860000861
Figure BDA0002062489860000871
Figure BDA0002062489860000881
Figure BDA0002062489860000891
Figure BDA0002062489860000901
Figure BDA0002062489860000911
Figure BDA0002062489860000921
Figure BDA0002062489860000931
Figure BDA0002062489860000941
Figure BDA0002062489860000951
Figure BDA0002062489860000961
Of these, compounds 219 and 220 are two single configuration enantiomers separated from the corresponding racemic compounds by chiral preparative chromatography. The chiral resolution conditions are as follows: the column was CHIRALPAK IG 20 mm by 250 mm; the mobile phase is 20% ethanol and 80% n-heptane; the detection wavelength is 254 nm; the flow rate was 15 mL/min. In this method, the compound obtained by evaporating the solvent from the first mobile phase is compound 219, and the compound obtained by evaporating the solvent from the second mobile phase is compound 220.
Compounds 230 and 231 are two single configuration enantiomers separated by chiral preparative chromatography from the corresponding racemic compounds. The chiral resolution conditions are as follows: the column was CHIRALPAK IG 20 mm by 250 mm; the mobile phase is 20% ethanol and 80% n-heptane; the detection wavelength is 254 nm; the flow rate was 15 mL/min. In this method, the compound obtained by evaporating the solvent from the first mobile phase is compound 230, and the compound obtained by evaporating the solvent from the second mobile phase is compound 231.
Compounds 233 and 234 are two single configuration enantiomers separated from the corresponding racemic compounds by chiral preparative chromatography. Under chromatographic conditions (column CHIRALPAK IG 4.6.6 × 250 mm; mobile phase (n-heptane + 0.1% diethylamine): 8:2 (ethanol + 0.1% diethylamine); detection wavelength 254 nm; flow rate 1 mL/min; temperature 30 ℃), retention time of compound 234 was 5.244min and retention time of compound 233 was 5.744 min.
Example 2
Compound 300
N- (1- (4- (3-amino-5-chloropyridin-2-yl) -2-fluorophenyl) cyclopropyl) -4-fluorobenzamide
Figure BDA0002062489860000971
a)1- (4-bromo-2-fluorophenyl) cyclopropane-1-amine
4-bromo-2-fluorobenzonitrile (2.00 g, 10.0mmol) and Ti (OiPr)4(2.84 g, 10.0mmol) was dissolved in 100mL tetrahydrofuran, cooled to-78 deg.C, EtMgBr (6.67 g, 20.0mmol) was slowly added dropwise thereto, the mixture was warmed to room temperature, and the reaction was stirred for 2 hours. Then, the reaction liquid was cooled to 0 degrees, and a boron trifluoride ether solution (2.84 g, 20.0mmol) was added dropwise thereto. After the addition, the temperature was raised to room temperature, and the reaction was continued for 5 hours. After the reaction, 2mol/L aqueous sodium hydroxide solution was added to quench, followed by filtration through celite, the filter cake was washed with 100mL of methanol, the filtrates were combined and evaporated to dryness, and the resulting residue was separated by column chromatography (mobile phase: methanol/dichloromethane ═ 0 to 10%) to give 1- (4-bromo-2-fluorophenyl) cyclopropane-1-amine (300mg) as a yellow oil. The yield thereof was found to be 13.0%. MS (M/z) 230.0 (M +1)+。
b) N- (1- (4-bromo-2-fluorophenyl) cyclopropyl) -4-fluorobenzamide
1- ((4-bromo-2-fluorophenyl) cyclopropane-1-amine ((300mg, 1.304mmol), 4-fluorobenzoic acid (182.7mg, 1.304mmol), HATU (743.7mg, 1.956mmol) and DIEA (505.6mg, 3.912mmol) were dissolved in DMF and the mixture was reacted at room temperature overnightThe product is separated by column chromatography (mobile phase: methanol/water 0-100%) to obtain the target compound as a yellow solid. The yield thereof was found to be 65.2%. MS (M/z):352.0(M +1)+。
c) 4-fluoro-N- (1- (2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) benzamide
N- (1- (4-bromo-2-fluorophenyl) cyclopropyl) -4-fluorobenzamide (300mg, 0.852mmol), pinacol diboride diborate (216.4mg, 0.852mmol), KOAc (162.7mg, 1.704mmol) and Pd (dppf) Cl2·CH2Cl2(69.4mg, 0.085mmol) was dissolved in 40mL dioxane and the mixture was reacted at 80 ℃ for 4 hours under nitrogen. After completion of the reaction, it was cooled and concentrated, and the obtained residue was separated by column chromatography (mobile phase: methanol/water 0 to 100%) to obtain the objective compound (300mg) as a yellow solid. The yield thereof was found to be 73.9%. MS (M/z):400.2(M +1)+。
d) N- (1- (4- (3-amino-5-chloropyridin-2-yl) -2-fluorophenyl) cyclopropyl) -4-fluorobenzamide
4-fluoro-N- (1- (2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) benzamide (120mg, 0.301mmol), 2-bromo-5-chloropyridin-3-amine (62.4mg, 0.301mmol), K2CO3(83.2mg, 0.602mmol) and Pd (dppf) Cl2·CH2Cl2(24.5mg, 0.03mmol) was dissolved in 10mL dioxane and 2mL water and the reaction was refluxed overnight under nitrogen. After completion of the reaction, it was cooled, concentrated, and the resulting residue was separated by column chromatography (mobile phase: methanol/water 0 to 100%) to give the objective compound (66mg) as a yellow solid. The yield thereof was found to be 56.5%. MS (M/z):400.1 (M +1)+。1H NMR(399MHz,DMSO-d6)9.23(s,1H),7.92–7.85(m,2H), 7.83(d,J＝2.2,1H),7.62(t,J＝8.2,1H),7.39(dd,J＝8.0,1.7,1H),7.32 (dd,J＝12.2,1.7,1H),7.27–7.21(m,2H),7.17(d,J＝2.2,1H),5.51(s, 2H),1.27–1.15(m,4H)。
The following compounds were prepared following the procedure for compound 300 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.
Figure BDA0002062489860000991
Figure BDA0002062489860001001
Figure BDA0002062489860001011
Figure BDA0002062489860001021
Example 3
Compound 318
N- (1- (5 '-chloro- [2,2' -bipyridine ] -5-yl) cyclopropyl) -4-ethynylbenzamide
Figure BDA0002062489860001031
a) Synthesis of 1- (6-bromopyridin-3-yl) cyclopropane-1-amine
6-bromonicotinonitrile (2.34 g, 12.8mmol) was dissolved in diethyl ether (60mL), cooled to-78 deg.C, and Ti (OiPr) was slowly added dropwise thereto4(4.16mL, 14.1mmol) and stirring was continued for 5 minutes, then 1mol/L EtMgBr solution (28.1mL, 28.1mmol) was added and stirring was continued at-78 deg.C for 30 minutes, slowly warmed to room temperature and stirred for 1 hour. Then, boron trifluoride diethyl etherate (3.22mL, 25.6mmol) was added thereto, and the mixture was reacted at room temperature for 2 hours. After the reaction, 1M hydrochloric acid solution was added to the reaction solution to quench, extraction was performed with ether, the separated aqueous phase was adjusted to pH 10 with saturated sodium carbonate solution, extraction was performed with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (1.6g, 58.7%) as a yellow liquid. MS (m/z): 212.9[ M +1 ]]+。
b) (1- (6-Bromopyridin-3-yl) cyclopropyl) carbamic acid tert-butyl ester
1- (6-Bromopyridin-3-yl) cyclopropane-1-amine (1.6g, 7.51mmol) was dissolved in dichloromethane (30mL), TEA (1.6mL, 11.3mmol) and di-tert-butyl dicarbonate (1.97g, 9.01mmol) were added in this order, and the mixture was stirred at room temperature overnight. After the reaction was concentrated, the reaction mixture was separated by column chromatography (ethyl acetate/petroleum ether: 0 to 60%) to obtain the objective compound (950mg) as a yellow liquid. Yield: 40 percent. MS (m/z): 313.0[ M +1 ]]+
c) (1- (5 '-chloro- [2,2' -bipyridin ] -5-yl) cyclopropyl) carbamic acid tert-butyl ester
(1- (6-Bromopyridin-3-yl) cyclopropyl) carbamic acid tert-butyl ester (313mg, 1mmol) was dissolved in toluene (6mL) and 5-chloro-2- (tributylstannyl) pyridine (563mg, 1.4mmol) and Pd (PPh) were added sequentially3)4(87mg, 0.075mmol), nitrogen exchange, and the mixture was reacted at 100 ℃ overnight. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated, and the filtrate was separated by column chromatography (ethyl acetate/petroleum ether ═ 0 to 70%) to obtain the objective compound (175mg) as a yellow solid. Yield: 68 percent. MS (m/z): 346.0[ M +1 ]]+。
d) N- (1- (5 '-chloro- [2,2' -bipyridine ] -5-yl) cyclopropyl) -4-ethynylbenzamide
To (1- (5 '-chloro- [2,2' -bipyridine)]-5-yl) cyclopropyl) carbamic acid tert-butyl ester (240mg, 0.69mmol) in dichloromethane (12mL) TFA (3mlmL) was added dropwise and the mixture was stirred at room temperature overnight. After the reaction, the reaction solution was concentrated, adjusted to pH 10 with saturated sodium carbonate solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid. Then, the above yellow solid was dissolved in DMF (8mg), followed by addition of p-ethynylbenzoic acid (123mg, 0.84mmol), DIEA (0.24mL, 1.38mmol) and HATU (340mg, 0.9mmol) in this order, and reaction at room temperature for 5 hours. After the reaction, water was added to the reaction mixture, and extraction was performed with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate/petroleum ether ═ 0 to 70%) to obtain the objective compound (175mgmg) as a yellow solid. Yield: 68 percent. MS (m/z): 374.0[ M +1 ]]+。1HNMR(399MHz, DMSO-d6)9.38(s,1H),8.68(dd,J＝2.5,0.6Hz,1H),8.50(dd,J＝2.4, 0.6Hz,1H),8.32(dd,J＝8.6,0.6Hz,1H),8.23(dd,J＝8.4,0.6Hz,1H), 8.02(dd,J＝8.6,2.5Hz,1H),7.93–7.86(m,2H),7.71(dd,J＝8.4,2.5Hz, 1H),7.61–7.53(m,2H),4.37(s,1H),1.40(t,J＝6.4Hz,2H),1.42-1.39(m, 2H),1.35-1.32(m,2H)。
The following compounds are prepared following the procedure for compound 318 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.
Figure BDA0002062489860001051
Figure BDA0002062489860001061
Example 4
Compound 325
N- (3- (4- (5-chloropyridin-2-yl) phenyl) azetidin-3-yl) -4-ethynylbenzamide
Figure BDA0002062489860001062
a)3- (4-bromophenyl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester
1, 4-dibromobenzene (2.36 g, 10.0mmol) was dissolved in 50mL of tetrahydrofuran, cooled to-78 deg.C, and then a solution of n-butyllithium in n-hexane (6.25mL, 1.6mol/L) was added dropwise thereto, and the mixture was stirred at this temperature for 1 hour. Then, at this temperature, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.71 g, 10.0mmol) in 5mL of tetrahydrofuran was added dropwise thereto, and after completion of the addition, the mixture was warmed to room temperature and reacted overnight. After completion of the reaction, the reaction mixture was quenched by addition of 50mL of an ammonium chloride solution, extracted twice with 100mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was concentrated and separated by column chromatography (mobile phase: ethyl acetate/petroleum ether: 1/3) to obtain the objective compound (2.1 g) as a yellow solid. Yield: 64.0 percent. MS (M/z) 272.0/274(M-56+1)+。
b)3- (4-bromophenyl) -3- ((methylsulfonyl) oxy) azetidine-1-carboxylic acid tert-butyl ester
Tert-butyl 3- (4-bromophenyl) -3-hydroxyazetidine-1-carboxylate (1.0 g, 3.04mmol) and DIEA (784mg, 6.08mmol) were dissolved in dichloromethane (30mL), cooled to 0 deg.C, MsCl (521mg, 4.57mmol) was added dropwise thereto, and the mixture was allowed to warm to room temperature and reacted overnight. After completion of the reaction, 30mL of a saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted twice with 100mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (1.23 g, 3.04mmol) as a yellow oil, which was directly charged into the next step. MS (M/z) 210.0/212.0(M-195)+。
c) 3-azido-3- (4-bromophenyl) azetidine-1-carboxylic acid tert-butyl ester
Tert-butyl 3- (4-bromophenyl) -3- ((methylsulfonyl) oxy) azetidine-1-carboxylate (1.23 g, 3.04mmol) and sodium azide (392mg, 6.04mmol) were dissolved in succession in 15mL of DMF, and the mixture was stirred at 60 ℃ for reaction overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 50mL of water was added thereto, and the mixture was extracted twice with dichloromethane, the organic phases were combined, concentrated, and the residue obtained by concentration was separated by column chromatography (mobile phase: ethyl acetate/petroleum ether: 1/20 to 1/1), whereby the title compound (700mg, 1.97mmol) was obtained as a yellow oil in 65.0% yield. MS (M/z) 210.0/212.0(M-142)+。
d)3- (4-bromophenyl) -3- ((triphenyl-lambda)5-Phosphoylidinylamino) azetidine-1-carboxylic acid tert-butyl ester
3-azido-3- (4-bromophenyl) azetidine-1-carboxylic acid tert-butyl ester (700mg, 1.97mmol) and PPh3(774mg, 2.96mmol) was dissolved in 30mL of tetrahydrofuran, then 1mL of aqueous ammonia was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated, and the residue obtained by concentration was separated by column chromatography (mobile phase: ethyl acetate/petroleum ether: 1/10 to 1/1) to obtain the objective compound (500mg) as a white solid. The yield thereof was found to be 43.1%. MS (M/z):587.2/589.2(M +1)+。
e)3- (4- (5-Chloropyridin-2-yl) phenyl) -3- ((triphenyl-Lambda)5Phosphorus leafRad) amino) azetidine-1-carboxylic acid tert-butyl ester
Reacting 3- (4-bromophenyl) -3- ((triphenyl-lambda)5-Folialidide) amino) azetidine-1-carboxylic acid tert-butyl ester (386mg, 0.66mmol), 5-chloro-2- (tributylstannyl) pyridine (317mg, 0.79mmol), and Pd (PPh)3)4(76mg, 0.066mmol) was dissolved in 30mL dioxane and reacted at 110 deg.C under nitrogen overnight. After completion of the reaction, the reaction mixture was cooled, and 5mL of an aqueous potassium fluoride solution was added to the reaction mixture to quench the reaction mixture, followed by concentration and column chromatography of the residue obtained by concentration (mobile phase: methanol/water 1 to 100%) to obtain the objective compound (270mg) as a yellow solid. The yield thereof was found to be 66.0%. MS (M/z):620.3(M +1)+。
f) 3-amino-3- (4- (5-chloropyridin-2-yl) phenyl) azetidine-1-carboxylic acid tert-butyl ester
Reacting 3- (4- (5-chloropyridin-2-yl) phenyl) -3- ((triphenyl-lambda)5-phosphorus ylide) amino) azetidine-1-carboxylic acid tert-butyl ester (270mg, 0.44mmol) was dissolved in 5mL methanol, 2mL of 2mol/L aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature for reaction overnight. After completion of the reaction, the reaction mixture was concentrated, and the obtained residue was separated by column chromatography (mobile phase: methanol/water 1 to 100%) to obtain the objective compound (140mg) as a yellow solid. The yield thereof was found to be 88.4%. MS (M/z) 360.1 (M +1)+。
g)3- (4- (5-Chloropyridin-2-yl) phenyl) -3- (4-ethynylbenzoylamino) azetidine-1-carboxylic acid tert-butyl ester
Tert-butyl 3-amino-3- (4- (5-chloropyridin-2-yl) phenyl) azetidine-1-carboxylate (140mg, 0.39mmol) was dissolved in DMF (5mL), 4-ethynylbenzoic acid (57mg, 0.39mmol), HATU (222mg, 0.59mmol) and DIEA (100mg, 0.78mmol) were added sequentially thereto, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated, and the obtained residue was separated by column chromatography (mobile phase: methanol/water 1-100%) to obtain the objective compound (100mg) as a yellow solid. The yield thereof was found to be 53.8%. MS (M/z) 488.0(M +1)+。
h) N- (3- (4- (5-chloropyridin-2-yl) phenyl) azetidin-3-yl) -4-ethynylbenzamide
Tert-butyl 3- (4- (5-chloropyridin-2-yl) phenyl) -3- (4-ethynylbenzoylamino) azetidine-1-carboxylate (100mg, 0.21mmol) was dissolved in 1mL TFA and the mixture was stirred at room temperature for 5 min. After completion of the reaction, the reaction mixture was concentrated, and the obtained residue was separated by column chromatography (mobile phase: methanol/water 1-100%) to obtain the objective compound (48mg) as a yellow solid. Yield: 59.1 percent. MS (M/z) 388.1(M +1)+。1H NMR(399MHz,CD3OD)8.57(m, 1H),8.00(m,2H),7.89–7.83(m,4H),7.68(m,2H),7.56(m,2H),4.17(dd, J＝34.1,9.4Hz,4H),3.69(s,1H)。
The following compounds are prepared following the procedure for compound 325 using the corresponding intermediates and reagents under conditions deemed appropriate by those skilled in the art.
Figure BDA0002062489860001091
Example 5
Compound 327
N- (1- (4- (6-acetamidopyridin-3-yl) phenyl) cyclopropyl) -4-ethynylbenzamide
Figure BDA0002062489860001092
The compound N- (1- (4- (6-aminopyridin-3-yl) phenyl) cyclopropyl) -4-ethynylbenzamide (100mg,0.283mmol) (prepared by a similar method to that described in example 1) was dissolved in tetrahydrofuran (10mL), cooled to 0 deg.C, DIEA (0.140mL, 0.849mmol) and acetyl chloride (44.4mg,0.566mmol) were added successively, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, and the obtained residue was separated by column chromatography (mobile phase: methanol/water 10 to 100%) to obtain the objective compound (60mg) as a yellow solid. Yield: 53.7 percent. MS (m/z): 396.2(M +1)+。1H NMR(399MHz,DMSO-d6)10.54(s,1H),9.30(s,1H), 8.57(d,J＝2.5Hz,1H),8.11(d,J＝8.7Hz,1H),8.01(dd,J＝8.7,2.5Hz, 1H),7.95–7.82(m,2H),7.64–7.50(m,4H),7.26(d,J＝8.5Hz,2H),4.37 (s,1H),2.08(s,3H),1.28(s,4H)。
Example 6
Determination of IDO1 Activity in SKOV-3 cells
1. Reagents and materials
SKOV-3 cells: SKOV-3 cells were purchased from ATCC cell banks of the American Standard Biometrics Collection, and were cultured in DMEM medium containing 3.7g/L sodium bicarbonate and 4.5g/L glucose supplemented with 2mM glutamine and 10% fetal bovine serum FBS at 5% CO2Normally culturing in a cell culture box at 37 ℃;
DMEM: GIBCO, cat # 31053028;
glutamine (Glutamax): GIBCO, cat # 35050061;
fetal Bovine Serum (FBS): GIBCO, cat # 10099- & 141;
human IFN γ: r & D Systems, cat # 285-IF-100;
tryptophan (L-Trp): Sigma-Aldrich, cat # T0254;
trichloroacetic acid (6.1N): Sigma-Aldrich, cat # T0699;
p- (N, N-dimethyl) benzaldehyde: Sigma-Aldrich, cat # 156477;
kynurenine (L-Kynurenine): Sigma-Aldrich, cat # K8625;
micropore board appearance of reading: SpectraMax M2, Molecular Devices;
96-well plate: beckman Dickinson, cat # 353072.
2. Preparation of solutions
Standard curve stock solution: the stock solution of kynurenine standard curve was diluted in serial concentrations in cell culture medium DMEM. Final gradient concentrations were 240, 120, 60, 30, 15, 7.5, 3.75 and 1.87 μ M.
3. Method of producing a composite material
When the activity of the compound is determined, SKOV-3 cells are measured according to the specification of 1.0x 104Individual cells/well, i.e., 180. mu.L/well, were seeded into 96-well plates in 5% CO2And cultured in a cell culture box at 37 ℃. After the cells are attached to the wall, the compound to be tested is diluted to corresponding concentration by 3 times gradient in serum-free DMEM medium on the day, and then the compound to be tested (the compound to be tested) with different concentrations after 10 mu L/hole dilution is addedFinal concentrations of 1.0, 0.33, 0.11, 0.037, 0.012, 0.0041, 0.0014 and 0.00046 μ M DMSO final concentration of 0.25%) or 10 μ L/well control solution (0.25% DMSO) were added to 180 μ L/well cell culture system, followed by 10 μ L/well serum-free DMEM diluted human IFN γ (final concentration of 50ng/mL) and L-Trp (final concentration of 150 μmol/L) mixed solution in 5% CO2Incubated at 37 ℃ for 48 hours in a cell culture incubator.
And (3) sucking 140 mu L/well culture supernatant into each well of a 96-well plate, adding 10 mu L/well trichloroacetic acid into the new 96-well plate, mixing, incubating in a 65 ℃ water bath for 20 minutes, centrifuging (1200g) for 10 minutes, sucking 100 mu L/well supernatant into the new 96-well plate, finally adding 20g/L p- (N, N-dimethyl) benzaldehyde prepared by glacial acetic acid into 100 mu L/well, and uniformly mixing.
4. Detection of
After mixing for 1 minute, the absorbance optical density signal was detected at a wavelength of 480nm using a SpectraMax M2 microplate reader. The kynurenine standards were diluted in cell culture medium in serial concentrations and the optical density values were measured at each concentration point after treatment according to the procedure described above. And then drawing a kynurenine standard curve graph by taking the optical density signal as a vertical coordinate and the kynurenine concentration as a horizontal coordinate in EXCEL software, fitting a linear regression equation, and calculating the kynurenine concentration in the to-be-detected compound processing hole and the human IFN-gamma control processing hole of each concentration according to the equation. The inhibition rate (%) of each concentration is calculated according to the concentration of kynurenine in each hole, and then the inhibition rate (%) is calculated by using a model 205 in XL-Fit 5.3 software (ID Business Solutions Limited) to obtain IC50The value is obtained.
The inhibition rate was calculated as follows:
the inhibition rate (%) - (test compound-treated kynurenine concentration/human IFN- γ control-treated kynurenine concentration) × 100%, wherein,
test compound treatment well kynurenine concentration: indicates the kynurenine concentration in the cell well containing human IFN-. gamma.and the test compound.
Human IFN- γ control treatment well kynurenine concentration: indicates kynurenine concentration in the wells containing human IFN-. gamma.only.
5. Test results
Figure BDA0002062489860001121
Figure BDA0002062489860001131
Figure BDA0002062489860001141
Figure BDA0002062489860001151
Example 7
Determination of IDO1 Activity in Hela cells
1. Reagents and materials
HeLa cells: hela cells were purchased from ATCC cell bank of American Standard Biometrics Collection, and supplemented with 2mM glutamine and 10% fetal bovine serum FBS in 5% CO in DMEM medium containing 3.7g/L sodium bicarbonate and 4.5g/L glucose2Normally culturing in a cell culture box at 37 ℃;
DMEM: GIBCO, cat # 31053028;
glutamine (Glutamax): GIBCO, cat # 35050061;
fetal Bovine Serum (FBS): GIBCO, cat # 10099- & 141;
human IFN γ: r & D Systems, cat # 285-IF-100;
tryptophan (L-Trp): Sigma-Aldrich, cat # T0254;
trichloroacetic acid (6.1N): Sigma-Aldrich, cat # T0699;
p- (N, N-dimethyl) benzaldehyde: Sigma-Aldrich, cat # 156477;
kynurenine (L-Kynurenine): Sigma-Aldrich, cat # K8625;
micropore board appearance of reading: SpectraMax M2, Molecular Devices;
96-well plate: beckman Dickinson, cat # 353072.
2. Preparation of solutions
Standard curve stock solution: the stock solution of kynurenine standard curve was diluted in serial concentrations in cell culture medium DMEM. Final gradient concentrations were 240, 120, 60, 30, 15, 7.5, 3.75 and 1.87 μ M.
3. Method of producing a composite material
For compound activity assay, HeLa cells were assayed at 7.0X103Individual cells/well, i.e., 180. mu.L/well, were seeded into 96-well plates in 5% CO2And cultured overnight in a cell culture chamber at 37 ℃. The next day, the test compound was diluted to the corresponding concentration in a 3-fold gradient in serum-free DMEM medium, then 10. mu.L/well diluted test compounds of different concentrations (final test compound concentration of 1.0, 0.33, 0.11, 0.037, 0.012, 0.0041, 0.0014 and 0.00046. mu.M, final DMSO concentration of 0.5%) or 10. mu.L/well control solution (0.5% DMSO) were added to 180. mu.L/well cell culture system, then 10. mu.L/well diluted serum-free DMEM medium human IFN γ (final concentration of 50ng/mL) and L-Trp (final concentration of 50. mu. mol/L) mixed solution were added to 5% CO2Incubated at 37 ℃ for 48 hours in a cell culture incubator.
And (3) sucking 140 mu L/well culture supernatant into each well of a 96-well plate, adding 10 mu L/well trichloroacetic acid into the new 96-well plate, mixing, incubating in a 65 ℃ water bath for 20 minutes, centrifuging (1200g) for 10 minutes, sucking 100 mu L/well supernatant into the new 96-well plate, finally adding 20g/L p- (N, N-dimethyl) benzaldehyde prepared by glacial acetic acid into 100 mu L/well, and uniformly mixing.
4. Detection of
After mixing for 1 minute, the absorbance optical density signal was detected at a wavelength of 480nm using a SpectraMax M2 microplate reader. The kynurenine standards were diluted in cell culture medium in serial concentrations and the optical density values were measured at each concentration point after treatment according to the procedure described above. Then, a kynurenine standard substance curve graph is drawn in EXCEL software by taking the optical density signal as the ordinate and the kynurenine concentration as the abscissa, and a linear regression method is fittedAnd (3) calculating the kynurenine concentration in the test compound treatment hole and the human IFN-gamma control treatment hole of each concentration according to the equation. The inhibition rate (%) of each concentration is calculated according to the concentration of kynurenine in each hole, and then the inhibition rate (%) is calculated by using a model 205 in XL-Fit 5.3 software (ID Business Solutions Limited) to obtain IC50The value is obtained.
The inhibition rate was calculated as follows:
Figure BDA0002062489860001171
wherein:
test compound treatment well kynurenine concentration: indicates the kynurenine concentration in the cell well containing human IFN-. gamma.and the test compound.
Human IFN- γ control treatment well kynurenine concentration: indicates kynurenine concentration in the wells containing human IFN-. gamma.only.
EXAMPLE 8 determination of IDO1 Activity in human Whole blood
1. Reagents and materials
Human peripheral whole blood: at 5% CO2Normally culturing in a cell culture box at 37 ℃;
RPMI-1640: GIBCO, cat # 11875-;
human IFN γ: r & D Systems, cat # 285-IF-100;
lipopolysaccharide (LPS, Salmonella typhimurium), Calbiochem, cat # 437650;
tryptophan (L-Trp): Sigma-Aldrich, cat # T0254;
kynurenine (L-Kynurenine): Sigma-Aldrich, cat # K8625;
96-well plate: beckman Dickinson, cat # 353072;
dimethyl sulfoxide (DMSO). Sigma-Aldrich, cat # 34869-4L.
2. Preparation of solutions
Preparation of standard curve sample: and respectively adding 5 mu L of standard curve working solution into 45 mu L of blank plasma obtained by removing endogenous kynurenine through activated carbon, and fully whirling to obtain a standard curve sample. The final gradient concentrations were 50, 20, 5.0, 2.0, 1.0, 0.50, 0.20, 0.10 and 0.050 μ M.
3. Method of producing a composite material
For compound activity assay, collected peripheral human whole blood was seeded at 180. mu.L/well in 96-well plates at 5% CO2And cultured in a cell culture box at 37 ℃. Half an hour later, the test compound was diluted to the corresponding concentration by 3-fold gradient in serum-free RPMI-1640 medium, then 10. mu.L/well diluted test compound (final concentration of test compound is 0.30, 0.10, 0.033, 0.011, 0.0037 and 0.0012. mu.M, final concentration of DMSO is 0.25%) or 10. mu.L/well control solution (0.25% DMSO) was added to 180. mu.L/well human whole blood culture system, then 10. mu.L/well diluted human IFN γ (final concentration is 150ng/mL), LPS (final concentration is 150ng/mL) and L-Trp (final concentration is 50. mu. mol/L) mixed solution in 5% CO RPMI-1640 medium was added2Incubated at 37 ℃ for 24 hours in a cell incubator.
After centrifugation of the 96-well plate for 10 minutes, 70. mu.L of plasma supernatant was pipetted into each well and added to a new 1.5mL tube before detection.
4. Detection of
And (3) determining the concentration of the kynurenine in the sample by adopting a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis method. The peak areas of the kynurenine and the internal standard compound are automatically collected and integrated by software analysis 1.6.2, a standard curve for quantification is obtained by fitting a kynurenine theoretical concentration and the peak area ratio of the kynurenine and the internal standard compound by a linear regression equation, and then the concentration of the kynurenine in each sample is calculated according to the standard curve. The inhibition (%) at each concentration was calculated from the concentration of kynurenine in each well and then calculated using model 205 in XL-Fit 5.3 software (ID Business Solutions Limited) to obtain the IC50 value.
The inhibition rate was calculated as follows:
inhibition ratio (%) - { (test compound-treated well-control-treated well)/(human IFN- γ -control-treated well) } × 100%, wherein,
test compound treatment wells: indicates the concentration of kynurenine in the plasma of human whole blood treated with human IFN-. gamma.and the test compound.
Human IFN- γ control treated wells: indicates the concentration of kynurenine in the plasma of human whole blood treated with human IFN-gamma alone.
Control treatment wells: indicates the kynurenine concentration in plasma of human whole blood without culture.
5. Test results
Figure BDA0002062489860001191
Example 9
Assay of compound for CYP enzyme inhibitory activity:
1. test materials and methods
1.1. Experimental Material
The test compounds, Diclofenac sodium salt (Diclofenac sodium), 4 '-Hydroxydiclofenac (4' -Hydroxydiclofenac), Dextromethorphan hydrobromide (dextromeorphan), dextrorphan tartrate (dextorphan), Quinidine (Quinidine anhydride), Sulfaphenazole (Sulfaphenazole), and the like, were purchased from Sigma-Aldrich, usa. Mixed human liver microsome fractions (HLM) were purchased from CellzDirect, Life Technologies, USA. Glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase (G-6-PDH), and Nicotinamide Adenine Dinucleotide Phosphate (NADP) were purchased from Sigma-Aldrich, USA. Internal standard: 7-Hydroxycoumarin (used for CYP2C9) and phenacetin (used for CYP2D6) are all products of Sigma-Aldrich in America. Acetonitrile, methanol (chromatographically pure) was obtained from Fisher Scientific, USA, and formic acid (chromatographically pure) was obtained from Sigma-Aldrich, USA. DMSO, EDTA and MgCl2Purchased from the national pharmaceutical group chemical agents limited. Pure water for analysis was prepared from a Millipore ultrapure water system.
1.2. Incubation conditions
The incubation conditions of different subtype enzymes, such as substrate type and concentration, protein content, incubation time, positive inhibitor type and concentration, internal standard and other information are shown in Table 1. The detailed constitution of the incubation system is shown in Table 2. According to the experimental requirements, the reagents are prepared according to the tableA microsome preparation solution, a phosphate buffer solution, a substrate working solution and the like. The NADPH regenerating system included G-6-P (final concentration of 5mM, pH 7.4), G-6-PD (final concentration of 1U/mL, pH 7.4), NADP (final concentration of 1mM, pH 7.4), MgCl2(final concentration: 3mM), EDTA (final concentration: 1mM) and phosphate buffer (final concentration: 50mM, pH 7.4), and the above solutions were mixed, incubated in a water bath at 37 ℃ for 10min, and then cooled on ice for use. The test compounds were dissolved in DMSO to prepare stock solutions of 10mM, and then diluted with 80% acetonitrile to 1mM working solutions. The proportion of organic solvent contained in the final incubation system does not exceed 1%. The test compound and each positive inhibitor are provided with a solvent control group (the blank solvent does not contain the test compound or the positive inhibitor). The individual components were added as described in table 2 and the total volume of the incubation system was 125 μ L. Wherein the test compound and positive inhibitor are premixed with the microsomal solution, then added to the NDAPH regeneration system and placed in a 37 ℃ water bath to start the reaction. The reaction was stopped by incubating at 37 ℃ for 20 minutes and adding 125. mu.L of glacial acetonitrile (containing the corresponding concentration of internal standard) (see Table 1). The terminated reaction solution was centrifuged at 4400rpm at 4 ℃ for 10min, and the supernatant was analyzed by LC-MS/MS.
1.3 data analysis
Substrate metabolites as well as internal standards were integrated using Analyst 1.4.2(Applied biosystems, USA) software. The peak area ratio of the substrate metabolite to the internal standard is used for calculation, and the calculation formula of the residual activity percentage of the enzyme is as follows:
the percentage of remaining activity of the enzyme is equal to the metabolite production amount of the inhibitor group/the metabolite production amount of the solvent control group multiplied by 100%
TABLE 1 incubation conditions
Figure BDA0002062489860001211
TABLE 2 composition of the components of the incubation System
Figure BDA0002062489860001221
The compounds of the invention were tested to have weak inhibitory effect on 2D6 and 2C 9.
Example 10
Evaluation of transmembrane permeability of Compounds Using Caco-2 cell monolayer model
1. Experimental materials:
caco-2 (human colon adenocarcinoma) cells were purchased from the Shanghai Life sciences institute cell resource center. 1 XHank's Balanced salt solution (HBSS) and hydroxyethylpiperazine ethanesulfonic acid (HEPES) were purchased from Life technologies, Inc., USA. Cortisone, propranolol hydrochloride, sodium fluorescein salt and formic acid were purchased from Sigma-Aldrich, USA. Methanol, acetonitrile, isopropanol, and ethyl acetate were all chromatographically pure and purchased from Fisher Scientific, usa. DMSO (dimethyl sulfoxide) was purchased from national pharmaceutical group chemical Co. Deionized Water (resistivity ≥ 18 M.OMEGA.cm) from the same company
Figure BDA0002062489860001231
A water purification system is prepared. HTS
Figure BDA0002062489860001232
A24-well cell culture system was purchased from Corning, USA, and comprises a nested plate containing 24 cells (hereinafter, referred to as A-side cell) and a common 24-well cell culture plate (hereinafter, referred to as B-side cell), wherein the bottom of the A-side cell is a polycarbonate-permeable support with a pore size of 0.4 μm and the bottom area is 0.33cm2。
2. Solution preparation:
10mM stock of test compound: weighing a certain amount of a compound to be detected, dissolving the compound by using a proper volume of DMSO, and preparing a stock solution with the concentration of 10mM for later use.
Propranolol (internal standard, positive ion) stock: weighing a certain amount of propranolol hydrochloride, dissolving the propranolol hydrochloride by using a proper volume of DMSO (dimethyl sulfoxide), and preparing a stock solution with the concentration of 10mM for later use.
Fluorescein sodium stock solution: weighing a certain amount of fluorescein sodium, dissolving the fluorescein sodium by using a proper volume of DMSO, and preparing a stock solution with the concentration of 10mM for later use.
Cortisone (internal standard, negative ion) stock: weighing a certain amount of cortisone, dissolving with a proper volume of DMSO, and preparing into stock solution with the concentration of 50mM for later use.
Solution 1: 495mL HBSS +5mL HEPES + 5. mu.L 10mM propranolol.
Diluent 1: 400mL deionized water +400mL acetonitrile + 8. mu.L 10mM propranolol + 16. mu.L 50mM cortisone.
Preparation of dosing agent: 4.99mL of solution 1+ 5. mu.L of 10mM test compound + 5. mu.L of 10mM fluorescein sodium.
3. The experimental method comprises the following steps:
first, after 21 days in a cell culture box
Figure BDA0002062489860001233
The culture medium in the chamber on the side A and the culture plate on the side B of the culture system was removed, and both sides of A, B were washed once with solution 1 at 37 ℃ and then added with 0.3mL and 1.0mL of solution 1, respectively. After addition, the cells were pre-incubated for 30 minutes in a shaker. After the pre-incubation is finished, measuring transmembrane resistance and calculating TEER; only the TEER value is larger than 150 omega cm2For subsequent transport experiments. When the transport in the direction of A → B is tested, the pre-incubation solution on the side A is sucked out, and 0.3mL of dosing reagent is added; for testing the transport in the B → A direction, the B side pre-incubation was aspirated and 1.0mL dosing reagent was added. Immediately after the addition of the drug, 10. mu.L of each sample was taken from the drug addition side as a 0h sample. The culture system was then placed on a shaker and incubated for 60 minutes, samples were collected on both sides after incubation was complete, and then transmembrane resistance was measured again and TEER values calculated.
Both the 0h and dosing side samples were diluted 20-fold with solution 1. Diluting 200. mu.L of the diluted sample or 150. mu.L of the undiluted receiver-side sample with 1-fold dilution solution, respectively; after mixing uniformly, 150 mu L of solution is respectively taken to carry out the concentration analysis of the substance to be detected and the measurement of the fluorescence intensity of the fluorescein.
4. Analysis method and data processing:
the concentration of the compound in the sample is determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis method. The peak area ratio of the compound and the internal standard was used as the relative concentration to calculate each parameter.
Using PerkinElmer VICTOR3TM1420 microplate reader measures the fluorescence intensity of fluorescein. 150 μ L of the pretreated sample was placed in a 96-well plate, and the fluorescence intensity was read under the conditions of an excitation wavelength of 485 nm and an emission wavelength of 535 nm.
The calculation formula of each parameter is as follows:
Figure BDA0002062489860001241
Figure BDA0002062489860001242
ratio of outer row Papp,B-A/Papp,A-B
Figure BDA0002062489860001243
Papp: an apparent permeability coefficient;
Papp,B-A: base side to top side apparent permeability coefficient;
Papp,A-B: the top-to-base apparent permeability coefficient;
Papp,LY: the apparent permeability coefficient of fluorescein;
Cr,t: drug concentration at the receiving side at time t;
Cd,t: the drug concentration on the drug adding side at time t;
Cd,0: drug concentration at dosing side at start of incubation (zero);
Vr: receive side volume (1 mL for A → B test; 0.3mL for B → A test);
Vd: dosing side volume (0.3 mL for A → B test; 1mL for B → A test);
s: surface area of monolayer, 0.33cm2；
t: incubation time (seconds);
RFUr,t: relative Fluorescence Units (RFU) at time t on the receive side;
RFUblank: relative fluorescence units of the blank solution;
RFUd,0: relative fluorescence units on the dosing side at the beginning of incubation (zero point).
The compounds of the invention have better transmembrane permeability as tested above.

Claims (49)

1. A compound of formula (I):
Figure FDA0002062489850000011
or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein:
x is N or CR3(ii) a Y is N or CR4；
R1、R2、R3And R4Each independently selected from: hydrogen, halogen, -OH, -CN, -NH2、C1-6Alkyl radical, C1-6Haloalkyl, -O (C)1-6Alkyl), -NH (C)1-6Alkyl) or-N (C)1-6Alkyl radical)2；
Z is O, NR5Or CR6R7；
R5Selected from: hydrogen, C1-6Alkyl or C3-6A cycloalkyl group;
R6and R7Each independently selected from: hydrogen, halogen, -CN, C1-6Haloalkyl, -O (C)1-6Haloalkyl), -OH, C)1-6Alkyl radical, C3-6Cycloalkyl or-O (C)1-6Alkyl groups);
Figure FDA0002062489850000012
is phenyl, 5-6 membered heteroaryl or indazolyl; each of which is optionally substituted with one or more groups selected fromSubstituted with: halogen, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-O(C1-6Alkyl) or-O (C)1-6Haloalkyl);
Figure FDA0002062489850000013
is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, each of which is optionally substituted with one or more groups selected from: halogen, - (C)1-6Alkyl radical)n-CN、-NO2、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, - (C)1-6Alkyl radical)n-C3-6Cycloalkyl, - (C)1-6Alkyl radical)n-phenyl, - (C)1-6Alkyl radical)n-4-6 membered heterocyclyl, - (C)1-6Alkyl radical)n-5-6 membered heteroaryl, - (C)1-6Alkyl radical)n-NR1’R2’、-(C1-6Alkyl radical)n-CONR1’R2’、-(C1-6Alkyl radical)n-NR1’R2’C(O)R3’、-(C1-6Alkyl radical)n-C(O)R3’-、-(C1-6Alkyl radical)n-C(O)OR4’、-(C1-6Alkyl radical)n-OR5’、-(C1-6Alkyl radical)n-S(O)mNR1’R2’、-(C1-6Alkyl radical)n-NR1’R2’S(O)mR6’、-(C1-6Alkyl radical)n-S(O)mR6' and- (C)1-6Alkyl radical)n-SR7'; wherein, said phenyl, C3-6Cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with one or more groups selected from: halogen, -CN, -OH, -NH2、C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6Alkyl, -O (C)1-6Alkyl), -NH (C)1-6Alkyl), -N (C)1-6Alkyl radical)2、C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group;
n is 0 or 1;
m is 1 or 2;
p is 0 or 1;
R1’、R2’、R3’、R4’、R5’、R6' and R7' independently from each other are selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, - (C)1-6Alkyl) -O- (C1-6Alkyl), - (C)1-6Alkyl) -OH, - (C)1-6Alkyl) -CN, - (C)1-6Alkyl) -NH2Or C3-6A cycloalkyl group; or R1’、R2' together with the N atom to which they are attached form a 4-6 membered heterocyclic ring.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein X is CR3(ii) a Y is CR4。
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein R is1、R2、R3And R4Each independently selected from hydrogen or halogen.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein R is1、R2、R3And R4Are all hydrogen.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein X is CH; y is N.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein X is N; y is N.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein p is 0 and Z is CR6R7。
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein Z is CH2。
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein p is 1 and Z is CHR6。
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein R is6Is hydrogen, -OH, C1-6Alkyl or-O (C)1-6Alkyl groups).
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein p is1, Z is NR5。
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein R is5Is hydrogen or C1-6An alkyl group.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein p is 1 and Z is O.
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000041
is phenyl or 5-6 membered heteroaryl, optionally substituted with one or more groups selected from: halogen, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-O(C1-6Alkyl) or-O (C)1-6Haloalkyl).
15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000042
is phenyl, pyridyl, pyrimidinyl, indolyl, pyrrolyl, pyrazolyl or thienyl, which are optionally substituted by one or more groups selected fromGeneration: halogen, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-O(C1-6Alkyl) or-O (C)1-6Haloalkyl).
16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000043
is phenyl, optionally substituted with one or more groups selected from: halogen, CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, -NH2、-OH、-O(C1-6Haloalkyl) or-O (C)1-6Alkyl groups).
17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000051
is phenyl, optionally substituted with one or more groups selected from: F. cl, Br, CN, methyl, ethyl, ethynyl, trifluoromethyl, -O (trifluoromethyl), -OCHF2Or a methoxy group.
18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000052
is phenyl, which isSubstituted with one or more groups selected from: F. cl, Br, CN, methyl, ethyl, -CF3、-OCF3、-OCHF2Or a methoxy group.
19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000053
is phenyl substituted by ethynyl.
20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000054
is phenyl substituted by halogen.
21. The compound of claim 18, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000055
is a quilt-OCF3or-OCHF2A substituted phenyl group.
22. The compound of claim 18, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000056
is phenyl substituted by CN.
23. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein the compound has the structure of formula (I-1):
Figure FDA0002062489850000061
wherein R isaSelected from: halogen, CN, C1-6Alkyl radical, C2-6Alkynyl, C1-6Haloalkyl, -O (C)1-6Haloalkyl) or-O (C)1-6Alkyl), X, Y, Z and
Figure FDA0002062489850000062
as defined in any one of claims 1 to 6.
24. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein the compound has the structure of formula (I-2):
Figure FDA0002062489850000063
wherein R isaSelected from: halogen, CN, C1-6Alkyl radical, C2-6Alkynyl, C1-6Haloalkyl, -O (C)1-6Haloalkyl) or-O (C)1-6Alkyl), X, Y, Z and
Figure FDA0002062489850000064
as defined in any one of claims 1 to 6.
25. The compound as claimed in claim 23 or 24Or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof, wherein R isaSelected from: F. cl, Br, CN, methyl, ethyl, ethynyl, trifluoromethyl, -O (trifluoromethyl), -OCHF2Or a methoxy group.
26. The compound of claim 23 or 24, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein R isaIs an ethynyl group.
27. The compound of claim 23 or 24, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein R isaIs halogen.
28. The compound of claim 23 or 24, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein R isaIs CN.
29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000071
is a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl group, optionally substituted with one or more groups selected from:
1) halogen;
2)-NO2；
3) oxo;
4)-(C1-6alkyl radical)n-CN；
5)C1-6An alkyl group;
6)C1-6a haloalkyl group;
7)C3-6a cycloalkyl group;
8)(C1-6alkyl radical)n-a 4-6 membered heterocyclyl group;
9)5-6 membered heteroaryl;
10)(C1-6alkyl radical)n-NR1’R2’；
11)-CONR1’R2’；
12)-NR1’R2’C(O)R3’；
13)-C(O)OR4’；
14)-(C1-6Alkyl radical)n-OR5’；
15)-S(O)2NR1’R2'; or
16)-NR1’R2’S(O)2R6’；
Wherein said 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more groups selected from: c1-6Alkyl, -O (C)1-6Alkyl) or-NH (C)1-6Alkyl groups);
n is 0 or 1;
R1’、R2’、R3’、R4’、R5' and R6' independently from each other are selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, - (C)1-6Alkyl) -O- (C1-6Alkyl), - (C)1-6Alkyl) -OH, - (C)1-6Alkyl) -CN, - (C)1-6Alkyl) -NH2Or C3-6A cycloalkyl group; or R1’、R2' together with the N atom to which they are attached form a 4-6 membered heterocyclic ring.
30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000081
is a pyridyl, pyrimidinyl or pyridazinyl group substituted by one, two or three groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
31. The compound of claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000082
is pyridyl substituted by amino, pyrimidinyl substituted by amino or pyridazinyl substituted by amino, each of which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
32. The compound of claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000091
is a quilt- (C)1-6Pyridyl substituted by (C) alkyl) -OH1-6Pyrimidinyl substituted by alkyl) -OH or by- (C)1-6Alkyl) -OH substituted pyridazinyl, each of which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
33. The compound of claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000092
is composed of
Figure FDA0002062489850000093
Substituted with one, two or three groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000094
being substituted by amino groups
Figure FDA0002062489850000095
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
35. The compound of claim 33, or a pharmaceutically acceptable salt thereof, and/or deuteration thereofCompounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers, wherein,
Figure FDA0002062489850000096
is a quilt- (C)1-6Alkyl) -OH substituted
Figure FDA0002062489850000097
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000101
is a quilt- (C)1-6Alkyl) -OH and C1-6Substituted by haloalkyl
Figure FDA0002062489850000102
Figure FDA0002062489850000103
37. The compound of claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000104
is pyrimidinyl, optionally substituted with one or more groups selected from: halogen, -CN,C1-6Alkyl radical, C1-6Haloalkyl, 4-6-membered heterocyclyl, -NR1’R2' OR-OR5’；
R1’、R2' and R5' independently from each other are selected from hydrogen, C1-6Alkyl or C1-6A haloalkyl group.
38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000105
is a quilt- (C)1-6Alkyl) -OH substituted pyrimidinyl, which is simultaneously substituted with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000106
is pyrimidinyl substituted with amino, which is substituted simultaneously with one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
40. The compound of claim 38, or a pharmaceutically acceptable salt thereof, and/or a deuterated compound, solvate, racemic mixture, enantiomer thereofIsomers, diastereomers and tautomers, wherein,
Figure FDA0002062489850000111
is a quilt- (C)1-6Alkyl) -OH substituted
Figure FDA0002062489850000112
Which is substituted simultaneously by one or two groups selected from: halogen, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
41. The compound of claim 39, or a pharmaceutically acceptable salt thereof, and/or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein,
Figure FDA0002062489850000113
being substituted by amino groups
Figure FDA0002062489850000114
Which is substituted simultaneously by one or two groups selected from: halogen, C1-6Alkyl, CN, -NH2、-NH(C1-6Alkyl), -N (C)1-6Alkyl radical)2、-(C1-6Alkyl) -OH, C1-6Haloalkyl, -O (C)1-6Haloalkyl), C1-6An alkoxy group.
42. A compound of formula (I) according to claim 1, selected from compounds 1-327 or a pharmaceutically acceptable salt thereof.
43. A pharmaceutical composition comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
44. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease mediated by IDO or at least partially mediated by IDO in a subject.
45. The use of claim 44, wherein: the disease mediated by IDO or at least partially mediated by IDO is cancer, an autoimmune disease, obesity or an obesity-related disease.
46. The use of claim 45, wherein: the cancer is selected from solid tumors or hematologic malignancies; the autoimmune disease is selected from arthritis (e.g., rheumatoid arthritis, collagen-induced arthritis).
47. The use of claim 46, wherein: the cancer is selected from skin cancer (including melanoma and basal carcinoma), lung cancer (including non-small cell lung cancer), kidney cancer, head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer, endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, stomach cancer, esophageal cancer, brain tumors (including glioma and Glioblastoma (GBM)), thyroid cancer, mesothelial carcinoma, choriocarcinoma, adrenal cancer, sarcomas (including Kaposi's sarcoma)), leukemia, lymphoma, or myeloma.
48. A combination comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
49. The combination of claim 48, wherein: the additional therapeutic agent is an immune checkpoint inhibitor, a targeted therapeutic agent, or a chemotherapeutic agent.
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WO2022037585A1 (en) * 2020-08-18 2022-02-24 Hutchison Medipharma Limited Pyrimidinone compounds and uses thereof

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* Cited by examiner, † Cited by third party
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WO2022037585A1 (en) * 2020-08-18 2022-02-24 Hutchison Medipharma Limited Pyrimidinone compounds and uses thereof

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