WO2019076324A1 - Salt of indoleamine-2,3-dioxygenase inhibitor and preparation method therefor - Google Patents

Abstract

The present invention discloses a guanamine-2,3-dioxygenase inhibitor salt and a process for the preparation thereof. In particular, the present invention discloses salts of the compounds of formula I and their various amorphous and polymorphic forms, wherein each group is as defined in the specification. The salt has stable structure, good light stability, thermal stability, non-hygroscopicity and pharmacokinetic properties, good solubility, and improved purity and bioavailability, and is particularly suitable for developing and producing high quality IDO. Enzyme inhibitor.

Description

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

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

Background technique

Indoleamine-2,3-dioxygenase (IDO) inhibitor is a tumor immunotherapy drug. Patent application CN105481789A and CN disclose an IDO inhibitor comprising a sulfoximine and a 1,2,5-oxadiazole structure, the structure of which is shown in formula (I).

R ¹ is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ -C ₂₀ aryl, or 3-14 membered heteroaryl;

R ² is H, C ₆ -C ₂₀ aryl, 3-14 membered heteroaryl, C ₁ -C ₁₂ alkyl or C ₃ -C ₁₂ cycloalkyl;

R ³ and R ⁴ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl; or R ³ and R ⁴ together form a three to eight membered ring or a three to eight membered heterocyclic ring wherein the hetero atom is sulfur, Oxygen, NH or NR ^h ;

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

R ^{h is} selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ -C ₂₀ aryl, or 3-14 membered heteroaryl;

Wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, p-toluenesulfonate, besylate, methanesulfonate, phosphate or sulfate;

Unless otherwise stated, the substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, Amino, nitro, aldehyde, -CF ₃ , -CN or -SF ₅ .

The specific salt form of the drug may affect its solubility, absorbency, stability, crystallinity, and bioavailability, which may affect the clinical efficacy of the drug, drug dosage form selection, safety, production process, and packaging to some extent. There are currently no studies on the salts of the compounds of formula I, and salts of the compounds of formula I, as well as their polymorphs and amorphous forms have not yet been developed.

Therefore, there is an urgent 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 promoting its production and application.

Summary of the invention

It is an object of the present invention to provide various salt forms and crystal forms of IDO inhibitors to further improve their crystallinity, stability, hygroscopicity and process stability, thereby promoting their production and application.

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

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

In the formula,

R ¹ is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ -C ₂₀ aryl, or 3-14 membered heteroaryl;

R ² is H, C ₆ -C ₂₀ aryl, 3-14 membered heteroaryl, C ₁ -C ₁₂ alkyl or C ₃ -C ₁₂ cycloalkyl;

R ³ and R ⁴ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl; or R ³ and R ⁴ together form a three to eight membered ring or a three to eight membered heterocyclic ring wherein the hetero atom is sulfur, Oxygen, NH or NR ^h ;

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

n is an integer from 2 to 8;

R ^{h is} selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ -C ₂₀ aryl, or 3-14 membered heteroaryl;

Wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, p-toluenesulfonate, besylate, methanesulfonate, phosphate or sulfate;

Unless otherwise stated, the substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, Amino, nitro, aldehyde, -CF ₃ , -CN or -SF ₅ .

In another preferred embodiment, the compound of formula I is selected from the group consisting of I-1, I-2 or I-3 as follows:

Wherein, the definitions of Ar, R ³ and R ⁴ are as described 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 an amorphous or crystalline.

In another preferred embodiment, the X-ray powder diffraction pattern of the amorphous material is substantially characterized by a graph selected from the group consisting of: Figure 1-2, Figure 2-2, Figure 4-2, Figure 5-2, Figure 10-2, or Figure 11-2.

In another preferred embodiment, the infrared spectrum of the amorphous material is substantially characterized by a graph selected from the group consisting of: Figure 1-1, Figure 2-1, Figure 4-1, Figure 5-1, Figure 10- 1. Or Figure 11-1.

In another preferred embodiment, the crystal 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, the X-ray powder diffraction pattern of the Form N includes 3 or more characteristic peaks having a value of 2θ ± 0.2° selected from the corresponding Table N-1, wherein N It is 3, 6, 7, 8, 9, 12, 13 or 14.

In another preferred embodiment, the X-ray powder diffraction pattern of the Form N further comprises three or more characteristic peaks having a value of 2θ ± 0.2° selected from the corresponding Table N.

In another preferred embodiment, the X-ray powder diffraction pattern of Form N is substantially characterized as in Figure N-2, wherein N is 3, 6, 7, 8, 9, 12, 13, or 14.

In another preferred embodiment, the infrared spectrum of the crystalline form N is substantially characterized as in Figure N-1, wherein N is 3, 6, 12, 13, or 14.

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

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

In another preferred embodiment, the X-ray powder diffraction pattern of Form 3 is substantially as characterized by Figure 3-2.

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

In another preferred embodiment, the X-ray powder diffraction pattern of Form 6 is substantially characterized as in Figure 6-2.

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

In another preferred embodiment, the X-ray powder diffraction pattern of Form 7 is substantially characterized as in Figure 7.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 8 comprises 3 or more characteristic peaks having a value of 2θ ± 0.2 ° 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 Form 8 further comprises 3 or more characteristic peaks having a value of 2θ ± 0.2° selected from Table 8.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 8 is substantially characterized as in Figure 8.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 9 comprises 3 or more characteristic peaks having a value of 2θ ± 0.2 ° 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 Form 9 further comprises three or more characteristic peaks having a value of 2θ ± 0.2° selected from Table 9.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 9 is substantially characterized as in Figure 9.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 12 comprises three or more characteristic peaks having a value of 2θ ± 0.2 ° 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 Form 12 further comprises three or more characteristic peaks having a value of 2θ ± 0.2° selected from Table 12.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 12 is substantially as characterized by Figure 12-2.

In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form 13 comprises three or more characteristic peaks having a value of 2θ ± 0.2° 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 the crystalline form 13 further comprises three or more characteristic peaks having a value of 2θ ± 0.2° selected from Table 13.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 13 is substantially as characterized by Figure 13-2.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 14 comprises three or more characteristic peaks having a value of 2θ ± 0.2 ° 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 Form 14 further comprises three or more characteristic peaks having a value of 2θ ± 0.2° selected from Table 14.

In another preferred embodiment, the X-ray powder diffraction pattern of Form 14 is substantially as characterized by Figure 14-2.

In a second aspect of the 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 crystal or an amorphous substance, or an optical isomer thereof, or a solvate thereof.

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

In another preferred embodiment, the other anti-tumor drug is an immunotherapeutic drug (such as a targeted therapeutic drug) or a chemotherapeutic drug for cancer.

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

According to a third aspect of the invention, there is provided a 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 a guanamine-2,3-dioxygenase inhibitor;

(ii) preparing a medicament for preventing and/or treating a guanamine-2,3-dioxygenase mediated disease;

(iii) preparing a therapeutic tumor drug; or

(iv) Preparation of an anti-inflammatory drug.

In another preferred embodiment, the guanamine-2,3-dioxygenase mediated disease is a disease characterized by the pathology of an IDO-mediated tryptophan metabolism pathway.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated diseases are cancer, neurodegenerative diseases, eye diseases, psychological disorders, depression, anxiety, Alzheimer's disease and/or Or autoimmune disease.

In another preferred embodiment, the cancer includes, but is not limited to, colon cancer, breast cancer, gastric cancer, lung cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple Myeloma, chronic myeloid leukemia, hematological tumors, lymphoid tumors, including metastatic lesions in other tissues or organs remote from the primary site of the tumor.

According to a fourth aspect of the invention, there is provided a process for the preparation of a salt according to the first aspect of the invention, comprising the steps of: forming a salt of a compound of the formula I and an acid in an inert solvent or a compound of the formula I a salt, or a solvate thereof, is recrystallized in an inert solvent to give 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 includes water, ethers, alcohols, ketones, nitriles, esters, cyclic ethers, aliphatic hydrocarbons, or a combination thereof.

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

In another preferred embodiment, the method comprises the steps of dissolving a compound of formula I in an inert solvent and mixing with the acid to provide a salt as described in the first aspect of the invention.

According to a fifth aspect of the present invention, a method for preventing and/or treating a guanamine-2,3-dioxygenase-mediated disease, comprising administering to a subject in need thereof (such as a patient) A step of the salt or the pharmaceutical composition of the second aspect of the invention.

In another preferred embodiment, the indoleamine-2,3-dioxygenase mediated disease is cancer, the method further comprising administering to the patient an additional anticancer agent (also known as an antitumor drug, The steps of the antitumor drug as described above).

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to form a new or preferred technical solution. Due to space limitations, we will not repeat them here.

DRAWINGS

Figure 1-1 shows the infrared spectrum of amorphous 1; Figure 1-2 shows the X-ray powder diffraction pattern of amorphous 1.

Figure 2-1 shows the infrared spectrum of amorphous 2; Figure 2-2 shows the X-ray powder diffraction pattern of amorphous 2.

Figure 3-1 shows the infrared spectrum of Form 3; Figure 3-2 shows the X-ray powder diffraction pattern of Form 3.

Figure 4-1 shows the infrared spectrum of amorphous 4; Figure 4-2 shows the X-ray powder diffraction pattern of amorphous 4.

Figure 5-1 shows the infrared spectrum of amorphous 5; Figure 5-2 shows the X-ray powder diffraction pattern of amorphous 5.

Figure 6-1 shows the infrared spectrum of Form 6; Figure 6-2 shows the 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.

Figure 10-1 shows the infrared spectrum of amorphous 10; Figure 10-2 shows the X-ray powder diffraction pattern of amorphous 10.

Figure 11-1 shows the infrared spectrum of amorphous 11; Figure 11-2 shows the X-ray powder diffraction pattern of amorphous 11.

Figure 12-1 shows the infrared spectrum of Form 12; Figure 12-2 shows the X-ray powder diffraction pattern of Form 12.

Figure 13-1 shows the infrared spectrum of Form 13; Figure 13-2 shows the X-ray powder diffraction pattern of Form 13.

Figure 14-1 shows the infrared spectrum of Form 14; Figure 14-2 shows the X-ray powder diffraction pattern of Form 14.

Detailed ways

Through intensive and intensive research, the present inventors have unexpectedly discovered salts of the compounds of formula I and their various amorphous and polymorphic forms, said salts (including amorphous and polymorphic) being structurally stable, Good light stability, thermal stability, non-hygroscopicity and pharmacokinetic properties, good solubility, high purity and bioavailability, high efficiency inhibition of IDO enzymes, especially suitable for the development and production of high quality IDO enzymes Inhibitors are of great value for the formulation optimization and development of such IDO inhibitors. On this basis, the inventors completed the present invention.

definition

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, unless otherwise defined.

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

As used herein, the terms "containing" or "including" may be open, semi-closed, and closed. In other words, the terms also include "consisting essentially of," or "consisting of."

As used herein, the term "n or n or more selected from the group of 2" refers to any positive integer (eg, n, n+1, . . . ) comprising n and greater than n, wherein the upper limit Nup is all in the group The number of 2θ peaks. 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, ... The upper limit Nup is a positive integer, and includes a range of "4 or more", "5 or more", "6 or more", and the like.

The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having from 1 to 12 (preferably from 1 to 10) carbon atoms, including straight-chain and branched hydrocarbon groups such as methyl (i.e., CH ₃ -), ethyl ( That is, CH ₃ CH ₂ -), n-propyl (ie CH ₃ CH ₂ CH ₂ -), isopropyl (ie (CH ₃ ) ₂ CH-), n-butyl (ie CH ₃ CH ₂ CH ₂ CH ₂ - , isobutyl (ie (CH ₃ ) ₂ CHCH ₂ -), sec-butyl (ie (CH ₃ )(CH ₃ CH ₂ )CH-), tert-butyl (ie (CH ₃ ) ₃ C-), N-pentyl (ie CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ -), neopentyl (ie (CH ₃ ) ₃ CCH ₂ -).

As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms which has a monocyclic (eg phenyl) or fused ring (eg naphthyl) Or sulfhydryl), if the point of attachment is on the aromatic carbon, the fused ring may be non-aromatic (eg 2-benzoxazolone, 2H-1,4-benzoxazine-3(4H)-one-7 - base, etc.). Preferred aryl groups include phenyl and naphthyl.

As used herein, the term "cycloalkyl" refers to a ring having from 3 to 12 (preferably from 3 to 10) carbon atoms, having a monocyclic or polycyclic ring (including fused systems, bridged ring systems, and spiro ring systems). Alkyl group. In a fused ring system, one or more of the rings may be a cycloalkyl, heterocyclic, aryl or heteroaryl group as long as the attachment site is a ring through a 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 fluoro, chloro, bromo and iodo.

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

The term "substituted heteroaryl" as used herein refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the group consisting of The same substituent as defined by the aryl group.

As used herein, the term "heterocycle" or "heterocycle" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic), Has a single ring or a fused ring (including a bridged ring system and a spiro ring system having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring, in a fused ring system, one or more The ring may be a cycloalkyl, aryl or heteroaryl group as long as the point of attachment passes through the non-aromatic ring. In one embodiment, the nitrogen and/or sulfur atom of the heterocyclic group is optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.

The term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclic" as used herein refers to a heterocyclic group substituted by 1 to 5 (eg, 1 to 3) substituents. The substituent is the same as the substituent defined by the substituted cycloalkyl group.

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

As used herein, the term "tautomer" refers to an alternative form of a compound having a different proton position, such as an enol-ketone and an imine-enamine tautomer, or a tautomeric form of a heteroaryl group. The heteroaryl group comprises 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 an embodiment compound that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the Examples, or an active metabolite or residue thereof. Particularly preferred derivatives and prodrugs are those which, when administered to a subject, increase the bioavailability of the compound of the example (eg, the compound administered orally is more readily absorbed into the blood) or the parent compound relative to the parent species Derivatives and prodrugs to the bioregional compartment (such as the brain or lymphatic system). Prodrugs include the ester form of the compounds of the invention.

Compounds of formula I and their salts

In the formula,

The definitions of R ¹ , R ² , R ³ , R ⁴ and Ar are as described above.

Patent application CN105481789A describes an IDO inhibitor of the formula (I) containing a sulfoximine and a 1,2,5-oxadiazole structure, a process for its preparation and an activity test, the entire contents of which are incorporated herein by reference. .

The salt of the compound of formula I in the present invention is selected from the group consisting of hydrochloride, hydrobromide, p-toluenesulfonate, besylate, 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)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methyl) Sulfimide imine) propyl)amino)-1,2,5-oxadiazole-3-carboxamidine (Compound A).

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

Preferred salts of the invention include, but are not limited to, Compound A1, Compound A2, Compound A3, Compound A4, Compound A5, Compound A6, Compound Bl, Compound B2, Compound B3, Compound B4, or Compound B5.

Polymorph

The solid does not exist in an amorphous form or in a crystalline form. In the case of a crystalline form, the molecules are positioned within the three-dimensional lattice lattice. When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattices (this property is called "polymorphism"), forming crystals with different crystalline forms, and these various crystalline forms are It is called "polymorph". Different polymorphs of a given substance may differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, bulk mode, flowability, and/or solid state stability.

The polymorphic form of the compound can exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, and fluidity, etc., which are important factors influencing the drug-forming properties.

As used herein, the term "polymorph of the invention" includes polymorphs of the salts of the compounds of formula I.

Preferred polymorphs of the invention include, but are not limited to, the polymorph 3 of the compound of formula A3 (ie, Form 3), and the polymorphs of Formula A6 6, 7, 8, 9 (ie Form 6) , 7, 8, 9), a compound of formula B3 polymorph 12 (ie, form 12), a compound of formula B4, polymorph 13 (ie, form 13) or a compound of formula B5, form 14 (ie, crystalline form) 14).

Amorphous

The amorphous substance of the salt of the compound of the formula I provided by the invention has the advantages of large solubility, easy absorption by the human body, high oral bioavailability and the like. The amorphous form 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, and the like.

Preferred amorphous forms of the invention include, but are not limited to, the compound amorphous form of formula A1, the amorphous form of compound of formula A2, the amorphous form of compound of formula A4, the amorphous form of formula A5, the compound of formula B1 Amorph 10 or compound B of formula B2 is amorphous 11.

Solvate

During the contact of a compound or a drug molecule with a solvent molecule, external conditions and internal conditions cause the solvent molecule to form a eutectic with the compound molecule and remain in the solid matter. The substance formed after the drug and the solvent are crystallized is called a solvate. The solvent type which easily forms a solvate with an organic compound is water, methanol, benzene, ethanol, or the like.

Hydrate is a special solvate. In the pharmaceutical industry, hydrates have a separately discussed value for their specificity in the synthesis of drug substances, pharmaceutical preparations, drug storage, and drug activity evaluation.

crystallization

The solubility limit of the compound of interest can be exceeded by operating the solution to complete production-scale crystallization. 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. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods. The solubility of the compound of interest can be lowered by adding an antisolvent or a solvent having a low solubility in the compound or a mixture of such a solvent. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

If salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Similarly, in the final desired form of the medium having less solubility than the reactants, the completion of the synthesis reaction allows the final product to crystallize directly.

Optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed. 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 an appropriate volume of anti-solvent in a controlled manner to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals are maintained), and the crystallization is completed by cooling the system.

As used herein, the term "room temperature" generally refers to 4-30 ° C, preferably 20 ± 5 ° C.

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable carrier.

The "active ingredient" as used herein means a compound of the formula I according to the 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 a salt of a compound of formula I, including polymorphs and amorphous forms thereof.

The "active ingredient" and pharmaceutical compositions described herein are useful as IDO inhibitors. In another preferred embodiment, a medicament for the preparation and prevention or/or treatment of a tumor is prepared. In another preferred embodiment, a medicament for the preparation of a disease preventing and/or treating IDO mediated diseases. By "safe and effective amount" is meant that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose. Preferably, the "one dose" is a tablet.

"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.

The compounds of the preferred embodiments of the invention may be administered as separate active agents or in combination with one or more other agents useful in the treatment of cancer. The use of the compounds of the preferred embodiments of the invention in combination with known therapeutic agents and anticancer agents is also effective, and combinations of currently known compounds with other anticancer or chemotherapeutic agents are within the scope of the preferred embodiments. Examples of such agents can be found in "Cancer Principles and Practice of Oncology", VT Devita and S. Hellman (editor), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Press . One of ordinary skill in the art will be able to discern effective combinations of agents based on the particular nature of the drug and the cancer involved. Such anticancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinol receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, iseswagen Alkenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, cell proliferation and survival signal inhibitors, apoptosis inducers, and reagents that interfere with cell cycle checkpoints, CTLA4 antibodies , PD-1 antibody, PD-L1 antibody, 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 of the accepted modes of administration of agents having similar effects. The actual amount of the compound (i.e., active ingredient) of the preferred embodiment is determined by a number of factors, such as the severity of the condition to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors. . The drug can be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.

For the purposes of the preferred embodiment, the therapeutically effective dose can generally be the total daily dose administered to the patient in a single or divided dose, for example, from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about daily. 30 mg / kg body weight. A Dosage unit composition can include its dosage factor to form a daily dose. The choice of dosage form will depend on various factors such as the mode of administration and the bioavailability of the drug substance. In general, the compounds of the preferred embodiments can be administered as a pharmaceutical composition 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 a convenient daily dose can be adjusted depending on the degree of bitterness. The compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable compositions. Another preferred mode of administration of the preferred embodiment compounds is inhalation. This is an effective method of delivering a therapeutic agent directly to the respiratory tract (see, e.g., U.S. Patent No. 5,607,915).

Suitable pharmaceutically acceptable carriers or excipients include, for example, treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof. The liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, particularly carriers for injectable solutions, include water, saline, aqueous dextrose and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.

The term "pharmaceutically acceptable salt," as used herein, refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ by final isolation and purification of the compound of formula I, or by separately reacting a suitable organic or inorganic acid or base with a basic or acidic functional group. Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate , 2-naphthyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Further, the nitrogen-containing basic group can be quaternized by the following reagents: alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromide and iodide; dialkyl sulfate Such as dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl Base halides such as benzyl and phenethyl bromide. A water soluble or oil soluble or dispersible product is thus obtained. Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and citric acid. The base addition salt can be prepared in situ upon final isolation and purification of the compound of formula I, or by separately reacting the carboxylic acid moiety with a suitable base such as a hydroxide, carbonate or carbonate of a pharmaceutically acceptable metal cation. Hydrogen salt) or ammonia, or organic primary, secondary or tertiary amine reaction. Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including However, it is not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

The main advantages of the invention are:

(1) The salt of the compound of the formula I of the present invention (including an amorphous form and a polymorph) is structurally stable, has good photostability, thermal stability, non-hygroscopicity and pharmacokinetic properties, and has good solubility and purity. Significantly improved bioavailability, highly effective inhibition of IDO enzymes, especially suitable for the development and production of high quality IDO enzyme inhibitors.

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

(3) The salt of the compound of the formula I of the present invention has various pharmacological activities such as antitumor, neurodegenerative diseases (Alzheimer's disease), anti-inflammatory and the like.

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

The experimental materials and reagents used in the following examples are available from commercially available sources unless otherwise specified. Normal temperature or room temperature means 4 ° C to 30 ° C, preferably 15 to 25 ° C.

X-ray powder diffraction

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

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

X-ray reflection parameters: Cu, Kα

1.540598；Kα2

1.544426 Kα1

1.540598; Kα2

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 40 volts (kV)

Current: 40 milliamps (mA)

Scan range: 3.0 to 40.0 degrees

Example 1

S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 ,5-oxadiazole-3-carboxamidine (Compound A) hydrochloride preparation

Compound A (200 mg, 0.475 mmol) was dissolved in 2 mL of diethyl ether, then HCl solution (0.14 mL, 4M 1,4-dioxane solution) was added dropwise, and the mixture was stirred overnight. The solid was collected by filtration, washed with diethyl ether and dried. The solid is S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1 2,5-oxadiazol-3-carboxamidine hydrochloride amorphous 1 (175 mg). Melting point: 108.8-111.0 °C. The infrared spectrum is basically shown in Figure 1-1.

The XRD diffraction pattern of the obtained amorphous material 1 is basically as shown in Fig. 1-2, and the diffraction angle data is basically as shown in Table 1 below.

Table 1

Example 2

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

Compound A (100 mg) was dissolved in 2 mL of diethyl ether, then methanesulfonic acid (24 mg) was added dropwise, and the mixture was stirred overnight, and the solid was collected by filtration, washed with a small amount of diethyl ether and dried to give a solid of S-(Z)-nitro-(3- Bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2,5-oxadiazole-3-carboxamidine Methanesulfonate amorphous 2 (60 mg). Melting point: 98.7-101.7 °C. The infrared spectrum is basically shown in Figure 2-1.

The XRD diffraction pattern of the obtained amorphous material 2 is basically as shown in Fig. 2-2, and the diffraction angle data is basically as shown in Table 2 below.

Table 2

Example 3

S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 ,5-oxadiazole-3-carboxaldehyde sulfonate crystal form 3 preparation

Compound A (100 mg) was dissolved in 2 mL of diethyl ether, then benzenesulfonic acid (39.5 mg) was added dropwise and stirred overnight. The solid was collected by filtration, washed with a small amount of diethyl ether and dried to give S-(Z)-N-(3) -Bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimine)propyl)amino)-1,2,5-oxadiazole-3-methyl Toluenesulfonate crystal form 3 (125 mg). Melting point: 170.0-172.1 °C. The infrared spectrum is basically shown in Figure 3-1.

The XRD diffraction pattern of the obtained Form 3 is basically as shown in Fig. 3-2, and the diffraction angle data is basically as shown in Table 3 below.

table 3

Example 4

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

Compound A (100 mg) was dissolved in 2 mL of diethyl ether, then sulfuric acid (45 mg) was added dropwise, and the mixture was stirred overnight. The solid was collected by filtration, washed with diethyl ether and dried to give a solid of S-(Z)-nitro-(3-bromo 4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimine)propyl)amino)-1,2,5-oxadiazole-3-carboxamidine sulfate Salt amorphous 4 (90 mg). Melting point: 88.9-90.0 °C. The infrared spectrum is basically as shown in Figure 4-1.

The XRD diffraction pattern of the obtained amorphous material 4 is basically as shown in Fig. 4-2, and the diffraction angle data is basically as shown in Table 4 below.

Table 4

Example 5

S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 Preparation of 5-oxadiazole-3-carboxamide hemisulfate

Compound A (100 mg) was dissolved in 2 mL of diethyl ether, then sulfuric acid (23 mg) was added dropwise, and stirred overnight. The solid was collected by filtration, washed with a small amount of diethyl ether and then dried to give a solid of S-(Z)-nitro-(3-bromo -4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimine)propyl)amino)-1,2,5-oxadiazole-3-carboxamide Sulfate amorphous 5 (90 mg). Melting point: 133.1-135.0 °C. The infrared spectrum is basically shown in Figure 5-1.

The XRD diffraction pattern of the obtained amorphous material 5 is basically as shown in Fig. 5-2.

Example 6

S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 ,5-oxadiazole-3-carboxamidine p-toluenesulfonate crystal form 6 preparation

Compound A (200 mg) was dissolved in 2 mL of diethyl ether, then p-toluenesulfonic acid (90 mg, hydrate), and stirred overnight. The solid was collected by filtration, washed with diethyl ether and dried. -(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimine)propyl)amino)-1,2,5-oxadiazole- 3-Methylbenzene p-toluenesulfonate Form 6 (217 mg). Melting point: 127.8-129.0 °C. The infrared spectrum is basically shown in Figure 6-1.

The XRD diffraction pattern of the obtained Form 6 is basically as shown in Fig. 6-2, and the diffraction angle data is basically as shown in Table 6 below.

Table 6

Example 7

S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 ,5-oxadiazole-3-carboxamidine p-toluenesulfonate crystal form 7

Compound A (100 mg) was dissolved in 3 mL of ethyl acetate, then p-toluenesulfonic acid (49.6 mg, hydrate) was stirred overnight, and the reaction mixture was concentrated to 2.5 mL under reduced pressure, and then a small amount of n-hexane was slowly added until a solid precipitated. Stirring was continued for 2 hours, and the solid was collected by filtration, washed with a small amount of n-hexane and then dried to give a solid of S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro--hydroxy-4-(2) - (Sulfur-methyl sulfoximine) propyl) amino)-1,2,5-oxadiazole-3-carboxamidine p-toluenesulfonate Form 7 (100 mg). Melting point: 127.0-129.0 °C

The XRD diffraction pattern of the obtained Form 7 is basically as shown in Fig. 7, and the diffraction angle data is basically shown in Table 7 below.

Table 7

Example 8

S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 ,5-oxadiazole-3-carboxamidine p-toluenesulfonate crystal form 8

Compound A (100 mg) was dissolved in 3 mL of ethanol, then p-toluenesulfonic acid (49.6 mg, hydrate) was stirred overnight, and the reaction mixture was concentrated to 2.5 mL under reduced pressure, and then a small amount of n-hexane was slowly added until solids were precipitated and stirring was continued. After 2 hours, the solid was collected by filtration, washed with a small amount of n-hexane and then dried to give a solid of S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro--hydroxy-4-((2-) Sulfur-methyl sulfoximine) propyl)amino)-1,2,5-oxadiazole-3-carboxamidine p-toluenesulfonate Form 8 (90 mg). Melting point: 127.-128.9 °C.

The XRD diffraction pattern of the obtained Form 8 is basically as shown in Fig. 8, and the diffraction angle data is basically as shown in Table 8 below.

Table 8

Example 9

S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 ,5-oxadiazole-3-carboxamidine p-toluenesulfonate crystal form 9

Compound A (10 g) was suspended in 150 mL of methyl tert-butyl ether, and then a solution of p-toluenesulfonic acid (4.5 g, hydrate) in methyl tert-butyl ether (50 mL) was added dropwise and stirred overnight. With a small amount of methyl tert-butyl ether (10 mL), the obtained solid was S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(sulfo-) Methyl sulfoximine) propyl) amino)-1,2,5-oxadiazole-3-carboxamidine p-toluenesulfonate Form 9 (11.5 g). Melting point: 126-129 ° C. LCMS (liquid chromatography-mass spectroscopy): 420.9 ([M+1] ⁺ ).

The NMR data is as follows:

¹ H NMR (400 MHz, CD ₃ OD): δ 7.73 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.0 Hz), 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 basically as shown in Fig. 9, and the diffraction angle data is basically as shown in Table 9 below.

Table 9

Example 10

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

Compound B (43 mg,) was dissolved in 2 mL of diethyl ether, then HCl solution (0.05 mL, 4M 1,4-dioxane solution) was added dropwise, and stirred overnight. The solid was collected by filtration, washed with diethyl ether and dried. Is R-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1, 2,5-oxadiazol-3-carboxamidine hydrochloride amorphous 10 (35 mg). Melting point: 108.0-111.0 °C. The infrared spectrum is basically shown in Figure 10-1.

The XRD diffraction pattern of the obtained amorphous material 10 is basically as shown in Fig. 10-2, and the diffraction angle data is basically shown in Table 10 below.

Table 10

Example 11

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

Compound B (100 mg) was dissolved in 2 mL of diethyl ether, then sulfuric acid (45 mg) was added dropwise, and stirred overnight. The solid was collected by filtration, washed with diethyl ether and dried to give R-(Z)-nitro-(3-bromo 4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimine)propyl)amino)-1,2,5-oxadiazole-3-carboxamidine sulfate Salt amorphous 11 (90 mg). Melting point: 85.1-87.0 °C. The infrared spectrum is basically shown in Figure 11-1.

The XRD diffraction pattern of the obtained amorphous material 11 is basically as shown in Fig. 11-2, and the diffraction angle data is basically as shown in Table 11 below.

Table 11

Example 12

R-(Z)-N-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 Preparation of 5-oxadiazole-3-carboxamide hemisulfate (Form 12)

Example 12 was obtained by the same procedure as in Example 5 using Compound B as a starting material. Melting point: 133.1-135.0 °C. The infrared spectrum is basically as shown in Figure 12-1.

The XRD diffraction pattern of the obtained Form 12 is basically as shown in Fig. 12-2, and the diffraction angle data is basically as shown in Table 12 below.

Table 12

Example 13

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

Compound B (43 mg) was dissolved in 2 mL of diethyl ether, then methanesulfonic acid (10 mg) was added dropwise, and the mixture was stirred overnight. The solid was collected by filtration, washed with diethyl ether and dried to give R-(Z)-N-(3- Bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2,5-oxadiazole-3-carboxamidine Mesylate salt form 13 (35 mg). Melting point: 99.0-101.5 °C. The infrared spectrum is basically as shown in Figure 13-1.

The XRD diffraction pattern of the obtained crystal form 13 is basically as shown in Fig. 13-2, and the diffraction angle data is basically as shown in Table 13 below.

Table 13

Example 14

R-(Z)-N-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 ,5-oxadiazole-3-carboxamidine p-toluenesulfonate preparation

Compound B (43 mg) was dissolved in 2 mL of diethyl ether, then p-toluenesulfonic acid (90 mg, hydrate), and stirred overnight. The solid was collected by filtration, washed with diethyl ether and dried to give R-(Z)-N. -(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimine)propyl)amino)-1,2,5-oxadiazole- 3-Methylbenzene p-toluenesulfonate Form 14 (50 mg). Melting point: 127.6-129.7 °C. The infrared spectrum is basically as shown in Figure 14-1.

The XRD diffraction pattern of the obtained Form 14 is basically as shown in Fig. 14-2, and the diffraction angle data is basically as shown in Table 14 below.

Table 14

Example 15

S-(Z)-nitro-(3-bromo-4-fluorophenyl)-nitro'-hydroxy-4-((2-(thio-methylsulfoxideimide)propyl)amino)-1,2 Oral pharmacokinetics of 5-oxadiazole-3-carboindole p-toluenesulfonate (compound Ap-TsOH salt, Form 6) in mice

1. Dosing regimen

Six BALB/c mice, male, weighing 18-22 g, were intragastrically administered with the compound A-p-TsOH salt (Form 6, Example 6), as shown in Table 5 below:

table 5

The rats were orally administered with 0.5% HPMC as a suspension, fasted for 12 hours before the test, and free to drink water. Uniformly eaten 2 hours after administration.

2. Blood collection time and sample processing:

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

At the above set time point, 0.01 ml of blood was taken from the mouse femoral vein in a centrifuge tube, and 100 μL of a volume mixture solution containing 50 nM Verapamil acetonitrile was added to precipitate, vortexed for 1 min, and centrifuged (15,000 rpm) for 5 min. 10 μL of the supernatant was mixed with 30 μL of CH ₃ CN (acetonitrile): H ₂ O = 1:1 (v/v) and analyzed by injection.

3. Sample testing and data analysis

Instruments and equipment

Mass Spectrometer Xevo TQ-S, Waters

UPLC System UPLC I-Class, Waters

Software version MassLynx V4.1, Waters

Centrifuge Eppendorf 5424 centrifuge

Vortex machine MS3 digital display eddy current machine, IKA

Ultrasound system Gutel SG9200HE

Analytical balance Sartorius MSE125P-100-DA analytical balance

Chromatography method

Column: Acquity UPLC BEH C18 (50*2.1mm, 1.7μm)

Flow rate: 0.5mL/min

Gradient: as shown below

A: an aqueous solution containing 5 mM NH ₄ OAc and 0.1% formic acid

B: mixed solution of acetonitrile and methanol containing 0.1% formic acid, wherein CH ₃ CN: MeOH = 9:1 (v/v)

time rate A% B% curve Start 0.5 90 10 Start 1.5 0.5 30 70 6 1.8 0.5 10 90 6 2.3 0.5 90 10 1

Mass spectrometry

Compound ionization mode transition

R-00429-0T01 positive ion 421.032>308.938

Verapamil positive ion 455.248>150.034

4. Test results

The pharmacokinetic parameters of Compound A measured by intragastric administration of 140 mg/kg and 420 mg/kg of compound after Example 6 are shown in Table 15 and Table 16.

Table 15 Pharmacokinetic parameters of Compound A measured after intragastric administration of 140 mg/kg of compound Example 6

Table 16 Pharmacokinetics of Compound A measured after administration of 420 mg/kg of Compound Example 6 in mice

The results showed that after oral administration of 140 mg/kg and 420 mg/kg, the exposure amount of compound A in compound Example 6 (AUC _0-24h ) was 13151 ng·h/mL and 30034 ng·h/mL, respectively. The linear dose relationship ensures a dose-effect relationship of efficacy in clinical trials.

Example 16

Solubility test of the compound of Example 2 and Example 6 with free base compound A in different pH buffer solutions

The test compound (1-2 mg) was placed in two 1.5 mL glass vials, and 1 mL of PBS buffer solution of different pH was added. The sample was then placed on an Eppendorf Thermomixer comfort plate shaker. Shake for 24 hours at 1100 rpm. Then, 0.2 mL of the filtrate was taken out, and the filtrate was diluted 1000 times with methanol. The sample was quantitatively analyzed by the above LC/MS method, and the average concentration of the compound A in the two samples was calculated by the dilution factor.

Table 17 Solubility of Example 2 and Example 6 with Free Base Compound A in Different pH Buffer Solutions

The above test data shows a significant increase in the solubility of the compounds of Example 2 and Example 6 in PBS buffer solution.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the present invention.

Claims (10)

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

In the formula, R ¹ is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ -C ₂₀ aryl, or 3-14 membered heteroaryl; R ² is H, C ₆ -C ₂₀ aryl, 3-14 membered heteroaryl, C ₁ -C ₁₂ alkyl or C ₃ -C ₁₂ cycloalkyl; R ³ and R ⁴ are each independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl; or R ³ and R ⁴ together form a three to eight membered ring or a three to eight membered heterocyclic ring wherein the hetero atom is sulfur, Oxygen, NH or NR ^h ; Ar is a substituted or unsubstituted benzene ring, five- or six-membered heteroaryl group, and said substitution means that one or more hydrogen atoms on Ar are substituted by halogen; n is an integer from 2 to 8; R ^{h is} selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ -C ₂₀ aryl, or 3-14 membered heteroaryl; Wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, p-toluenesulfonate, besylate, methanesulfonate, phosphate or sulfate; Unless otherwise stated, the substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, Amino, nitro, aldehyde, -CF ₃ , -CN or -SF ₅ . The salt according to claim 1, wherein the compound of formula I is selected from the group consisting of I-1, I-2 or I-3 as follows:

Wherein, Ar, R ³ and R ⁴ are as defined in claim 1. The salt according to claim 2, wherein the compound of formula I is selected from the group consisting of:

The salt according to claim 2, wherein the salt is selected from the group consisting of:

The salt according to claim 1, wherein the salt is an amorphous substance or a crystal. The salt according to claim 5, wherein the crystal form of the crystal is selected from the group consisting of crystal form 3, crystal form 6, crystal form 7, crystal form 8, crystal form 9, crystal form 12, and crystal form. 13 or Form 14; or The X-ray powder diffraction pattern of the amorphous material is substantially characterized by a pattern selected from the group consisting of: Figure 1-2, Figure 2-2, Figure 4-2, Figure 5-2, Figure 10-2 or Figure 11- 2. The salt according to claim 6, wherein said X-ray powder diffraction pattern of Form N comprises 3 or more having a value of 2θ ± 0.2° selected from the corresponding Table N-1. Characteristic peaks, where N is 3, 6, 7, 8, 9, 12, 13 or 14. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: (a) a salt according to 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 use in: (i) preparing a guanamine-2,3-dioxygenase inhibitor; (ii) preparing a medicament for preventing and/or treating a guanamine-2,3-dioxygenase mediated disease; (iii) preparing a therapeutic tumor drug; or (iv) Preparation of an anti-inflammatory drug. A process for the preparation of a salt according to any one of claims 1 to 7, which comprises the steps of: salting a compound of the formula I and an acid in an inert solvent, or a compound of the formula I The salt, or a solvate thereof, is recrystallized in an inert solvent to obtain the 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.

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