CN111194309A

CN111194309A - Indoleamine-2, 3-dioxygenase inhibitor salt and preparation method thereof

Info

Publication number: CN111194309A
Application number: CN201880061367.0A
Authority: CN
Inventors: 王召印; 胡新波; 郭巍
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2017-10-18
Filing date: 2018-10-17
Publication date: 2020-05-22
Also published as: WO2019076324A1; CN109678813A

Abstract

The invention relates to indoleamine-2, 3-dioxygenase inhibitor salts and a preparation method thereof. In particular, the invention relates to salts of the compounds of formula I and various amorphous and polymorphic forms thereof, wherein the definitions of the groups are as described in the specification. The salt has stable structure, good light stability, thermal stability, non-hygroscopicity and pharmacokinetic properties, and good solubilityGood, obviously improved purity and bioavailability, and is particularly suitable for developing and producing high-quality IDO enzyme inhibitors.

Description

Indoleamine-2,3-dioxygenase inhibitor salt and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to indoleamine-2,3-dioxygenase inhibitor salt and a preparation method thereof.

Background

Indoleamine-2,3-dioxygenase (IDO) inhibitors are a drug for tumor immunotherapy. Patent applications CN105481789A and CN disclose an IDO inhibitor containing sulfoximine and 1,2, 5-oxadiazole structure, which has the structure shown in formula (I).

R¹Is C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl radical, C₆-C₂₀Aryl, or 3-14 membered heteroaryl;

R²is H, C₆-C₂₀Aryl, 3-14 membered heteroaryl, C₁-C₁₂Alkyl or C₃-C₁₂CycloalkanesA group;

R³and R⁴Each independently hydrogen, substituted or unsubstituted C₁-C₁₀An alkyl group; or R³And R⁴Together form a three-to eight-membered ring or a three-to eight-membered heterocyclic ring in which the heteroatom is sulfur, oxygen, NH or NR^h；

Ar is a substituted or unsubstituted benzene ring, five-membered or six-membered heteroaryl, wherein the substitution means that one or more hydrogen atoms on Ar are substituted by halogen; n is an integer of 2 to 8;

R^hselected from the group consisting of: c₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl radical, C₆-C₂₀Aryl, or 3-14 membered heteroaryl;

wherein the salt is selected from the group consisting of: hydrochloride, hydrobromide, p-toluenesulfonate, benzenesulfonate, methanesulfonate, phosphate or sulfate;

unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, amino, nitro, aldehyde, -CF₃-CN or-SF₅。

The solubility, absorbability, stability, crystallinity and bioavailability of the drug can be influenced by different specific salt forms of the drug, and further the clinical curative effect, the selection of drug dosage forms, safety, production process and packaging of the drug can be influenced to a certain extent. No study has been made on the salts of the compounds of formula I, and no salts of the compounds of formula I, as well as polymorphs and amorphous forms thereof, have been developed.

Therefore, there is a great need in the art to develop various salt forms and crystal forms of the compound of formula I to further improve its crystallinity, stability, hygroscopicity and process stability, thereby advancing its production and use.

Disclosure of Invention

The invention aims to provide various salt forms and crystal forms of the IDO inhibitor so as to further improve the crystallinity, stability, hygroscopicity and process stability of the IDO inhibitor, thereby promoting the production and application of the IDO inhibitor.

Another object of the present invention is to provide a process for the preparation and use of various salt forms of IDO inhibitors.

In a first aspect of the invention, there is provided a salt of a compound of formula I, or an optical isomer thereof:

in the formula (I), the compound is shown in the specification,

R²is H, C₆-C₂₀Aryl, 3-14 membered heteroaryl, C₁-C₁₂Alkyl or C₃-C₁₂A cycloalkyl group;

Ar is a substituted or unsubstituted benzene ring, five-membered or six-membered heteroaryl, wherein the substitution means that one or more hydrogen atoms on Ar are substituted by halogen;

n is an integer of 2 to 8;

In another preferred embodiment, the compound of formula I is selected from the following I-1, I-2 or I-3:

wherein, Ar and R³And R⁴Is as defined in the first aspect of the invention.

In another preferred embodiment, the compound of formula I is selected from the group consisting of:

in another preferred embodiment, the compound of formula I is

In another preferred embodiment, the salt is selected from the group consisting of:

in another preferred embodiment, the salt is amorphous or crystalline.

In another preferred embodiment, the amorphous form has an X-ray powder diffraction pattern substantially as characterized by a pattern selected from the group consisting of: FIG. 1-2, FIG. 2-2, FIG. 4-2, FIG. 5-2, FIG. 10-2, or FIG. 11-2.

In another preferred embodiment, the amorphous material has an infrared spectrum substantially characterized by a pattern selected from the group consisting of: FIG. 1-1, FIG. 2-1, FIG. 4-1, FIG. 5-1, FIG. 10-1, or FIG. 11-1.

In another preferred embodiment, the crystalline form of the crystal is selected from the group consisting of: form 3, form 6, form 7, form 8, form 9, form 12, form 13, or form 14.

In another preferred embodiment, said X-ray powder diffraction pattern of form N comprises 3 or more than 3 characteristic peaks having values selected from the corresponding 2 θ ± 0.2 ° values shown in table N-1, wherein N is 3, 6, 7, 8, 9, 12, 13 or 14.

In another preferred embodiment, the X-ray powder diffraction pattern of form N further comprises 3 or more than 3 characteristic peaks having values selected from the corresponding 2 θ ± 0.2 ° values shown in table N.

In another preferred embodiment, the crystalline form N has an X-ray powder diffraction pattern substantially as characterized in figure N-2, wherein N is 3, 6, 7, 8, 9, 12, 13, or 14.

In another preferred embodiment, the form N has an ir spectrum substantially as depicted in figure N-1, wherein N is 3, 6, 12, 13 or 14.

In another preferred embodiment, the salt has an infrared spectrum substantially characterized as a graph selected from the group consisting of: FIG. 1-1, FIG. 2-1, FIG. 3-1, FIG. 4-1, FIG. 5-1, FIG. 6-1, FIG. 10-1, FIG. 11-1, FIG. 12-1, FIG. 13-1, or FIG. 14-1.

In another preferred embodiment, the X-ray powder diffraction pattern of form 3 comprises 3 or more than 3 characteristic peaks having 2 θ ± 0.2 ° values selected from the following tables 3-1:

TABLE 3-1

2θ(°)
16.5
18.4
19.7
21.9
23.3
25.0
27.4

In another preferred embodiment, the X-ray powder diffraction pattern of said crystalline form 3 further comprises 3 or more than 3 characteristic peaks having a value of 2 θ ± 0.2 ° selected from table 3.

In another preferred embodiment, the form 3 has an X-ray powder diffraction pattern substantially as characterized in fig. 3-2.

In another preferred embodiment, the X-ray powder diffraction pattern of form 6 comprises 3 or more than 3 characteristic peaks having 2 θ ± 0.2 ° values selected from the following table 6-1:

TABLE 6-1

2θ(°)
6.5
13.0
18.7
19.5
21.7
26.1
26.4
27.0
27.2
39.6

In another preferred embodiment, the X-ray powder diffraction pattern of form 6 further comprises 3 or more than 3 characteristic peaks having a value of 2 θ ± 0.2 ° selected from table 6.

In another preferred embodiment, the form 6 has an X-ray powder diffraction pattern substantially as characterized in fig. 6-2.

In another preferred embodiment, the X-ray powder diffraction pattern of form 7 comprises 3 or more than 3 characteristic peaks having 2 θ ± 0.2 ° values selected from the following table 7-1:

TABLE 7-1

2θ(°)
6.4
12.9
15.9
16.1
18.8
19.4

21.6
26.0
26.3
27.1

In another preferred embodiment, the X-ray powder diffraction pattern of form 7 further comprises 3 or more than 3 characteristic peaks having a value of 2 θ ± 0.2 ° selected from table 7.

In another preferred embodiment, the form 7 has an X-ray powder diffraction pattern substantially as characterized in fig. 7.

In another preferred embodiment, the X-ray powder diffraction pattern of form 8 comprises 3 or more than 3 characteristic peaks having 2 θ ± 0.2 ° values selected from the following table 8-1:

TABLE 8-1

2θ(°)
6.4
12.9
15.9
18.9
19.5
19.7
21.6
26.0
26.3
27.1

In another preferred embodiment, the X-ray powder diffraction pattern of said crystalline form 8 further comprises 3 or more than 3 characteristic peaks having 2 θ ± 0.2 ° values selected from table 8.

In another preferred embodiment, the form 8 has an X-ray powder diffraction pattern substantially as characterized in fig. 8.

In another preferred embodiment, the form 9 has an X-ray powder diffraction pattern comprising 3 or more characteristic peaks having 2 θ ± 0.2 ° values selected from the following table 9-1:

TABLE 9-1

2θ(°)
13.0
16.0
16.2
18.6
18.9
21.0
21.6
26.3
27.2
31.7

In another preferred embodiment, the X-ray powder diffraction pattern of said crystalline form 9 further comprises 3 or more than 3 characteristic peaks having 2 θ ± 0.2 ° values selected from table 9.

In another preferred embodiment, the form 9 has an X-ray powder diffraction pattern substantially as characterized in fig. 9.

In another preferred embodiment, the X-ray powder diffraction pattern of form 12 comprises 3 or more than 3 characteristic peaks having 2 Θ ± 0.2 ° values selected from the following table 12-1:

TABLE 12-1

2θ(°)
18.4
18.8
21.6
24.0
24.4
24.8
27.8

In another preferred embodiment, the X-ray powder diffraction pattern of crystalline form 12 further comprises 3 or more than 3 characteristic peaks having values of 2 θ ± 0.2 ° selected from table 12.

In another preferred embodiment, the crystalline form 12 has an X-ray powder diffraction pattern substantially as characterized in fig. 12-2.

In another preferred embodiment, the X-ray powder diffraction pattern of form 13 comprises 3 or more characteristic peaks having 2 θ ± 0.2 ° values selected from the following table 13-1:

TABLE 13-1

2θ(°)
15.1
18.3
18.9
21.5
24.0
24.4
24.8
27.8

In another preferred embodiment, the X-ray powder diffraction pattern of said crystalline form 13 further comprises 3 or more than 3 characteristic peaks having 2 θ ± 0.2 ° values selected from table 13.

In another preferred embodiment, the form 13 has an X-ray powder diffraction pattern substantially as characterized in fig. 13-2.

In another preferred embodiment, the crystalline form 14 has an X-ray powder diffraction pattern comprising 3 or more characteristic peaks having 2 θ ± 0.2 ° values selected from the following table 14-1:

TABLE 14-1

2θ(°)
15.9
16.1
18.9
19.4
19.7
21.0
21.6
26.3
27.1

In another preferred embodiment, the X-ray powder diffraction pattern of said crystalline form 14 further comprises 3 or more than 3 characteristic peaks having 2 θ ± 0.2 ° values selected from table 14.

In another preferred embodiment, the crystalline form 14 has an X-ray powder diffraction pattern substantially as characterized in fig. 14-2.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising:

(a) a salt as described in the first aspect of the invention, and (b) a pharmaceutically acceptable carrier.

In another preferred embodiment, the salt is a crystalline or amorphous form, or an optical isomer thereof, or a solvate thereof.

In another preferred embodiment, the pharmaceutical composition further comprises other anti-tumor drugs.

In another preferred embodiment, the other anti-tumor drug is an immunotherapy drug (such as a targeted therapy drug) or a chemotherapy drug for cancer.

In another preferred embodiment, the other anti-tumor drug is selected from the group consisting of: PD-1 antibodies, CTLA-4 antibodies, PD-L1 antibodies, PD-L2 antibodies, other chemotherapeutic drugs, or combinations thereof.

In a third aspect of the invention, there is provided the use of a salt according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention for:

(i) preparing indoleamine-2,3-dioxygenase inhibitor;

(ii) preparing a medicament for the prevention and/or treatment of indoleamine-2,3-dioxygenase mediated diseases;

(iii) preparing a medicament for treating tumors; or

(iv) Preparing the anti-inflammatory medicine.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated disease is a disease that is pathologically characteristic of the IDO-mediated tryptophan metabolic pathway.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated disease is cancer, a neurodegenerative disease, an eye disease, a psychological disorder, depression, anxiety, alzheimer's disease and/or an autoimmune disease.

In another preferred example, the cancer includes, but is not limited to: colon cancer, breast cancer, stomach cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple myeloma, chronic myelogenous leukemia, hematologic tumors, lymphoid tumors, including metastatic lesions in other tissues or organs remote from the site of tumor origin.

In a fourth aspect of the present invention, there is provided a process for the preparation of a salt according to the first aspect of the present invention, comprising the steps of: salifying a compound of formula I and an acid in an inert solvent, or recrystallizing a salt of a compound of formula I, or a solvate thereof, in an inert solvent to obtain a salt according to the first aspect of the invention;

wherein the acid is hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, phosphoric acid or sulfuric acid.

In another preferred embodiment, the compound of formula I is a compound of formula I-1, I-2, or I-3. In another preferred embodiment, the compound of formula I is compound a or B.

In another preferred embodiment, the inert solvent comprises water, ethers, alcohols, ketones, nitriles, esters, cyclic ethers, aliphatic hydrocarbons, or combinations thereof.

In another preferred embodiment, the inert solvent is selected from the group consisting of: diethyl ether, t-butyl methyl ether, ethyl acetate, ethanol, acetonitrile, or a combination thereof.

In another preferred example, the method comprises the steps of: the compound of formula I is dissolved in an inert solvent and mixed with the acid to give the salt according to the first aspect of the invention.

In a fifth aspect of the present invention, there is provided a method for the prevention and/or treatment of indoleamine 2,3-dioxygenase mediated diseases comprising the step of administering to a subject (e.g. a patient) in need thereof a salt according to the first aspect of the present invention or a pharmaceutical composition according to the second aspect of the present invention.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated disease is cancer, and the method further comprises the step of administering to the patient an additional anti-cancer agent (also referred to as an anti-tumor agent, said anti-tumor agent being as described above).

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1-1 shows an infrared spectrum of amorphous 1; fig. 1-2 show the X-ray powder diffraction pattern of amorphous 1.

FIG. 2-1 shows an infrared spectrum of amorphous object 2; fig. 2-2 shows an X-ray powder diffraction pattern of amorphous object 2.

Figure 3-1 shows an infrared spectrum of form 3; fig. 3-2 shows an X-ray powder diffraction pattern of form 3.

FIG. 4-1 shows an infrared spectrum of amorphous object 4; fig. 4-2 shows an X-ray powder diffraction pattern of amorphous 4.

FIG. 5-1 shows an infrared spectrum of amorphous 5; fig. 5-2 shows an X-ray powder diffraction pattern of amorphous 5.

Figure 6-1 shows an infrared spectrum of form 6; figure 6-2 shows an X-ray powder diffraction pattern of form 6.

Figure 7 shows an X-ray powder diffraction pattern of form 7.

Figure 8 shows an X-ray powder diffraction pattern of form 8.

Figure 9 shows an X-ray powder diffraction pattern of form 9.

FIG. 10-1 shows an infrared spectrum of amorphous object 10; fig. 10-2 shows an X-ray powder diffraction pattern of amorphous object 10.

FIG. 11-1 shows an infrared spectrum of amorphous substance 11; fig. 11-2 shows an X-ray powder diffraction pattern of amorphous substance 11.

Figure 12-1 shows an infrared spectrum of form 12; figure 12-2 shows an X-ray powder diffraction pattern of form 12.

Figure 13-1 shows an infrared spectrum of form 13; figure 13-2 shows an X-ray powder diffraction pattern of form 13.

Figure 14-1 shows an infrared spectrum of form 14; figure 14-2 shows an X-ray powder diffraction pattern of form 14.

Detailed Description

The inventor unexpectedly discovers the salt of the compound shown in the formula I and various amorphous substances and polymorphic substances thereof through long-term and intensive research, wherein the salt (including the amorphous substances and the polymorphic substances) has stable structure, good light stability, thermal stability, non-hygroscopicity and pharmacokinetic properties, good dissolving performance, obviously improved purity and bioavailability, can effectively inhibit IDO enzyme, is particularly suitable for developing and producing high-quality IDO enzyme inhibitors, and has important value on the dosage form optimization and development of the IDO inhibitors. On this basis, the inventors have completed the present invention.

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….

As used herein, the term "n or more than n 2 θ values selected from the group" is meant to include n as well as any positive integer greater than n (e.g., n +1, ….), where the upper bound Nup is the number of all 2 θ peaks in the group. For example, "3 or more" includes not only 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, …, each positive integer of the upper limit Nup, but also ranges such as "4 or more", "5 or more", "6 or more".

The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 12 (preferably 1 to 10) carbon atoms, including straight and branched chain hydrocarbon groups, such as methyl (i.e., CH)₃-, ethyl (i.e. CH)₃CH₂-, n-propyl (i.e., CH)₃CH₂CH₂-), isopropyl (i.e., (CH)₃)₂CH-), n-butyl (i.e. CH)₃CH₂CH₂CH₂-, isobutyl (i.e., (CH)₃)₂CHCH₂-, sec-butyl (i.e., (CH)₃)(CH₃CH₂) CH-), tert-butyl (i.e., (CH)₃)₃C-), n-pentyl (i.e. CH)₃CH₂CH₂CH₂CH₂-, neopentyl (i.e. (CH))₃)₃CCH₂-)。

As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms having a single ring (e.g., phenyl) or a fused ring (e.g., naphthyl or anthryl) which may be non-aromatic if the point of attachment is at an aromatic carbon atom (e.g., 2-benzoxazolone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 12 (preferably 3 to 10) carbon atoms, having a single ring or multiple rings (including fused, bridged and spiro ring systems). In fused ring systems, one or more rings may be cycloalkyl, heterocyclic, aryl or heteroaryl, provided that the attachment site is through the ring of the cycloalkyl group. Examples of suitable cycloalkyl groups include: for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

As used herein, the term "heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring, such heteroaryl groups can be monocyclic (e.g., pyridyl or furyl) or fused rings (e.g., indolizinyl or benzothienyl), wherein the fused rings can be non-aromatic and/or contain one heteroatom, so long as the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the ring atoms nitrogen and/or sulfur of the heteroaryl group are optionally oxidized to the N-oxide (N-O), sulfinyl, or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furyl. In one embodiment, heteroaryl refers to 3-14 membered heteroaryl, preferably 5-12 membered heteroaryl.

The term "substituted heteroaryl" as used herein refers to heteroaryl substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic) having a single or fused ring (including bridged ring systems and spiro ring systems, with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring, in the fused ring system, one or more rings may be cycloalkyl, aryl or heteroaryl, so long as the point of attachment is through a non-aromatic ring.

As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group that is substituted with from 1 to 5 (e.g., 1 to 3) substituents as defined for substituted cycloalkyl.

As used herein, the term "stereoisomer" refers to a compound in which the chirality of one or more stereocenters is different. Stereoisomers include enantiomers and diastereomers.

As used herein, the term "tautomer" refers to alternative forms of compounds that differ in the position of the proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain a ring atom attached to the-NH-moiety of the ring and the ═ N-moiety of the ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

"prodrug" refers to any derivative of a compound of the examples which, when administered to a subject, is capable of providing, directly or indirectly, the compound of the examples or an active metabolite or residue thereof. Particularly preferred derivatives and prodrugs are those that, when administered to a subject, enhance the bioavailability of the compounds of the examples (e.g., the compounds administered orally are more readily absorbed into the blood) or enhance the transport of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Prodrugs include ester forms of the compounds of the present invention.

Compounds of formula I and salts thereof

In the formula (I), the compound is shown in the specification,

R¹、R²、R³、R⁴and Ar is as defined above.

Patent application CN105481789A, the entire content of which is incorporated herein by reference, describes a compound of formula (I) as an IDO inhibitor containing sulfoximine and 1,2, 5-oxadiazole structures, and a method for its preparation and activity test.

The salts of the compounds of formula I according to the invention are selected from the group consisting of: hydrochloride, hydrobromide, p-toluenesulfonate, benzenesulfonate, methanesulfonate, phosphate or sulfate.

In another preferred embodiment, the compound of formula I is a compound of formula I-1, I-2, or I-3.

In another preferred embodiment, the compound of formula I is S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (compound a).

In another preferred embodiment, the compound of formula I is R- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (compound B).

Preferred salts of the present invention include (but are not limited to): compound a1, compound a2, compound A3, compound a4, compound a5, compound a6, compound B1, compound B2, compound B3, compound B4, or compound B5.

Polymorphic substance

The solid is present either in amorphous or crystalline form. In the case of crystalline forms, the molecules are positioned within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (this property is known as "polymorphism"), forming crystals with different crystalline forms, each of which is known as a "polymorph". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, packing pattern, flowability, and/or solid state stability.

Polymorphic forms of a compound may exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, flowability, and the like, which are important factors affecting drug-forming properties.

As used herein, the term "polymorph of the invention" includes polymorphs of a salt of the compound of formula I.

Preferred polymorphs of the present invention include (but are not limited to): polymorph 3 of the compound of formula A3 (i.e., form 3),

polymorph

6, 7, 8, 9 of the compound of formula a6 (i.e.,

form

6, 7, 8, 9), polymorph 12 of the compound of formula B3 (i.e., form 12), polymorph 13 of the compound of formula B4 (i.e., form 13), or polymorph 14 of the compound of formula B5 (i.e., form 14).

Amorphous material

The amorphous substance of the salt of the compound shown in the formula I has the advantages of high solubility, easiness in absorption by a human body, high oral bioavailability and the like. Amorphous forms of the salt of the compound of formula I can be obtained by dissolving the salt of the compound of formula I in a suitable solvent, by freeze-drying, spray-drying, or the like.

Preferred amorphous materials of the present invention include (but are not limited to): amorphous 1 of the compound of formula a1, amorphous 2 of the compound of formula a2, amorphous 4 of the compound of formula a4, amorphous 5 of the compound of formula a5, amorphous 10 of the compound of formula B1, or amorphous 11 of the compound of formula B2.

Solvates

In the process of contacting a compound or a drug molecule with a solvent molecule, the solvent molecule and the compound molecule form eutectic crystals and remain in the solid substance due to external condition and internal condition factors, which is difficult to avoid. The material formed after crystallization of the drug with the solvent is called the solvate (solvate). The solvent which can easily form a solvate with an organic compound is selected from water, methanol, benzene, ethanol, etc.

Hydrates are a particular solvate. In the pharmaceutical industry, hydrates have separately discussed value for their specificity, whether in the synthesis of drug substances, pharmaceutical formulations, drug storage, and evaluation of drug activity.

Crystallization of

Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallation, third edition, J W Mullins, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.

Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One way is to dissolve the compound of interest in a solvent and then add the appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and crystallization completed by cooling the system.

As used herein, the term "room temperature" generally means 4-30 deg.C, preferably 20. + -. 5 deg.C.

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising a safe and effective amount of the active ingredient, and a pharmaceutically acceptable carrier.

The "active ingredient" of the present invention refers to the compound of general formula I of the present invention or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof.

In another preferred embodiment, the "active ingredient" of the present invention refers to salts of the compounds of formula I, including polymorphs and amorphous forms thereof.

The "active ingredients" and pharmaceutical compositions described herein are useful as IDO inhibitors. In another preferred embodiment, the compound is used for preparing medicaments for preventing and/or treating tumors. In another preferred embodiment, the compound is used for preparing a medicament for preventing and/or treating IDO mediated diseases. "safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient.

The compounds of the preferred embodiments of the present invention may be administered as the sole active agent or in combination with one or more other agents useful in the treatment of cancer. The compounds of the preferred embodiments of the present invention are also effective for use in combination with known therapeutic and anti-cancer agents, and combinations of presently known compounds with other anti-cancer or chemotherapeutic agents are within the scope of the preferred embodiments. Examples of such agents are described in Cancer Principles and Practice Oncology, v.t. devita and s.hellman (editor), 6 th edition (2.15.2001), Lippincott Williams & Wilkins press. One of ordinary skill in the art will be able to identify effective combinations of agents based on the particular nature of the drug and the cancer involved. Such anti-cancer agents include (but are not limited to) the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis-inducing agents and agents that interfere with cell cycle checkpoints, CTLA4 antibodies, PD-1 antibodies, PD-L1 antibodies, and the like. The compounds of the preferred embodiments are also effective when administered concurrently with radiation therapy.

In general, the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any acceptable mode of administration of the agents having a similar effect. The actual amount of the compound (i.e., active ingredient) of the preferred embodiment will depend on a number of factors, such as the severity of the condition being treated, the age and relative health of the patient, the potency of the compound being administered, the route and form of administration, and other factors. The medicament may be administered multiple times a day, preferably once or twice a day. All of these factors are considered by the attending physician.

For purposes of the preferred embodiments, a therapeutically effective dose will generally be a total daily dose administered to a patient in one dose or in divided doses, e.g., from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about 30 mg/kg body weight per day. A unit dose composition (Dosage unit composition) may include its Dosage factors to form a daily dose. The choice of dosage form depends on various factors, such as the mode of administration and the bioavailability of the drug substance. In general, the compounds of the preferred embodiments may be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). The preferred mode of administration is oral, and convenient daily dosages may be adjusted to the bitter taste. The composition may take the form of a tablet, pill, capsule, semi-solid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other suitable composition. Another preferred mode of administering the compounds of the preferred embodiments is by inhalation. This is an effective method of delivering therapeutic agents directly to the respiratory tract (see, e.g., U.S. patent No. 5,607,915).

Suitable pharmaceutically acceptable carriers or excipients include: such as treatment agents and drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methyl cellulose, carboxymethyl cellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting waxes, ion exchange resins, and the like, and combinations of any two or more thereof. The liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal oils, vegetable oils, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose solutions, and glycols. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack pub. Co., New Jersey (1991), which is incorporated herein by reference.

As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of formula I or by reacting a suitable organic or inorganic acid or base, respectively, with a basic or acidic functional group. Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. In addition, the nitrogen-containing basic groups may be quaternized with the following agents: alkyl halides such as methyl, ethyl, propyl, butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromide, and the like. Thus obtaining a water-soluble or oil-soluble or dispersible product. Examples of acids which may be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulphonic acid, succinic acid, citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compounds of formula I, or by reacting the carboxylic acid moiety with a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) or ammonia, or an organic primary, secondary or tertiary amine, respectively. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The main advantages of the invention are:

(1) the salt (including amorphous and polymorphic substances) of the compound shown in the formula I has stable structure, good light stability, thermal stability, non-hygroscopicity and pharmacokinetic properties, good solubility, obviously improved purity and bioavailability, can effectively inhibit the IDO enzyme, and is particularly suitable for developing and producing high-quality IDO enzyme inhibitors.

(2) The preparation method of the salt (including amorphous substance and polymorphic substance) of the compound shown in the formula I is simple, rapid and mild, simple and easy to operate, low in cost, stable in process, good in reproducibility, high in yield and suitable for industrial mass production.

(3) The salt of the compound shown in the formula I has various pharmacological activities of resisting tumors, neurodegenerative diseases (Alzheimer disease), resisting inflammation and the like.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

The test materials and reagents used in the following examples are commercially available without specific reference. The normal temperature or room temperature is 4-30 deg.C, preferably 15-25 deg.C.

Powder X-ray diffraction

Methods for determining the X-ray powder diffraction of crystals are known in the art.

The X-ray Powder diffraction pattern is collected on a PANalytical X' Pert Powder X-ray Powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:

x-ray reflection parameter Cu, K α

Kα1

1.540598；Kα2

1.544426

The strength ratio of K α 2/K α 1 is 0.50

Voltage: 40 KV (kV)

Current: 40 milliampere (mA)

Scanning range: 3.0 to 40.0 degree

Example 1

Preparation of S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (Compound A) hydrochloride

Compound A (200mg,0.475mmol) was dissolved in 2mL of diethyl ether, then HCl solution (0.14mL,4M1, 4-dioxane solution) was added dropwise, stirred overnight, the precipitated solid collected by filtration and dried after washing with a small amount of diethyl ether to give S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxidate imine) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine hydrochloride amorphous 1(175 mg). Melting point: 108.8 to 111.0 ℃. The IR spectrum is substantially as shown in FIG. 1-1.

The XRD diffraction pattern of the resulting amorphous 1 is substantially as shown in FIGS. 1-2, and the diffraction angle data is substantially as shown in Table 1 below.

TABLE 1

Example 2

Preparation of S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine methanesulfonate

Compound A (100mg) was dissolved in 2mL of diethyl ether, followed by dropwise addition of methanesulfonic acid (24mg), stirring overnight, and the precipitated solid was collected by filtration, washed with a small amount of diethyl ether and dried to obtain S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxidate imine) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine methanesulfonate as an amorphous form 2(60 mg). Melting point: 98.7-101.7 ℃. The IR spectrum is substantially as shown in FIG. 2-1.

The XRD diffraction pattern of the resulting amorphous 2 is substantially as shown in FIG. 2-2, and the diffraction angle data is substantially as shown in Table 2 below.

TABLE 2

Example 3

Preparation of S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine benzenesulfonate crystalline form 3

Compound a (100mg) was dissolved in 2mL of diethyl ether, then benzenesulfonic acid (39.5mg) was added dropwise, stirred overnight, the precipitated solid was collected by filtration, washed with a small amount of diethyl ether and dried to give a solid as S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxylimide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine benzenesulfonate crystalline form 3(125 mg). Melting point: 170.0-172.1 ℃. The IR spectrum is substantially as shown in FIG. 3-1.

The XRD diffraction pattern of the obtained form 3 is substantially as shown in fig. 3-2, and the diffraction angle data is substantially as shown in table 3 below.

TABLE 3

Example 4

Preparation of S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine sulfate

Compound A (100mg) was dissolved in 2mL of diethyl ether, followed by dropwise addition of sulfuric acid (45mg), stirring overnight, and the precipitated solid was collected by filtration, washed with a small amount of diethyl ether and dried to give S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxidate imine) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine sulfate amorphous 4(90 mg). Melting point: 88.9-90.0 ℃. The IR spectrum is substantially as shown in FIG. 4-1.

The XRD diffraction pattern of the resulting amorphous 4 is substantially as shown in FIG. 4-2, and the diffraction angle data is substantially as shown in Table 4 below.

TABLE 4

Example 5

Preparation of S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine hemisulfate

Compound A (100mg) was dissolved in 2mL of diethyl ether, followed by dropwise addition of sulfuric acid (23mg), stirring overnight, and the precipitated solid was collected by filtration, washed with a small amount of diethyl ether and dried to give S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxidate imine) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine hemisulfate amorphous form 5(90 mg). Melting point: 133.1-135.0 ℃. The IR spectrum is substantially as shown in FIG. 5-1.

The XRD diffraction pattern of the resulting amorphous 5 is substantially as shown in FIG. 5-2.

Example 6

Preparation of S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine p-methylbenzenesulfonate crystalline form 6

Compound a (200mg) was dissolved in 2mL of diethyl ether, then p-toluenesulphonic acid (90mg, hydrate) was stirred overnight, the precipitated solid was collected by filtration and washed with a small amount of diethyl ether and dried to give S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulphinimide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine p-toluenesulphonate salt form 6(217 mg). Melting point: 127.8-129.0 ℃. The IR spectrum is substantially as shown in FIG. 6-1.

The XRD diffraction pattern of the obtained form 6 is substantially as shown in fig. 6-2, and the diffraction angle data is substantially as shown in table 6 below.

TABLE 6

Example 7

Preparation of S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine p-methylbenzenesulfonate crystalline form 7

Dissolving a compound A (100mg) in 3mL ethyl acetate, stirring the solution overnight for p-methylbenzenesulfonic acid (49.6mg, hydrate), concentrating the reaction solution under reduced pressure to 2.5mL, slowly adding a small amount of n-hexane until a solid is precipitated, continuing to stir for 2 hours, filtering and collecting the solid, washing the solid with a small amount of n-hexane and drying the solid to obtain the S- (Z) -nitrogen- (3-bromo-4-fluorophenyl) -nitrogen' -hydroxy-4- ((2- (thio-methylsulfoxide imine) propyl) amino) -1,2, 5-oxadiazole-3-formamidine p-methylbenzenesulfonate in a crystal form of 7(100 mg). Melting point: 127.0-129.0 deg.C

The XRD diffraction pattern of form 7 obtained is substantially as shown in fig. 7, and the diffraction angle data is substantially as shown in table 7 below.

TABLE 7

Example 8

Preparation of S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-formamidine p-methylbenzenesulfonate crystalline form 8

Dissolving a compound A (100mg) in 3mL of ethanol, stirring the solution overnight for p-methylbenzenesulfonic acid (49.6mg, hydrate), concentrating the reaction solution under reduced pressure to 2.5mL, slowly adding a small amount of n-hexane until a solid is precipitated, continuing to stir for 2 hours, filtering and collecting the solid, washing the solid with a small amount of n-hexane and drying the solid to obtain the S- (Z) -nitrogen- (3-bromo-4-fluorophenyl) -nitrogen' -hydroxy-4- ((2- (thio-methylsulfoxide imine) propyl) amino) -1,2, 5-oxadiazole-3-formamidine p-methylbenzenesulfonate in a crystal form of 8(90 mg). Melting point: 127.-128.9 ℃.

The XRD diffraction pattern of form 8 obtained is substantially as shown in fig. 8, and the diffraction angle data is substantially as shown in table 8 below.

TABLE 8

Example 9

Preparation of S- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-formamidine p-methylbenzenesulfonate crystalline form 9

Compound a (10g) was suspended in 150mL of methyl tert-butyl ether, then a solution of p-methylbenzenesulfonic acid (4.5g, hydrate) in methyl tert-butyl ether (50mL) was added dropwise, stirred overnight, the solid collected by filtration, using a small amount of methyl tert-butyl ether (10mL), and the resulting solid was S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxidate imine) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine p-methylbenzenesulfonate crystalline form 9(11.5 g). Melting point: 126 ℃ and 129 ℃. LCMS (liquid chromatography-Mass Spectrometry) 420.9([ M +1 ]]⁺)。

The nuclear magnetic resonance data are as follows:

¹H NMR(400MHz,CD₃OD):δ7.73(d,2H,J＝8.4Hz),7.25(d,2H,J＝8.0Hz),7.14-7.16(m,1H),7.05-7.09(m,1H),6.86-6.90(m,1H),4.10-4.24(m,2H),3.98-4.00(m,2H),3.69(s,3H),2.39(s,3H).

the XRD diffraction pattern of the obtained form 9 is substantially as shown in fig. 9, and the diffraction angle data are substantially as shown in table 9 below.

TABLE 9

Example 10

Preparation of R- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (Compound B) hydrochloride

Compound B (43mg) was dissolved in 2mL of diethyl ether, followed by dropwise addition of HCl solution (0.05mL of 4M1, 4-dioxane solution), stirring overnight, and the precipitated solid was collected by filtration, washed with a small amount of diethyl ether and dried to give R- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxidate imine) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine hydrochloride amorphous 10(35 mg). Melting point: 108.0-111.0 ℃. The IR spectrum is substantially as shown in FIG. 10-1.

The XRD diffraction pattern of the resulting amorphous 10 is substantially as shown in FIG. 10-2, and the diffraction angle data is substantially as shown in Table 10 below.

Watch 10

Example 11

Preparation of R- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine sulfate

Compound B (100mg) was dissolved in 2mL of diethyl ether, followed by dropwise addition of sulfuric acid (45mg), stirring overnight, and the precipitated solid was collected by filtration, washed with a small amount of diethyl ether and dried to give R- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxidate imine) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine sulfate amorphous substance 11(90 mg). Melting point: 85.1-87.0 ℃. The IR spectrum is substantially as shown in FIG. 11-1.

The XRD diffraction pattern of the resulting amorphous material 11 is substantially as shown in FIG. 11-2, and the diffraction angle data is substantially as shown in Table 11 below.

TABLE 11

Example 12

Preparation of R- (Z) -n- (3-bromo-4-fluorophenyl) -n' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine hemisulfate (form 12)

Example 12 crystalline form 12 was prepared by the same method as example 5 starting from compound B. Melting point: 133.1-135.0 ℃. The IR spectrum is substantially as shown in FIG. 12-1.

The XRD diffraction pattern of the obtained form 12 is substantially as shown in fig. 12-2, and the diffraction angle data are substantially as shown in table 12 below.

TABLE 12

Example 13

Preparation of R- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine methanesulfonate

Compound B (43mg) was dissolved in 2mL of diethyl ether, followed by dropwise addition of methanesulfonic acid (10mg), stirring overnight, precipitation of a solid, collection by filtration, washing with a small amount of diethyl ether and drying to give the solid R- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulphinimide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine methanesulfonate as crystalline form 13(35 mg). Melting point: 99.0-101.5 ℃. The IR spectrum is substantially as shown in FIG. 13-1.

The XRD diffraction pattern of the obtained form 13 is substantially as shown in fig. 13-2, and the diffraction angle data are substantially as shown in table 13 below.

Watch 13

Example 14

Preparation of R- (Z) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine p-methylbenzenesulfonate

Compound B (43mg) was dissolved in 2mL of diethyl ether, then p-toluenesulphonic acid (90mg, hydrate) was stirred overnight, the precipitated solid was collected by filtration and washed with a small amount of diethyl ether and dried to give R- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulphinimide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine p-toluenesulphonate salt form 14(50 mg). Melting point: 127.6-129.7 ℃. The IR spectrum is substantially as shown in FIG. 14-1.

The XRD diffraction pattern of the obtained form 14 is substantially as shown in fig. 14-2, and the diffraction angle data are substantially as shown in table 14 below.

TABLE 14

Example 15

Oral pharmacokinetics in mice of S- (Z) -aza- (3-bromo-4-fluorophenyl) -aza' -hydroxy-4- ((2- (thio-methylsulfoxide) propyl) amino) -1,2, 5-oxadiazole-3-carboxamidine p-methylbenzenesulfonate (compound a-p-TsOH salt, form 6)

1. Dosing regimens

BALB/c mice 6, male, weighing 18-22g, gavage Compound A-p-TsOH salt (form 6, example 6), as shown in Table 5 below:

TABLE 5

Gavage was performed by suspending 0.5% HPMC in water, fasted for 12h before testing, and allowed free access to water. The diets were uniformly fed 2h after dosing.

2. Blood sampling time points and sample treatment:

intragastric administration: 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12 and 24h after administration;

at the above set time point, 0.01ml of blood was taken from the femoral vein of the mouse and put into a centrifuge tube, and 100. mu.L of an equal volume of a mixed solution containing 50nM Verapamil (Verapamul) acetonitrile methanol was added for precipitation, vortexed for 1min, and centrifuged (15000rpm) for 5 min. Taking 10 μ L of supernatant and 30 μ L of CH₃CN (acetonitrile) H₂Mixing O1: 1(v/v), and analyzing by sample injection.

3. Sample testing and data analysis

Apparatus and device

Mass spectrometer Xevo TQ-S, Watts (Waters)

UPLC System UPLC I-Class, Vortex

Software version MassLynx V4.1, Vortex

Eppendorf 5424 type centrifuge of centrifuge

Vortex machine MS3 digital display type vortex machine IKA

Ultrasonic Gutel SG9200HE

Analytical balance Sadoris MSE125P-100-DA type analytical balance

Chromatographic process

A chromatographic column: acquity UPLC BEH C18 (50X 2.1mm, 1.7 μm)

Flow rate: 0.5mL/min

Gradient: as shown below

A: containing 5mM NH₄Aqueous solution of OAc and 0.1% formic acid

B: acetonitrile and methanol mixed solution containing 0.1% formic acid, wherein CH₃CN:MeOH＝9:1(v/v)

Time of day	Rate of speed	A％	B％	Curve line
Start of	0.5	90	10	Start of
1.5	0.5	30	70	6
1.8	0.5	10	90	6
2.3	0.5	90	10	1

Mass spectrometry method

Compound ionization mode Transition (Transition)

R-00429-0T01 positive ion 421.032>308.938

Verapamil (Verapamul) positive ion 455.248>150.034

4. Test results

Pharmacokinetic parameters for compound A after gavage of mice with 140mg/kg and 420mg/kg of compound example 6 are shown in tables 15 and 16.

TABLE 15 pharmacokinetic parameters of Compound A measured after gavage of 140mg/kg Compound in mice example 6

TABLE 16 pharmacokinetic values of Compound A measured after gavage of 420mg/kg Compound in mice example 6

The results show that compound example 6 is exposed to Compound A in mice following oral administration at 140mg/kg and 420mg/kg (AUC)_0-24h) 13151ng · h/mL and 30034ng · h/mL respectively, and has obvious linear dose relationship, thereby ensuring the dose-effect relationship of the drug effect in clinical tests.

Example 16

Examples 2 and 6 solubility testing of the Compounds with free base Compound A in buffer solutions of different pH

The test compound (1-2mg) was placed in two 1.5mL glass vials, 1mL of PBS buffer solutions of different pH were added, and the samples were then placed in an Edwardsiellow type thermostatic mixer (Eppendorf Thermomixer comfort) plate shaker and shaken at 1100rpm for 24 hours. Then 0.2mL of the filtrate was removed and filtered, the filtrate was diluted 1000-fold with methanol, samples were quantitatively analyzed by the LC/MS method described above, and the average concentration of Compound A in both samples was calculated by the dilution factor.

Table 17 solubility of examples 2 and 6 with free base compound a in buffer solutions of different pH

The above experimental data show a significant increase in solubility of the compounds of example 2 and example 6 in PBS buffer.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

A compound of formula I, or a salt of an optical isomer thereof:

in the formula (I), the compound is shown in the specification,

R¹is C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl radical, C₆-C₂₀Aryl, or 3-14 membered heteroaryl;

R²is H, C₆-C₂₀Aryl, 3-14 membered heteroaryl, C₁-C₁₂Alkyl or C₃-C₁₂A cycloalkyl group;

R³and R⁴Each independently hydrogen, substituted or unsubstituted C₁-C₁₀An alkyl group; or R³And R⁴Together form a three-to eight-membered ring or a three-to eight-membered heterocyclic ring in which the heteroatom is sulfur, oxygen, NH or NR^h；

Ar is a substituted or unsubstituted benzene ring, five-membered or six-membered heteroaryl, wherein the substitution means that one or more hydrogen atoms on Ar are substituted by halogen;

n is an integer of 2 to 8;

R^hselected from the group consisting of: c₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl radical, C₆-C₂₀Aryl, or 3-14 membered heteroaryl;

wherein the salt is selected from the group consisting of: hydrochloride, hydrobromide, p-toluenesulfonate, benzenesulfonate, methanesulfonate, phosphate or sulfate;

unless otherwise specified, the substitution refers to the substitution of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, amino, nitro, aldehyde, -CF₃-CN or-SF₅。
The salt of claim 1, wherein the compound of formula I is selected from the group consisting of I-1, I-2, and I-3:

wherein, Ar and R³And R⁴Is as defined in claim 1.
The salt of claim 2, wherein the compound of formula I is selected from the group consisting of:
the salt of claim 2, wherein the salt is selected from the group consisting of:
the salt of claim 1, wherein the salt is amorphous or crystalline.
The salt of claim 5, wherein the crystalline form is selected from the group consisting of: form 3, form 6, form 7, form 8, form 9, form 12, form 13, or form 14; or

The amorphous form has an X-ray powder diffraction pattern substantially characterized as a pattern selected from the group consisting of: FIG. 1-2, FIG. 2-2, FIG. 4-2, FIG. 5-2, FIG. 10-2, or FIG. 11-2.
The salt of claim 6, wherein form N has an X-ray powder diffraction pattern comprising 3 or more characteristic peaks selected from the corresponding values of 2 θ ± 0.2 ° shown in Table N-1, wherein N is 3, 6, 7, 8, 9, 12, 13, or 14.
A pharmaceutical composition, comprising:

(a) the salt of any one of claims 1-7, and (b) a pharmaceutically acceptable carrier.
Use of a salt according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for:

(i) preparing indoleamine-2,3-dioxygenase inhibitor;

(ii) preparing a medicament for the prevention and/or treatment of indoleamine-2,3-dioxygenase mediated diseases;

(iii) preparing a medicament for treating tumors; or

(iv) Preparing the anti-inflammatory medicine.
A process for the preparation of a salt according to any one of claims 1 to 7, comprising the steps of: salifying a compound of formula I and an acid in an inert solvent, or recrystallizing a salt of a compound of formula I, or a solvate thereof, in an inert solvent to obtain a salt according to any one of claims 1 to 7;

wherein the acid is hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, phosphoric acid or sulfuric acid.