Solid forms of beta-lactamase inhibitors for oral delivery and their uses

Abstract

Disclosed herein is a crystalline form of ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate. Also disclosed herein is a method of treating bacteria with the crystalline form of ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 828,349, filed April 2, 2019, which is incorporated herein by reference in its entirety.

[0003] Statement Regarding Federally Sponsored Research

[0004] This invention was made with U.S. government support under Grant No. R43AI109879 awarded by the National Institutes of Health (NIH), Grant No. R44AI109879 awarded by the National Institutes of Health (NIH), Grant No. R01AI111539 awarded by the National Institutes of Health (NIH), and Contract No. HHSN272201600029C awarded by the National Institutes of Health (NIH). The U.S. government has certain rights in this invention. Background Art

[0005] Antibiotics are the most effective drugs for treating bacterial infectious diseases. They are widely used clinically due to their good antibacterial effects and limited side effects. Among them, β-lactam antibiotics (e.g., penicillin, cephalosporin, monobactam and carbapenem) are preferred because they act bactericidal and their targets do not exist in eukaryotic cells, thus having low toxicity.

[0006] To counter the efficacy of various β-lactams, bacteria have evolved to produce variants of β-lactam inactivating enzymes known as β-lactamases, and have evolved in the ability to share this tool vertically and horizontally between and within species. These β-lactamases are classified as "serine" or "metallo" based, respectively, based on the presence of a key serine or zinc in the enzyme active site. The rapid induction, selection, and spread of this bacterial resistance mechanism can severely limit the options for an entire class of β-lactam treatments in hospitals and the community. There is a need for effective and safe therapeutics that can treat such resistant infections. Summary of the invention

[0007] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0008]

[0009] in:

[0010] M is hydrogen, halogen, -CD3, -CF3, -CN, -OR 4 、-C(=O)R 4 、-C(=O)NR 4 R5 、-SR 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)2NR 4 R 5 、-NR 4 R 5 、-NR 4 C(=O)R 5 、-NR 4 C(=O)NR 4 R 5 、-NR 4 S(=O)2R 5 or alkynyl;

[0011] Each R 1 and R 2 are independently hydrogen, deuterium, halogen, -OR 4 、-SR 4 、-NR 4 R 5 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl or optionally substituted C1-C6 aminoalkyl;

[0012] or R 1 and R 2 together with the carbon to which they are attached form an optionally substituted cycloalkyl;

[0013] or when n is at least 2, two R 1 together to form a double bond;

[0014] or when n is at least 2, two R 1 and two R 2 Taken together to form a triple bond; n is 0, 1, 2, 3, 4, 5 or 6;

[0015] Each R is independently -COOR 3 , R a , R b or R c ;

[0016] m is 0, 1, 2, 3 or 4;

[0017] R 3 For R 31 、-(R 30 ) q OR 31 、-(R 30 ) q O(R 30 ) q OR31 , -R 30 OC(O)R 31 , -R 30 OC(O)OR 31 , -R 30 OC(O)NHR 31 or -R 30 OC(O)N(R 31 )2;

[0018] Each q is independently 2, 3, 4, 5 or 6;

[0019] Each R 30 are independently -CH2-, -CH(CH3)-, -C(CH3)2- or optionally substituted 1,1-cyclopropylene;

[0020] Each R 31 are independently optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 haloalkyl, optionally substituted C1-C 12 Hydroxyalkyl, optionally substituted C1-C 12 aminoalkyl, optionally substituted C1-C 12 Alkoxyalkyl, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C6 alkyl)cycloalkyl, optionally substituted (C1-C6 alkyl)heterocycloalkyl, optionally substituted (C1-C6 alkyl)aryl, or optionally substituted (C1-C6 alkyl)heteroaryl; or

[0021] Two R's 31 together with the nitrogen to which they are attached form a heterocycloalkyl group;

[0022] R a , R b and R c are independently hydrogen, deuterium, halogen, -OR 4 、-NR 4 R 5 、-SR 4 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0023] R d is hydrogen or optionally substituted C1-C6 alkyl;

[0024] R 4 and R 5 are independently hydrogen, -OH, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0025] or R 4 and R 5 together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl; and

[0026] R 6 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C1-C6 alkyl)cycloalkyl, optionally substituted (C1-C6 alkyl)heterocycloalkyl, optionally substituted (C1-C6 alkyl)aryl or optionally substituted (C1-C6 alkyl)heteroaryl.

[0027] In some embodiments of the compound of formula (I), the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0028]

[0029] In some embodiments of the compound of Formula (I) or (Ia), R a , R b and R c are independently hydrogen, halogen, -OR 4 、-NR 4 R 5 、-SR 4 or optionally substituted C1-C6 alkyl. In some embodiments of the compound of formula (I) or (Ia), R a , R b and R c is independently hydrogen, halogen, -OH or -OCH3. In some embodiments of the compound of Formula (I) or (Ia), R a , R b and R c In some embodiments of the compound of Formula (I) or (Ia), R d is hydrogen or C1-C4 alkyl. In some embodiments of the compound of formula (I) or (Ia), Rd For hydrogen.

[0030] In some embodiments of compounds of formula (I) or (Ia), n is 0, 1, 2 or 3. In some embodiments of compounds of formula (I) or (Ia), n is 2. In some embodiments of compounds of formula (I) or (Ia), n is 1. In some embodiments of compounds of formula (I) or (Ia), each R 1 and R 2 R is independently hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 haloalkyl. 1 and R 2 In some embodiments of the compound of Formula (I) or (Ia), each R 1 and R 2 In some embodiments of the compound of formula (I) or (Ia), M is hydrogen, -CN, -C(=O)R 4 or alkynyl. In some embodiments of the compound of formula (I) or (Ia), M is hydrogen. In some embodiments of the compound of formula (I) or (Ia), the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0031]

[0032] In some embodiments of the compound of Formula (I) or (Ia) or (Ib), R 3 For R 31 In some embodiments of the compound of Formula (I) or (Ia) or (Ib), R 3 For-R 30 OC(O)R 31 or -R 30 OC(O)OR 31 In some embodiments of the compound of Formula (I) or (Ia) or (Ib), R 3 For-R 30 OC(O)R 31 In some embodiments of the compound of Formula (I) or (Ia) or (Ib), R 30 In some embodiments of the compound of Formula (I) or (Ia) or (Ib), R 30 In some embodiments of the compound of Formula (I) or (Ia) or (Ib), each R 31 are independently optionally substituted C1-C 12In some embodiments of the compound of Formula (I) or (Ia) or (Ib), each R 31 are independently optionally substituted C1-C 12 In some embodiments of the compound of formula (I) or (Ia) or (Ib), the compound is a compound of formula (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0033]

[0034] In some embodiments of the compound of Formula (I) or (Ia) or (Ib) or (Ic), R 6 In some embodiments of the compound of formula (I) or (Ia) or (Ib) or (Ic), R 6 It is methyl, ethyl, propyl or butyl.

[0035] In some embodiments of the compound of formula (I) or (Ia) or (Ib), the compound is a compound of formula (Id), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: In some embodiments of the compound of Formula (I) or (Ia) or (Ib) or (Ic), the compound is: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments of the compound of formula (I) or (Ia) or (Ib) or (Ic), the compound is: or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the compound of formula (I) or (Ia) or (Ib) or (Ic), the compound is: In some embodiments of the compound of Formula (I) or (Ia) or (Ib) or (Ic), the compound is: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments of the compound of formula (I) or (Ia) or (Ib) or (Ic), the compound is: or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the compound of formula (I) or (Ia) or (Ib) or (Ic), the compound is:

[0036] This article also discloses In some embodiments, the crystalline form has an X-ray powder diffraction (XRPD) pattern similar to Figure 4In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises characteristic peaks at about 6.1°±0.1°2θ, about 9.9°±0.1°2θ, and about 16.0°±0.1°2θ. In some embodiments, the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 19.3°±0.1°2θ, about 6.8°±0.1°2θ, and about 17.9°±0.1°2θ. In some embodiments, the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 14.3°±0.1°2θ and about 21.2°±0.1°2θ. In some embodiments, the DSC thermogram of the crystalline form is Figure 6 In some embodiments, the DSC thermogram of the crystalline form has a broad endotherm starting at about 112.8°C. In some embodiments, the crystalline form 1 H spectrum and Figure 1A In some embodiments, the crystalline form of 13 C spectrum and Figure 1B In some embodiments, the FT-IR spectrum of the crystalline form is substantially the same as that of Figure 2 In some embodiments, the Raman spectrum of the crystalline form is substantially the same as that of Figure 3 Basically the same as shown.

[0037] In some embodiments, the crystalline form has an X-ray powder diffraction (XRPD) pattern similar to Fig.10 In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises characteristic peaks at about 9.3°±0.1°2θ, about 12.9°±0.1°2θ, and about 21.5°±0.1°2θ. In some embodiments, the X-ray powder diffraction (XRPD) pattern further comprises characteristic peaks at about 8.8°±0.1°2θ, about 14.6°±0.1°2θ, and about 17.3°±0.1°2θ. In some embodiments, the DSC thermogram of the crystalline form is Fig.11 In some embodiments, the DSC thermogram of the crystalline form has a broad endotherm starting at about 116.9°C. In some embodiments, the FT-Raman spectrum of the crystalline form is substantially the same as shown in Fig. 9A Basically the same as shown.

[0038] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is a penicillin, a cephalosporin, a carbapenem, a monobactam, or a combination thereof.

[0039] Also disclosed herein is a method of treating a bacterial infection in a subject, comprising administering to the subject a compound disclosed herein in combination with a therapeutically effective amount of a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is ceftibuten or a salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1A Compound 1-ethanolate Form A (in CD2Cl2) is shown 1 H NMR spectrum.

[0041] Figure 1B Compound 1-ethanolate Form A (in CD2Cl2) is shown 13 C NMR spectrum.

[0042] Figure 2 The FT-IR spectrum of Compound 1-ethanolate Form A is shown.

[0043] Figure 3 The FT-Raman spectrum of Compound 1-ethanolate Form A is shown.

[0044] Figure 4 An XRPD pattern of Compound 1-ethanolate Form A is shown.

[0045] Figure 5 An indexing scheme for Compound 1-ethanolate Form A using Cu-Kα radiation is shown.

[0046] Figure 6 The DSC thermogram of Compound 1-ethanolate Form A is shown.

[0047] Figure 7 DVS analysis (wt % vs. relative humidity) of Compound 1-ethanolate Form A is shown.

[0048] Figure 8 An overlay of FT-IR spectra of Compound 1-ethanolate forms is shown. Top: Form B; Bottom: Form A.

[0049] Fig. 9A The FT-Raman spectrum of Compound 1-ethanolate Form B is shown.

[0050] Fig. 9B An overlay of the Raman spectra of Compound 1-ethanolate forms is shown. Top: Form B; Bottom: Form A.

[0051] Fig.10 An indexing scheme for Compound 1-ethanolate Form B using Cu-Kα radiation is shown.

[0052] Fig.11 The DSC thermogram of Compound 1-ethanolate Form B is shown.

[0053] Fig.12 DVS analysis (wt % vs. relative humidity) of Compound 1-ethanolate Form B is shown.

[0054] Fig.13 The X-ray structure of compound 1-methoxide is shown.

[0055] Fig.14A Shown is an optical microscopy image of Compound 1-ethanolate Form A recorded without the use of crossed polarizers. The sample clearly has a needle-like morphology.

[0056] Fig. 14B Shown is an optical microscopy image recorded using crossed polarizers of Compound 1-ethanolate Form A. The sample clearly has a needle-like morphology.

[0057] Fig.15A Shown is an optical microscopy image of Compound 1-ethanolate Form B recorded without the use of crossed polarizers. The sample generally has a plate-like morphology.

[0058] Fig. 15B Shown are optical microscopy images recorded using crossed polarizers of Compound 1-ethanolate Form B. The samples generally had a flake-like morphology. DETAILED DESCRIPTION

[0059] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

[0060]

[0061]

[0062] in:

[0063] M is hydrogen, halogen, -CD3, -CF3, -CN, -OR 4 、-C(=O)R 4 、-C(=O)NR 4 R 5 、-SR 4 、-S(=O)R 4、-S(=O)2R 4 、-S(=O)2NR 4 R 5 、-NR 4 R 5 、-NR 4 C(=O)R 5 、-NR 4 C(=O)NR 4 R 5 、-NR 4 S(=O)2R 5 or alkynyl;

[0064] Each R 1 and R 2 are independently hydrogen, deuterium, halogen, -OR 4 、-SR 4 、-NR 4 R 5 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl or optionally substituted C1-C6 aminoalkyl;

[0065] or R 1 and R 2 together with the carbon to which they are attached form an optionally substituted cycloalkyl;

[0066] or when n is at least 2, two R 1 together to form a double bond;

[0067] or when n is at least 2, two R 1 and two R 2 Taken together to form a triple bond; n is 0, 1, 2, 3, 4, 5 or 6;

[0068] Each R is independently -COOR 3 , R a , R b or R c ;

[0069] m is 0, 1, 2, 3 or 4;

[0070] R 3 For R 31 、-(R 30 ) q OR 31 、-(R 30 ) q O(R 30 ) q OR 31 , -R 30 OC(O)R 31, -R 30 OC(O)OR 31 , -R 30 OC(O)NHR 31 or -R 30 OC(O)N(R 31 )2;

[0071] Each q is independently 2, 3, 4, 5 or 6;

[0072] Each R 30 are independently -CH2-, -CH(CH3)-, -C(CH3)2- or optionally substituted 1,1-cyclopropylene;

[0073] Each R 31 are independently optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 haloalkyl, optionally substituted C1-C 12 Hydroxyalkyl, optionally substituted C1-C 12 aminoalkyl, optionally substituted C1-C 12 Alkoxyalkyl, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C6 alkyl)cycloalkyl, optionally substituted (C1-C6 alkyl)heterocycloalkyl, optionally substituted (C1-C6 alkyl)aryl, or optionally substituted (C1-C6 alkyl)heteroaryl; or

[0074] Two R's 31 together with the nitrogen to which they are attached form a heterocycloalkyl group;

[0075] R a , R b and R c are independently hydrogen, deuterium, halogen, -OR 4 、-NR 4 R 5 、-SR 4 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0076] R d is hydrogen or optionally substituted C1-C6 alkyl;

[0077] R 4 and R 5are independently hydrogen, -OH, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0078] or R 4 and R 5 together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl; and

[0079] R 6 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C1-C6 deuterated alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C1-C6 alkyl)cycloalkyl, optionally substituted (C1-C6 alkyl)heterocycloalkyl, optionally substituted (C1-C6 alkyl)aryl or optionally substituted (C1-C6 alkyl)heteroaryl.

[0080] In some embodiments of compounds of formula (I), m is 1, 2, 3 or 4. In some embodiments of compounds of formula (I), m is 1, 2 or 3. In some embodiments of compounds of formula (I), m is 1 or 2.

[0081] In some embodiments of the compound of formula (I), the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0082]

[0083] In some embodiments of the compound of Formula (I) or (Ia), R a , R b and R c are independently hydrogen, halogen, -OR 4 、-NR 4 R 5 、-SR 4 or optionally substituted C1-C6 alkyl. In some embodiments of the compound of formula (I) or (Ia), R a , R b and R c is independently hydrogen, halogen, -OH or -OCH3. In some embodiments of the compound of Formula (I) or (Ia), R a , R b and R c For hydrogen.

[0084] In some embodiments of the compound of Formula (I) or (Ia), R d is hydrogen or C1-C4 alkyl. In some embodiments of the compound of formula (I) or (Ia), R d For hydrogen.

[0085] In some embodiments of compounds of Formula (I) or (Ia), n is 0, 1, 2, or 3. In some embodiments of compounds of Formula (I) or (Ia), n is 1 or 2. In some embodiments of compounds of Formula (I) or (Ia), n is 2. In some embodiments of compounds of Formula (I) or (Ia), n is 1.

[0086] In some embodiments of the compound of Formula (I) or (Ia), each R 1 and R 2 R is independently hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 haloalkyl. 1 and R 2 In some embodiments of the compound of Formula (I) or (Ia), each R 1 and R 2 For hydrogen.

[0087] In some embodiments of the compounds of Formula (I) or (Ia), M is hydrogen, halogen, -CF3, -CN, -OR 4 、-C(=O)R 4 、-SR 4 In some embodiments of the compound of Formula (I) or (Ia), M is hydrogen, -CN, -OR 4 、-C(=O)R 4 、-SR 4 In some embodiments of the compound of Formula (I) or (Ia), M is hydrogen, -CN, -C(=O)R 4 or alkynyl. In some embodiments of a compound of Formula (I) or (Ia), M is hydrogen. In some embodiments of a compound of Formula (I) or (Ia), M is hydrogen.

[0088] In some embodiments of the compound of formula (I) or (Ia), the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0089]

[0090] In some embodiments of compounds of Formula (I), (Ia) or (Ib), R 3 For R 31In some embodiments of the compounds of Formula (I), (Ia) or (Ib), R 3 For-R 30 OC(O)R 31 or -R 30 OC(O)OR 31 In some embodiments of the compounds of Formula (I), (Ia) or (Ib), R 3 For-R 30 OC(O)R 31 .

[0091] In some embodiments of compounds of Formula (I), (Ia) or (Ib), R 30 In some embodiments of the compounds of Formula (I), (Ia) or (Ib), R 30 are independently -CH2-.

[0092] In some embodiments of compounds of Formula (I), (Ia) or (Ib), each R 31 are independently optionally substituted C1-C 12 In some embodiments of compounds of Formula (I), (Ia) or (Ib), each R 31 are independently optionally substituted C1-C 12 In some embodiments of compounds of Formula (I), (Ia) or (Ib), each R 31 Independently C1-C 12 In some embodiments of compounds of Formula (I), (Ia) or (Ib), each R 31 Independently In some embodiments of compounds of Formula (I), (Ia) or (Ib), each R 31 for

[0093] In some embodiments of the compound of Formula (I), (Ia) or (Ib), the compound is a compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0094]

[0095] In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, (C1-C6 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl or (C1-C6 alkyl)heteroaryl; each of which is optionally substituted with deuterium, halogen, -OH, -OMe, -COMe, -COOH, -COOMe, NH2, -NHMe, NMe2, cycloalkyl or heterocycloalkyl.

[0096] In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6 is an optionally substituted C1-C6 alkyl group, an optionally substituted cycloalkyl group or an optionally substituted heterocycloalkyl group.

[0097] In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6 is a C1-C6 alkyl group optionally substituted with deuterium, halogen, -OH, -OMe, -COOH, -COOMe, NH2, -NHMe or NMe2. In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6 It is a C1-C6 alkyl group which is optionally substituted with -OH.

[0098] In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6 is a cycloalkyl group optionally substituted with deuterium, halogen, -OH, -OMe, -COOH, -COOMe, NH2, -NHMe, NMe2, -CH2OH or -CH2OMe. In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6 is cycloalkyl optionally substituted by halogen, -OH or -CH2OH.

[0099] In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6 In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6 is methyl, ethyl, propyl or butyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), R 6 In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R 6 In some embodiments of the compounds of Formula (I), (Ia), (Ib) or (Ic), R6 It is polyethylene glycol.

[0100] In some embodiments of the compound of formula (I) or (Ia), the compound is a compound of formula (Id), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0101]

[0102] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (Id), the compound is or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic) or (Id), the compound is or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (Id), the compound is:

[0103]

[0104] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (Id), the compound is or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic) or (Id), the compound is or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (Id), the compound is:

[0105]

[0106] Compound 1

[0107] Also disclosed herein is ((2-ethylbutanoyl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate:

[0108] In some embodiments, ((2-ethylbutanoyl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate is also referred to as Compound 1. In some embodiments, Compound 1 exists in an equilibrium state as shown below:

[0109] In some embodiments, Compound 1 exists in equilibrium between a "closed" cyclic form (as shown above) and an "open" acyclic form: ((R)-(2-(3-((((2-ethylbutanoyl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propionamidoethyl)boronic acid). In some embodiments, Compound 1 associates as an intramolecular dimer, trimer, and any combination thereof. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable solvate. Generally, for the compounds and methods provided herein, the solvated forms are considered equivalent to the unsolvated forms. In some embodiments, Compound 1 is in the form of pharmaceutically acceptable salts and solvates.

[0110] Compound 1-ethanolate

[0111] In some embodiments, Compound 1 exists as a covalently bound solvate in solid form. In some embodiments, Compound 1 exists as a covalently bound ethanolate in solid form. In some embodiments, the solid form of Compound 1 is ((2-ethylbutyryl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate: In some embodiments, Compound 1-ethanolate exists in an equilibrium state as shown below:

[0112] In some embodiments, Compound 1-ethanolate is converted to Compound 1 upon contact with water:

[0113]

[0114] Compound 1-methanolate

[0115] In some embodiments, Compound 1 exists as a covalently bound solvate in solid form. In some embodiments, Compound 1 exists as a covalently bound methanolate in solid form. In some embodiments, the solid form of Compound 1 is ((2-ethylbutyryl)oxy)methyl (R)-2-methoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate: In some embodiments, Compound 1-methoxide exists in an equilibrium state as shown below:

[0116] In some embodiments, Compound 1-methanolate is converted to Compound 1 upon contact with water:

[0117]

[0118] Polymorphic form

[0119] Disclosed herein are ((2-ethylbutyryl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate, pharmaceutically acceptable salts, solvates, or crystalline forms of pharmaceutically acceptable salts and solvates thereof. In some embodiments, disclosed herein are crystalline forms of ((2-ethylbutyryl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate.

[0120] Also described herein are methods for preparing crystalline polymorph Forms A and B.

[0121] Polymorph Form A

[0122] The term "polymorph Form A" or "Form A" refers to a crystalline form of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate that exhibits Figure 4 substantially the same X-ray powder diffraction pattern as shown and / or Figure 6 In some embodiments, the polymorph of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate is characterized by Figure 4 In some embodiments, the main peak is Figure 4 A peak that has at least 20%, at least 15%, or at least 10% of the maximum intensity in the XRPD pattern of the present invention.

[0123] In one embodiment, ((2-ethylbutyryl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate polymorph Form A exhibits an X-ray powder diffraction pattern characterized by the diffraction patterns summarized in Table 1. In some embodiments, ((2-ethylbutyryl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate polymorph Form A comprises at least 3 peaks of Table 1 (±0.1° 2θ). In certain embodiments, polymorph Form A of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate comprises at least 4 peaks of (±0.1°2θ) of Table 1, at least 5 peaks of (±0.1°2θ) of Table 1, at least 6 peaks of (±0.1°2θ) of Table 1, at least 7 peaks of (±0.1°2θ) of Table 1, at least 8 peaks of (±0.1°2θ) of Table 1, or at least 9 peaks of (±0.1°2θ) of Table 1.

[0124] Polymorph Form A crystallizes as needles ( Fig.14A and Fig. 14B ), and is thermodynamically stable. In some embodiments, polymorph Form A is more thermodynamically stable than polymorph Form B. In some embodiments, polymorph Form A has a lower density than polymorph Form B. In some embodiments, the less dense polymorph form is preferred for formulation purposes.

[0125] Table 1. Form A Characteristic XRPD Signals (2θ, Cu)

[0126] Angle 2-θ° Intensity, normalized d-value, angstrom 3.95 2.7 22.3567 5.14 100.0 17.1938 6.11 71.8 14.4653 6.81 14.9 12.9761 9.00 4.3 9.8237 9.58 5.0 9.2208 9.89 17.4 8.9401 12.23 10.9 7.2318 12.35 13.8 7.1636 12.66 28.7 6.9892 13.62 8.8 6.4982 14.29 11.4 6.1922 15.52 13.8 5.7067 15.78 63.0 5.6111 16.02 16.7 5.5281 16.33 8.9 5.4233 16.51 4.8 5.3641 17.14 19.4 5.1686 17.87 12.3 4.9588 18.10 6.5 4.8967 19.34 16.0 4.5865 19.84 7.2 4.4706 20.59 33.8 4.3105 21.19 10.8 4.1890 21.91 18.0 4.0542 22.14 9.3 4.0127 22.52 10.6 3.9458

[0127] In certain embodiments, polymorph Form A of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate comprises characteristic peaks at about 5.1°±0.1°2θ, about 6.1°±0.1°2θ, and about 15.8°±0.1°2θ.

[0128] In certain embodiments, polymorph Form A of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate further comprises characteristic peaks at about 12.7°±0.1°2θ, about 17.1°±0.1°2θ, and about 20.6°±0.1°2θ.

[0129] In certain embodiments, polymorph Form A of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate comprises characteristic peaks at about 6.1°±0.1°2θ, about 9.9°±0.1°2θ, and about 16.0°±0.1°2θ.

[0130] In certain embodiments, polymorph Form A of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate further comprises characteristic peaks at about 19.3°±0.1°2θ, about 6.8°±0.1°2θ, and about 17.9°±0.1°2θ.

[0131] In certain embodiments, polymorph Form A of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate further comprises characteristic peaks at about 14.3°±0.1°2θ and about 21.2°±0.1°2θ.

[0132] In certain embodiments, polymorph Form A of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][l,2]oxaborin-8-carboxylate has a broad endotherm with an onset at about 112.8 °C.

[0133] Polymorph Form B

[0134] The term "polymorph Form B" or "Form B" refers to a crystalline form of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate that exhibits Fig.10 substantially the same X-ray powder diffraction pattern as shown and / or Fig.11 Essentially the same DSC thermogram is shown.

[0135] In one embodiment, ((2-ethylbutyryl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate polymorph Form B exhibits an X-ray powder diffraction pattern characterized by the diffraction patterns summarized in Table 2. In some embodiments, ((2-ethylbutyryl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate polymorph Form B comprises at least 3 peaks of Table 2 (±0.1° 2θ). In certain embodiments, polymorph Form B of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate comprises at least 4 peaks of (±0.1°2θ) of Table 2, at least 5 peaks of (±0.1°2θ) of Table 2, at least 6 peaks of (±0.1°2θ) of Table 2, at least 7 peaks of (±0.1°2θ) of Table 2, at least 8 peaks of (±0.1°2θ) of Table 2, or at least 9 peaks of (±0.1°2θ) of Table 2.

[0136] Polymorph Form B crystallizes as large platelets ( Fig.15A and Fig. 15B ). In some embodiments, large flakes are easier to handle and purify.

[0137] Table 2. Form B characteristic XRPD signals (2θ, Cu Kα1)

[0138] Angle 2-θ° Intensity, normalized d-value, angstrom 5.10 100.0 17.3010 8.80 10.5 10.0414 9.29 20.8 9.5172 12.02 11.1 7.3557 12.35 13.6 7.1589 12.86 21.6 6.8783 14.60 10.5 6.0637 15.06 5.4 5.8780 15.34 7.0 5.7702 15.56 39.5 5.6923 16.76 4.1 5.2858 17.33 15.0 5.1121 18.48 5.2 4.7966 18.64 7.4 4.7565 19.92 12.2 4.4536 20.25 3.2 4.3819 20.50 21.4 4.3280 20.92 4.0 4.2429 21.54 17.4 4.1222 21.97 5.8 4.0429 22.31 7.9 3.9810 23.49 5.0 3.7846 24.60 6.5 3.6166 27.84 4.5 3.2016

[0139] In certain embodiments, polymorph Form B of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate comprises characteristic peaks at about 5.1°±0.1°2θ, about 12.9°±0.1°2θ, and about 15.6°±0.1°2θ.

[0140] In certain embodiments, polymorph Form B of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate further comprises characteristic peaks at about 9.3°±0.1°2θ, about 20.5°±0.1°2θ, and about 21.5°±0.1°2θ.

[0141] In certain embodiments, polymorph Form B of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate comprises characteristic peaks at about 9.3°±0.1°2θ, about 12.9°±0.1°2θ, and about 21.5°±0.1°2θ.

[0142] In certain embodiments, polymorph Form B of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate further comprises characteristic peaks at about 8.8°±0.1°2θ, about 14.6°±0.1°2θ, and about 17.3°±0.1°2θ.

[0143] Treatment

[0144] The present disclosure also provides a method for inhibiting bacterial growth by, for example, reducing bacterial resistance to β-lactam antibiotics, such methods comprising contacting a bacterial cell culture or a bacterially infected cell culture, tissue or organism with a compound 1-ethanolate, a pharmaceutically acceptable salt thereof, a solvate, or a pharmaceutically acceptable salt and solvate thereof. In some embodiments, the bacteria to be inhibited by administering a compound 1-ethanolate, a pharmaceutically acceptable salt thereof, a solvate, or a pharmaceutically acceptable salt and solvate thereof are bacteria resistant to β-lactam antibiotics. The term "resistant" is fully understood by those of ordinary skill in the art (see, for example, Payne et al., Antimicrobial Agents and Chemotherapy 38 767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 30 1120-1126 (1995)).

[0145] These methods can be used to inhibit bacterial growth in a variety of situations. In certain embodiments, compound 1-ethanolate, its pharmaceutically acceptable salt, solvate, or pharmaceutically acceptable salt and solvate are applied to experimental cell cultures in vitro to prevent the growth of β-lactam-resistant bacteria. In certain other embodiments, compound 1-ethanolate, its pharmaceutically acceptable salt, solvate, or pharmaceutically acceptable salt and solvate are applied to mammals, including humans, to prevent the growth of β-lactam-resistant bacteria in vivo. The method according to this embodiment includes administering a therapeutically effective amount of a β-lactamase inhibitor to mammals, including humans, for a period of time that is effective for treatment. Preferably, the β-lactamase inhibitor is administered in the form of a pharmaceutical composition as described above. In some embodiments, an antibiotic is co-administered with a β-lactamase inhibitor. In some embodiments, the antibiotic is a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is ceftibuten or a salt thereof. In some embodiments, the β-lactam antibiotic is cefixime or a salt thereof.

[0146] On the other hand, provided herein is a method for treating a bacterial infection, the method comprising administering to a subject a pharmaceutical composition comprising a compound 1-ethanolate, a pharmaceutically acceptable salt, a solvate, or a pharmaceutically acceptable salt and solvate thereof as described above, and a pharmaceutically acceptable excipient. In some embodiments, the bacterial infection is an upper respiratory tract infection or a lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection.

[0147] In some embodiments, the infection being treated or prevented comprises a bacterium comprising Elizabethkingiameningoseptica, Pseudomonas aeruginosa, Pseudomonasfluorescens, Pseudomonas acidovorans, Pseudomonas alkaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi. paratyphi), Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticushaemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides gibbsii, distasonis), Bacteroides 3452A homologous group, Bacteroides vulgarisvulgatus), Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

[0148] In some embodiments, the infection being treated or prevented comprises a bacterium comprising Elizabethkingiameningoseptica, Pseudomonas aeruginosa, Pseudomonasfluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, cloacae), Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersiniapseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori pylori), Campylobacter fetus, Campylobacter jejuni, Campylobacter colicoli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus.

[0149] Some definitions

[0150] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Certain preferred methods, devices and materials are now described, but any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the embodiments described herein.

[0151] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" refers to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

[0152] The term "about" is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value.

[0153] The term "or" used in the claims is intended to mean "and / or" unless explicitly stated to refer to only alternatives or the alternatives are mutually exclusive, but the present disclosure supports a definition referring to only alternatives and "and / or."

[0154] The terms "comprising," "having," and "including" are open-ended linking verbs. Any form or tense of one or more of these verbs is also open-ended. For example, any method that "comprising," "having," or "includes" one or more steps is not limited to having only the one or more steps, but also encompasses other unlisted steps.

[0155] “Optional” or “optionally” may mean that the subsequently described structure, event, or circumstance may or may not occur, and that the description includes instances where said event occurs and instances where said event does not occur.

[0156] As used in this specification and the appended claims, the following terms have the meanings set forth below unless indicated otherwise.

[0157] "Fat chain" refers to a straight chain chemical moiety consisting only of carbon and hydrogen. In some embodiments, the fat chain is saturated. In some embodiments, the fat chain is unsaturated. In some embodiments, the unsaturated fat chain contains one degree of unsaturation. In some embodiments, the unsaturated fat chain contains more than one degree of unsaturation. In some embodiments, the unsaturated fat chain contains two degrees of unsaturation. In some embodiments, the unsaturated fat chain contains one double bond. In some embodiments, the unsaturated fat chain contains two double bonds.

[0158] "Alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monovalent group having 1 to about 10 carbon atoms, or 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Whenever a numerical range such as "C1-C6 alkyl" appears herein, it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the definition also covers the term "alkyl" that appears without specifying a numerical range. In some embodiments, the alkyl group is C1-C6. 10In some embodiments, the alkyl group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkyl group is optionally substituted with oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkyl group is optionally substituted with halogen.

[0159] "Alkenyl" refers to an optionally substituted straight chain or optionally substituted branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group can be in cis or trans conformation around the double bond, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this article, a numerical range such as "C2-C6 alkenyl" means that the alkenyl can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the definition also covers the term "alkenyl" that appears without specifying a numerical range. In some embodiments, the alkenyl is C2-C6. 10 Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl or C2 alkenyl.Unless specifically indicated in this specification, alkenyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2.In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe.In some embodiments, the alkenyl is optionally substituted by halogen.

[0160] "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears in this article, a numerical range such as "C2-C6 alkynyl" means that the alkynyl can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also covers the term "alkynyl" that appears without specifying a numerical range. In some embodiments, the alkynyl is C2-C6. 10 Alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl or C2 alkynyl.Unless specifically indicated in this specification, alkynyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2.In some embodiments, alkynyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe.In some embodiments, alkynyl is optionally substituted by halogen.

[0161] "Alkylene" refers to a divalent hydrocarbon chain of a straight or branched chain. Unless specifically indicated otherwise in this specification, alkylene may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkylene is optionally substituted by halogen.

[0162] "Alkoxy" refers to a group of the formula -OR a A group in which R a For alkyl groups as defined above. Unless specifically indicated in addition in this specification, alkoxy can be optionally replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, alkoxy is optionally replaced by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkoxy is optionally replaced by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkoxy is optionally replaced by halogen.

[0163] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0164] "Aryl" refers to a group derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through aromatic ring atoms) or bridged ring system. In some embodiments, the aryl is a 6 to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl groups include, but are not limited to, anthracene, naphthyl, phenanthrenyl, anthracene, azulene, benzene, Fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenanthene, phenanthren, pyrene, pyrene and triphenylene hydrocarbon ring system derived aryl group. In some embodiments, the aryl is phenyl. Unless specifically indicated otherwise in this specification, aryl can be optionally substituted by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the aryl is optionally substituted by halogen.

[0165] "Cycloalkyl" refers to a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include a fused ring (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), a bridged ring, or a spirocyclic ring system. Representative cycloalkyl groups include, but are not limited to, groups having 3 to 15 carbon atoms (C3-C 15 cycloalkyl), 3 to 10 carbon atoms (C3-C 10In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic rings include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane and bicyclo [3.3.2] decane and 7,7-dimethyl-bicyclo [2.2.1] heptane. Partially saturated cycloalkyl includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless specifically indicated otherwise in this specification, cycloalkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the cycloalkyl is optionally substituted by halogen.

[0166] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five or six deuteriums. Deuterated alkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D or CH2CHD2. In some embodiments, the deuterated alkyl is CD3.

[0167] "Haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. In some embodiments, the haloalkyl is trifluoromethyl.

[0168] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0169] "Assorted alkyl" refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon, for example, oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulfur or a combination thereof. Assorted alkyl is connected to the remainder of the molecule at the carbon atom of the assorted alkyl group. On the one hand, assorted alkyl is a C1-C6 assorted alkyl group, in which the assorted alkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, for example, oxygen, nitrogen (e.g., -NH-, -N (alkyl)-), sulfur or a combination thereof, in which the assorted alkyl group is connected to the remainder of the molecule at the carbon atom of the assorted alkyl group. The example of such assorted alkyl group is, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3 or -CH(CH3)OCH3. Unless specifically indicated otherwise in this specification, assorted alkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0170] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0171] "Heterocycloalkyl" refers to a stable 3-24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur. Unless otherwise specifically indicated in this specification, the heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded by a non-aromatic ring atom) or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, 2 to 15 carbon atoms (C2-C 15 Heterocycloalkyl), 2 to 10 carbon atoms (C2-C 10In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuran ... The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) (i.e., the backbone atoms of the heterocycloalkyl ring) constituting the heterocycloalkyl. Unless specifically indicated otherwise in this specification, heterocycloalkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted by halogen.

[0172] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. Examples include, but are not limited to, aza benzo[b][1,4]dioxazolyl, benzo[b][1,4]dioxazolyl, benzo[b][1,4]benzo[ ... 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolanyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl or benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine substituted with halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heteroaryl is optionally substituted by halogen.

[0173] As used herein, the term "therapeutic agent" refers to an agent used to treat, combat, alleviate, prevent or ameliorate an undesirable condition or disease in a patient.

[0174] When used in conjunction with treatment, "administering" refers to administering a therapeutic agent systemically or locally, such as directly into or onto a target tissue, or administering a therapeutic agent to a patient, whereby the therapeutic agent actively affects the tissue to which it is directed. "Administering" a pharmaceutical composition can be accomplished by injection, topical administration, oral administration, or by other methods alone or in combination with other known techniques.

[0175] The term "animal" as used herein includes, but is not limited to, human and non-human vertebrates, such as wild, domestic and farm animals. As used herein, the terms "patient," "subject," and "individual" are intended to include living organisms in which certain conditions as described herein may occur. Examples include humans, monkeys, cattle, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In preferred embodiments, the patient is a primate. In certain embodiments, the primate or subject is a human. In some cases, the human is an adult. In some cases, the human is a child. In further cases, the human is 12 years old or less. In some cases, the human is an elderly person. In other cases, the human is 60 years old or more. Other examples of subjects include experimental animals, such as mice, rats, dogs, cats, goats, sheep, pigs, and cattle.

[0176] By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0177] The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, such as Compound 1-ethanolate, whereby the composition is suitable for studying a specific effective outcome in a mammal, such as, but not limited to, a human. One of ordinary skill in the art will understand and know the techniques suitable for determining whether an active ingredient has a desired effective outcome based on the needs of the technician.

[0178] As used herein, "therapeutically effective amount" or "effective amount" refers to the amount of an active compound or agent that elicits the biological or medical response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which response includes one or more of the following: (1) preventing disease; for example, preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but does not yet experience or display the pathology or symptoms of the disease, (2) inhibiting disease; for example, inhibiting the disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptoms of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptoms), and (3) ameliorating disease; for example, ameliorating the disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptoms of the disease, condition or disorder (i.e., reversing the pathology and / or symptoms).

[0179] As used herein, the terms "treatment" or "treatment" refer to therapeutic treatment in some embodiments, and to prophylactic or preventive measures in other embodiments, wherein the purpose is to prevent or slow down (mitigate) an undesirable physiological condition, disorder or disease, or to obtain a beneficial or desired clinical result. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, relief of symptoms; reduction in the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the condition, disorder or disease state; delayed onset or slowed progression of the condition, disorder or disease; improvement of the condition, disorder or disease state; and detectable or undetectable relief (partial or complete) or enhancement or improvement of the condition, disorder or disease. Treatment includes inducing a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival without treatment. The preventive benefits of treatment include preventing a condition, delaying the progression of a condition, stabilizing a condition, or reducing the likelihood of a condition occurring. As used herein, "treatment" or "treatment" includes prevention in some embodiments.

[0180] As used herein, the term "substantially the same as" refers to a powder X-ray diffraction pattern or a differential scanning calorimetry pattern that is not exactly the same as depicted herein, but is within the limits of experimental error when considered by one of ordinary skill in the art.

[0181] Example

[0182] Analytical methods

[0183] High Resolution Mass Spectrometry (HRMS)

[0184] Using electrospray ionization source, collect high resolution mass spectra of 50 to 3000Da with Bruker Maxis-Plus QTOF mass spectrometer.Use Bruker Compass v.4.4 software to control instrument and analyze data.Mass spectrometer is calibrated before analysis, and uses electrospray ionization (ESI) source to operate in positive ionization mode.Prepare sample by diluting in absolute ethanol (does not contain denaturant) or HPLC grade water, inject directly into ion source afterwards.

[0185] Raman spectroscopy

[0186] Raman spectra were acquired on a Bruker MultiRAM using OPUS 7.0 software. Samples were measured using a truncated NMR tube filled in a glove box filled with N2 at approximately 0% RH. The samples were irradiated with 300 mW laser power from a Nd:YAG laser (1064 nm excitation wavelength). Each spectrum represents a 2 cm -1 64 co-added scans collected at spectral resolution. FT-IR spectroscopy (FT-IR)

[0187] Infrared spectra were acquired using a Nicolet 6700 Fourier transform infrared (FT-IR) spectrophotometer (ThermoNicolet) equipped with an Ever-Glo mid / far infrared source, an extended range potassium bromide (KBr) beam splitter, and a deuterated triglycine sulfate (DTGS) detector. Wavelength verification was performed using NIST SRM1921b (polystyrene). An attenuated total reflectance (ATR) accessory (Thunderdome TM , Thermo Spectra-Tech) for data acquisition. Each sample was directly placed on a clean Ge crystal for analysis. Each spectrum represents a 4 cm -1 256 co-added scans were collected with a spectral resolution of 1.5 Å. The background data set was acquired using a clean Ge crystal.

[0188] X-ray powder diffraction

[0189] XRPD patterns were collected under two conditions. The PANalytical X'Pert PRO MPD diffractometer used an incident beam of Cu Kα radiation, which was produced using a long, fine focus source and a nickel filter. Cu Kα X-rays were focused through the specimen and onto the detector using an elliptical gradient multilayer mirror. Data were collected and analyzed using Data Collector software v.2.2b. Prior to analysis, silicon specimens (NIST SRM 640e) were analyzed to verify that the observed Si 111 peak positions were consistent with those certified by NIST. The sample specimens were sandwiched between 3-μm thick films and analyzed in transmission geometry. Anti-scatter slits (SS) were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize the broadening of divergence from the axial direction. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) 240 mm from the sample and DataCollector software v.2.2b. The data acquisition parameters for each pattern are displayed above the image in the data section of this report, including the divergence slit (DS).

[0190] The second method used a Bruker D8 Advance with Cu Kα radiation at 40 kV / 40 mA. Data were collected with a LynxEye detector in Bragg-Brentano reflection geometry with a step size of 0.02 0 2q, step time 37 seconds, range 2.5-50 0 2q. The powder samples were measured in a 0.05 mm deep silicon single crystal sample holder covered with Kapton foil to prevent moisture. The samples were placed in an inert atmosphere environment (N2-filled glove box), but no other special treatment was used in preparing the samples except applying slight pressure to obtain a flat surface. All samples were rotated during the measurement.

[0191] Indexing

[0192] XRPD patterns were indexed using TRIADS3. Indexing and structural refinement are computational studies. The consistency between the allowed peak positions (marked with red bars) and the observed peaks indicates consistent unit cell determination. The successful indexing of the pattern indicates that the sample is mainly composed of a single crystalline phase. Space groups consistent with the specified extinction symbol, unit cell parameters and derived quantities are listed below each figure showing a tentative indexing scheme. In order to confirm the tentative indexing scheme, the molecular packing motif within the crystal unit cell must be determined. No attempt at molecular packing was performed.

[0193] Polarized Light Microscopy (PLM)

[0194] Polarized light microscopy was performed using a Leica MZ12.5 or Fisher Scientific Stereomaster stereo microscope. Samples were observed using a 0.8-10x objective with crossed polarizers.

[0195] Differential Scanning Calorimetry (DSC) Analysis

[0196] DSC is performed using a TAInstruments 2920 or Q2000 differential scanning calorimeter equipped with a refrigerated cooling system (RCS). Temperature calibration is performed using NIST traceable indium metal. The sample is placed in an aluminum DSC pan, the lid is closed, and the weight is accurately recorded. A weighed aluminum pan configured as a sample pan is placed on the reference side of the cell. The data acquisition parameters and pan configuration for each thermogram are captured for each analysis. The method code on the thermogram is an abbreviation for the starting and ending temperatures and the heating rate; for example, -30-250-10 means "from -30°C to 250°C at a rate of 10°C / min."

[0197] Dynamic Vapor Sorption (DVS) Analysis

[0198] Water adsorption / desorption data were collected on a VTI SGA-100 Vapor Sorption Analyzer. NaCl and PVP were used as calibration standards. Samples were not dried prior to analysis. Adsorption and desorption data were collected over a 5% to 95% RH range in 10% RH increments under a nitrogen purge (RH = relative humidity). The equilibrium standard used for the analysis was a weight change of less than 0.0100% in 5 minutes with a maximum equilibrium time of 3 hours. The data were not corrected for the initial water content of the samples.

[0199] The second set of DVS experiments was performed using a step method from 0% RH to 60% RH with a step size of 10% RH and equilibrated for four hours at each humidity value. These data were collected on Project Messtechnik (now ProUmid) SPS11-100n. The sample was placed on an aluminum stand and allowed to equilibrate at 0% RH, after which the following predefined humidity program was started: keep at 0% RH for 4 hours, increase the humidity in steps of 10% RH, keep for 4 hours, repeat the above two steps five times until a value of 60% RH was reached. The crystallinity of the sample was then analyzed using a second set of XRPD conditions.

[0200] Hot Stage Microscopy (HSM)

[0201] Use the SPOT Insight TMHot stage microscopy was performed on a Linkam hot stage (FTIR 600) on a Leica DM LP microscope with a color digital camera. Temperature calibration was performed using USP melting point standards. The samples were placed on a cover glass and a second cover glass was placed on top of the samples. While the stage was heated, each sample was visually observed using a 20x objective with crossed polarizers and a first-order red compensator. Images were captured using SPOT software (v.4.5.9).

[0202] Thermogravimetric analysis (TGA)

[0203] TGA was performed using a TA Instruments Q5000 IR thermogravimetric analyzer. Nickel and Alumel TM Perform temperature calibration. Place sample in aluminum pan. Seal sample, pierce lid, and insert into TG furnace. TG furnace is heated under nitrogen. Data acquisition parameters for each thermogram are shown in the data image. The method code on the thermogram is an abbreviation for the start and end temperatures and the heating rate; for example, 00-350-10 means "from ambient to 350°C at a rate of 10°C / min".

[0204] Example 1: Preparation and characterization of Form A of ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate (Compound 1-ethanolate).

[0205]

[0206] A solution of ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate (Compound 1) in 18 volumes of cyclopentyl methyl ether (CPME) was distilled under vacuum until the volume was reduced to 7.5 volumes while maintaining the temperature below ≤ 65°C. A Karl Fischer titration was performed to ensure that the level of residual water was reduced to a value below 5000 ppm. The solution was diluted to 17 volumes with additional CPME and then 6 volumes of ethanol were added. The solution was distilled under vacuum until a volume of approximately 7.5 volumes was reached. The composition of the solution was checked to ensure that the level of residual water was below 1000 ppm according to KF and that the ethanol content was measured using 1H NMR spectroscopy determined to be 6-11% by volume. The temperature was raised to 55±5°C in 43 minutes, and methylcyclohexane (22.5 times by volume) was added in 50 minutes while maintaining the temperature at 55±5°C. The temperature was adjusted to 45±5°C, and 0.15% by weight of ((2-ethylbutyryl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate seed crystals Form A were added to the mixture. Solid formation was observed after the addition of the seed crystals. The slurry was stirred at 45±5°C for about 4 hours, then cooled to 20±5°C in about 2.5 hours, and stirred for another 11 hours at 20±5°C. The product was isolated by filtration under nitrogen. The solid was washed with methylcyclohexane (7 times by volume) over a period of about 7 hours. The resulting wet cake was vacuum dried at 30°C for about 68 hours to constant weight. The above process provided ((2-ethylbutanoyl)oxy)methyl (R)-2-ethoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate Form A at 79% with a purity of 99.7 AUC% according to UHPLC.

[0207] Elemental analysis

[0208] Elemental analysis (Intertek USA, Inc. QTI Whitehouse Station, NJ, USA) was performed on Compound 1-ethanolate Form A. Carbon, hydrogen, and nitrogen were determined by an elemental analyzer (Perkin-Elmer 2400 Elemental Analyzer), and the data are presented in Table 3.

[0209] Table 3. Elemental Analysis of Compound 1-Ethanolate Form A

[0210] element %theory % Measured boron 2.65 2.86 carbon 60.16 59.62 hydrogen 7.21 7.20 nitrogen 3.34 3.31

[0211] Mass spectrometry

[0212] The mass spectrum of Compound 1-ethanolate Form A was obtained using a Waters Q-Tof (quadrupole time-of-flight hybrid) micromass mass spectrometer operating in electrospray ionization (ESI) positive ion polarity mode. The sample was prepared in anhydrous ethanol at a concentration of approximately 2 μg / mL and injected directly into the mass spectrometer source, and the adjustment parameters were optimized for this compound.

[0213] Mass spectrometry includes [M+Na] + The peak at m / z 442.21 and for [2M+Na] + The peak at m / z 861.43 is consistent with the proposed molecular formula C 21 H 30The monoisotopic mass of BNO7 is consistent. The molecular weight of compound 1-ethanolate form A is 419.28 Da, and the accurate mass is 419.21 Da.

[0214] Nuclear Magnetic Resonance (NMR) Spectroscopy

[0215] Compound 1-ethanolate Form A was dissolved in 99.8% dichloromethane-d2 (CD2Cl2, 0.8 mL) containing 0.05% (v / v) tetramethylsilane (TMS) as solvent. To minimize moisture exposure, samples were prepared under a dry N2 environment. All NMR data were collected at 300K on a Bruker Biospin AVANCE 500MHz NMR spectrometer using a Bruker-Biospin 5mm gradient broadband probe. 1D proton and carbon-13 spectra were acquired at 500MHz and 125MHz, respectively. The spectra used tetramethylsilane resonances as references, and for 1 H and 13 C was set equal to 0.0 ppm.

[0216] 1D proton spectrum ( Figure 1A ) shows the expected chemical shifts, multiplicities, and integrations consistent with the structure of Compound 1-ethanolate. However, due to the presence of residual water in the CD2Cl2 solvent and / or Compound 1-ethanolate Form A sample, and / or possible absorption of water from the environment, the product of the hydrolysis of Compound 1-ethanolate Form A, i.e., ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate and free (unbound) ethanol, are also observed as minor resonances. From the 1D carbon-13 spectrum ( Figure 1B ) The observed chemical shifts are consistent with the chemical structure described for compound 1-ethanolate. 1 H and 13 C resonance (due to the existence of amide bond rotamers).

[0217] Table 4: Compound 1-ethanolate Form A in CD2Cl2 1 H and 13 C NMR chemical shift assignments [300K].

[0218]

[0219]

[0220] bdt = broad doublet triplet, bs = broad singlet, d = doublet, dd = doublet of doublet, m = multiplet, t = triplet, ppm = parts per million.

[0221] # several 1 H and 13 The splitting of the C resonance is most likely due to the presence of rotamers and / or hydrolysis products. NA = Not Applicable. ￥ Assignment is interchangeable. Broad triplet peak pair (not fully resolved). *H11 and H15 overlap (3 protons in total). H12 and H17 overlap (9 protons in total). Δ H19 overlaps with the CH3 peak of free ethanol.

[0222] Infrared spectroscopy

[0223] Fourier transform-infrared absorption (FT-IR) spectra of Compound 1-ethanolate Form A were obtained using attenuated total reflectance (ATR) on a Thermo-Nicolet Avatar 370 spectrophotometer using pure material (see Figure 2 ). The FT-IR spectral band assignments are provided in Table 5. The results are consistent with the chemical structure of compound 1-ethanolate.

[0224] Table 5. Characteristic infrared absorption bands (wavenumbers) and corresponding assignments of Compound 1-ethanolate Form A.

[0225]

[0226] Raman spectroscopy

[0227] FT-IR and Raman spectra of Compound 1 Form A were collected (see Figure 3 ). The peaks are shown in the table below:

[0228] peak <![CDATA[Wavenumber (cm -1 )]]> peak <![CDATA[Wavenumber (cm -1 )]]> peak <![CDATA[Wave number (cm -1 )]]> 1 3075 11 1366 21 919 2 2969 12 1346 22 896 3 2936 13 1323 23 844 4 2879 14 1249 24 804 5 2836 15 1171 25 753 6 2745 16 1150 26 637 7 1743 17 1107 27 562 8 1589 18 1048 28 386 9 1457 19 1018 29 301 10 1429 20 944 30 216

[0229] UV-Vis spectroscopy

[0230] The UV absorption spectrum of Compound 1-ethanolate Form A was obtained on a PerkinElmer Lambda 25 UV-Vis spectrophotometer. A 0.01 mg / mL sample solution was prepared in methanol. Table 6 provides the spectral absorption maxima and extinction coefficients.

[0231] Table 6: UV absorption spectrum absorption maximum and extinction coefficient of Compound 1-ethanolate Form A.

[0232]

[0233] Example 2. Solubility studies of Compound 1-ethanolate Form A.

[0234] The visual solubility estimates of Compound 1-ethanolate Form A were determined in a variety of solvents and solvent mixtures using the equal portion addition method to aid in experimental design. Typically, Compound 1-ethanolate Form A exhibits good solubility in most test solvents. Low solubility (<1 mg / mL) was observed in heptane and cyclohexane. Solubility results are provided in Table 7.

[0235] Table 7: Estimated solubility of Compound 1 -ethanolate Form A at ambient temperature.

[0236]

[0237]

[0238] Unless otherwise specified, solvents were Dry over molecular sieves.

[0239] b. Solvent ratios are by volume.

[0240] c. Solubility is calculated based on the total solvent used to provide the solution; actual solubility may be greater due to the volume of the solvent portion used or a slow dissolution rate. Solubility is rounded to the nearest mg / mL.

[0241] Example 3. XRPD Characterization of Compound 1-Ethanolate Form A.

[0242] XRPD analysis indicated that Compound 1-ethanolate Form A from Example 1 consisted of crystalline material. Figure 4 An XRPD pattern of Compound 1-ethanolate Form A is shown. Figure 5 An indexing scheme for Compound 1-ethanolate Form A using Cu-Ka radiation is shown.

[0243] The XRPD pattern of Compound 1-ethanolate Form A was successfully indexed, indicating that the sample consisted primarily or exclusively of a single crystalline phase.

[0244]

[0245] Example 4. Thermal Analysis of Compound 1-Ethanolate Form A.

[0246] Thermal analysis of Compound 1-ethanolate Form A is shown in Figure 6 The DSC thermogram of Compound 1-ethanolate Form A exhibits a small broad feature consistent with a single endotherm starting at 112.8°C (peak maximum). This single endotherm is attributed to melting based on hot stage microscopy. Between 24.8 and 120°C, a 1.2% weight loss was observed in the TGA.

[0247] Hot stage microscopy of Compound 1-ethanolate Form A was performed. Upon heating the sample, no changes were observed until the onset of melting (i.e., 77.3° C.). Melting was complete at 106.5° C., and upon cooling, no recrystallization of the melted sample was observed.

[0248] Example 5: Dynamic Vapor Sorption (DVS) Analysis of Compound 1-Ethanolate Form A.

[0249] DVS analysis of Compound 1-ethanolate Form A was performed in 10% RH increments from 5% relative humidity (RH) to 95% RH and back to 5% RH ( Figure 7 ). With the increase of RH, the sample shows an increase of about 0.3wt% between 5%RH and 55%RH, suggesting that Form A is non-hygroscopic at 5-55%RH. A loss of 1.8wt% was observed between 55%RH and 65%RH, which may be due to the replacement of ethanol by water. After 65%RH, the sample increased by 3.8wt% between 65%RH and 95%RH. It is worth noting that between 85%RH and 95%RH, and all RH intervals during desorption, the sample mass does not meet the balance criterion. A weight loss (about 7.6wt%) (i.e., desorption) was observed between 95%RH and 5%RH. After DVS analysis, it was noted that the sample had deliquesced.

[0250] Samples of Compound 1-ethanolate Form A were exposed to elevated RH (75%, 85% and 97%) at room temperature for approximately 3 hours and 24 hours (Table 8). After 3 hours, no deliquescence was observed at 75% RH, the sample was wet at 85% RH, solids were present, and deliquescence was observed at 97% RH, with a small amount of birefringent solids present. After 24 hours, samples exposed to 85% RH and 97% RH deliquescence, while samples at 75% RH began to deliquescence.

[0251] Table 8. Time course of water uptake by Compound 1 - ethanolate Form A at increasing relative humidity.

[0252]

[0253]

[0254] Separate DVS analysis using stepwise increasing relative humidity revealed that from 0% RH to 40% RH, the mass of Form A increased by 0.3 wt.-%. At higher humidities, a mass reduction was observed, which was due to the loss of ethanol from the boronate complex. However, up to 60% RH, the material retained its predominantly crystalline structure for at least four hours.

[0255] Example 6. Mass spectral analysis of Compound 1-ethanolate Form A. Evidence for conversion of Compound 1-ethanolate to ((2-ethylbutanoyl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate (Compound 1) in aqueous solution.

[0256] Mass spectrometry (MS) analysis was performed to confirm the structure of Compound 1-ethanolate Form A and to evaluate the ability of EtOH to dissociate from Compound 1-ethanolate in water. Amorphous preparations of Compound 1-ethanolate Form A and ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate were diluted in anhydrous EtOH or water and analyzed by high resolution mass spectrometry. Samples of amorphous ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate dissolved in anhydrous EtOH were spiked with water prior to analysis. The mass spectrum of Compound 1-ethanolate Form A diluted in anhydrous EtOH showed a sodiated Compound 1-ethanolate (M+Na) at a nominal 442 Da. + and the sodium-bound dimer of compound 1-ethanolate at nominal 861 Da (2M+Na) + The observed exact mass of the sodium compound 1-ethanolate is 442.2007 (difference from the theoretical value = 1.4 ppm: C 21 H 30 BNO7Na + :442.2013Da).

[0257] The mass spectrum of compound 1-ethanolate diluted in water showed a peak at a nominal 414 Da (M+Na) + 、787Da(2M-H2O+Na) + 、805Da(2M+Na) + 、1178Da(3M-H2O+Na) + and 1552Da(4M-2H2O+Na) + The main peak at , corresponds to ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate (Compound 1).

[0258] The mass spectrum of amorphous ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate diluted in anhydrous EtOH showed major peaks at nominally 442 Da and 861 Da corresponding to the sodiated compound 1-ethanolate (M+Na) + and the sodium-bound dimer of compound 1-ethanolate (2M+Na) + This is the same result observed when compound 1-ethanolate was diluted in EtOH and is likely due to the formation of the ethyl (boronic) ester during electrospray ionization, i.e., the azeotropic removal of water.

[0259] The mass spectrum of amorphous ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate dissolved in anhydrous EtOH and then spiked with water showed a peak at a nominal 414 Da (M+Na). + 、787Da(2M-H2O+Na) + 、805Da(2M+Na) + 、1178Da(3M-H2O+Na) + and 1552Da(4M-2H2O+Na) + They correspond to sodium ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate (M+Na) + 、(2M-H2O+Na) + 、(2M+Na) + 、(3M-H2O+Na) + and (4M-2H2O+Na) + These are the same results observed for samples of Compound 1-ethanolate Form A diluted in water, suggesting that Compound 1-ethanolate is rapidly converted to free boronic acid ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate in the presence of water.

[0260] Example 6. Preparation of Compound 1-Ethanolate Form B.

[0261] A unique crystalline material, referred to as Form B, was observed as a mixture with Compound 1-ethanolate Form A from the following four experiments: 1) heating / cooling experiments of Compound 1-ethanolate in heptane containing 5% EtOH; 2) a stirred solution obtained by adding heptane to a DCM solution of Compound 1-ethanolate; 3) a stirred turbid solution obtained by adding cyclohexane to a solution produced after cooling a solution of Compound 1-ethanolate in EtOAc:cyclohexane (1:3 v / v); and 4) a stirred sample obtained by adding heptane to a solution of anisole containing Compound 1-ethanolate.

[0262] An infrared spectrum was obtained of Form B containing a small amount of Form A. Overlay of the FT-IR spectra of Form B and Form A shows Figure 8 middle.

[0263] Compound 1-ethanolate Form B was further analyzed by Raman spectroscopy. Fig. 9A The peaks are shown in the table below:

[0264] peak <![CDATA[Wavenumber (cm -1 )]]> peak <![CDATA[Wavenumber (cm -1 )]]> peak <![CDATA[Wavenumber (cm -1 )]]> 1 3073 10 1429 19 944 2 2967 11 1367 20 918 3 2935 12 1345 21 895 4 2879 13 1322 22 844 5 2834 14 1249 23 805 6 2744 15 1171 24 753 7 1740 16 1150 25 636 8 1589 17 1108 26 556 9 1455 18 1018 27 217

[0265] The superposition of the Raman spectra of Form B and Form A is shown in Fig. 9B middle.

[0266] Example 7. XRPD Characterization of Compound 1-Ethanolate Form B.

[0267] The indexed XRPD pattern of Compound 1-ethanolate Form B containing a small amount of Form A is shown in Fig.10 The consistency between the allowed peak positions (marked with bars) and the observed peaks indicates a consistent unit cell determination. The successful indexing of the pattern indicates that the sample is mainly composed of a single crystalline phase. However, the very small peaks at 6.10 °, 9.60 °, 9.84 ° and 10.05 ° are inconsistent with the allowed peaks of the indexed XRPD pattern of Form B, thus suggesting the presence of additional crystalline phases, particularly Form A.

[0268]

[0269] Example 8. Thermal Analysis of Compound 1-Ethanolate Form B.

[0270] Thermal analysis (DSC) revealed that Form B exhibited a small, broad feature at 77.7°C (peak maximum) followed by an endotherm at 116.9°C (peak maximum), which may be attributed to melting ( Fig.11 ). By TGA analysis, a 1.2% weight loss was observed between 23.6°C and 125.0°C.

[0271] Example 9: Dynamic Vapor Sorption (DVS) Analysis of Compound 1-Ethanolate Form B.

[0272] DVS analysis of Compound 1-ethanolate Form B (with minor amounts of Form A) was performed in 10% RH increments from 5% RH to 95% RH and back to 5% RH ( Fig.12 ). The DVS isotherm of Form B is similar in nature to that of Form A. Form B lost 0.2wt% after equilibrium at about 5%RH. As RH increased, the sample showed an increase of about 0.5wt% between 5%RH and 45%RH. A weight loss of 1.1% was observed between 45%RH and 55%RH, which may be due to the replacement of ethanol with water. After 55%RH, the sample increased by 3.3wt% between 55%RH and 95%RH. Between 85%RH and 95%RH, and all RH intervals to 15%RH during desorption, the sample mass did not meet the equilibrium criteria. Weight loss (about 5.8wt%) was observed during the desorption process from 95%RH to 5%RH. After DVS analysis, it was noted that the sample seemed to have deliquesced.

[0273] Separate DVS analysis using stepwise increasing relative humidity revealed that from 0% RH to 40% RH, the mass of Form B increased by 0.4 wt.-%. At higher humidities, a mass reduction was observed, which was due to the loss of ethanol from the boronate complex. However, up to 60% RH, the material retained its predominantly crystalline structure for at least four hours.

[0274] Example 10. Interconversion slurry.

[0275] The difference in free energy between solid phases of the same composition (i.e., true polymorphs) is related to their relative solubility, with the most stable polymorph having the lowest solubility in any solvent compared to the metastable polymorph. Thus, a saturated solution of the most stable form is undersaturated relative to the less stable form. Thus, in the presence of seeds of a different polymorph, the less stable polymorph dissolves over time, leading to further growth of the most stable form.

[0276] Solvent-mediated slurry interconversion experiments were performed using seeds of different polymorphs to determine the most stable form of compound 1-ethanolate. A saturated solution of compound 1-ethanolate was prepared in 3% DCM in heptane and 5% EtOH in heptane. Approximately equal amounts of Form A and Form B (containing a small amount of Form A) were added to the filtered saturated solution, and the suspension was slurried at room temperature for about 2 weeks, and the separated solid was observed by polarized light microscopy (PLM), and analyzed by XRPD. The XRPD pattern of the solid separated from these two slurries is consistent with Form A. These data show that Form A is a stable form at room temperature.

[0277] Example 11: Preparation and Characterization of ((2-ethylbutyryl)oxy)methyl (R)-2-methoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate (Compound 1-methanolate)

[0278]

[0279] ((2-ethylbutyryl)oxy)methyl (R)-2-hydroxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate (Compound 1) in methanol yields ((2-ethylbutyryl)oxy)methyl (R)-2-methoxy-3-propionamido-3,4-dihydro-2H-benzo[e][1,2]oxaborin-8-carboxylate (Compound 1 - methanolate). Fig.13 The X-ray structure of compound 1-methoxide is shown.

Claims

1. The invention relates to a crystalline form of the present invention, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 6.1°±0.1°2θ, 6.8°±0.1°2θ, 9.9°±0.1°2θ, 14.3°±0.1°2θ, 16.0°±0.1°2θ, 17.9°±0.1°2θ, 19.3°±0.1°2θ and 21.2°±0.1°2θ.

2. The crystalline form of claim 1, wherein the X-ray powder diffraction (XRPD) pattern of the crystalline form is substantially the same as that shown in FIG. 4 .

3. The crystalline form of claim 1, wherein the DSC thermogram of the crystalline form is substantially the same as that shown in FIG. 6 .

4. The crystalline form of claim 1, wherein the DSC thermogram of the crystalline form has a broad endotherm with an onset at about 112.8°C.

5. The crystalline form of claim 1, wherein the crystalline form 1 The H spectrum is essentially the same as that shown in Figure 1A.

6. The crystalline form of claim 1, wherein the crystalline form 13 The C spectrum is essentially the same as that shown in Figure 1B.

7. The crystalline form of claim 1, wherein the FT-IR spectrum of the crystalline form is substantially the same as that shown in FIG.

2.

8. The crystalline form of claim 1, wherein the Raman spectrum of the crystalline form is substantially the same as that shown in FIG.

3.

9. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 8 and a pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9, further comprising a β-lactam antibiotic.

11. The pharmaceutical composition according to claim 10, wherein the β-lactam antibiotic is a penicillin, a cephalosporin, a carbapenem, a monobactam or a combination thereof.

12. Use of the crystalline form of any one of claims 1 to 8 in combination with a therapeutically effective amount of a beta-lactam antibiotic for the preparation of a medicament for treating a bacterial infection in a subject.

13. The use according to claim 12, wherein the β-lactam antibiotic is ceftibuten or a salt thereof.

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