Triterpenoid antifungal agents for the treatment of mucormycosis

Abstract

The present invention relates to enfumafungin derivative triterpenoid antifungal compounds for the treatment of mucormycosis. The enfumafungin derivative triterpenoids (or pharmaceutically acceptable salts or hydrates thereof) are inhibitors of (1,3)-beta-D-glucan synthesis and can be used alone or in combination with a second antifungal agent for the treatment of mucormycosis, including pulmonary mucormycosis.

Description

[0001] This invention was carried out with the support of the U.S. government under contract number HHSN272201700039I / 75N93022F00001 issued by the National Institute of Allergy and Infectious Diseases. The U.S. government has specific rights to this invention. Technical Field

[0002] This invention relates to the use of a triterpenoid antifungal agent in the treatment of fungal infections caused by molds. More specifically, this invention relates to the use of an enfumafungin derivative triterpenoid (or a pharmaceutically acceptable salt or hydrate thereof) (which is an inhibitor of (1,3)-β-D-glucan synthesis, resulting in a deficiency of (1,3)-β-D-glucan (a building block of fungal cell structure)) alone or in combination with another antifungal agent in the treatment of fungal infections caused by molds, particularly mucormycosis. Mucormycosis remains a life-threatening infection with suboptimal treatment options. According to the invention, the use of the triterpenoid antifungal agent SCY-247 alone or particularly in combination with amphotericin B can provide advantages in the treatment of mucormycosis, including pulmonary mucormycosis. Background Technology

[0003] Fungal infections caused by molds are a major healthcare problem with high associated mortality. Several molds (including species of the orders Mucorales (formerly Zygomycete), Aspergillus, Lomentospora, Fusarium, Scopuliopsis, Trichophyton, and Scedosporium) can cause systemic fungal infections. Despite the availability of antifungal agents active against the causative pathogens, diseases caused by Mucorales fungi (known as mucormycosis, formerly Zygomycosis) are among the most deadly and difficult to treat. Mortality rates associated with mucormycosis range from 40% to 78% across different case series. (Muthu et al., Has the mortality from pulmonary mucormycosis changed over time? A systematic review and meta-analysis. Clin Microbiol Infect. 2021 April; 27(4):538-549. doi: 10.1016 / j.cmi.2020.12.035. Epub 5 Jan 2021. PMID: 33418022.) The most common fungi in the Mucorales that cause human disease include species of the genera Rhizopus and Mucor, species of the genera Lichtheimia (formerly Absidia), species of the genera Apophysomyces, species of the genera Rhizomucor, and species of the genera Cunninghamella.

[0004] There are many risk factors that predispose patients to mucormycosis, including uncontrolled diabetes, neutropenia, hematologic malignancies, organ transplantation, trauma and burns, and use of immunosuppressants (such as corticosteroids). Mucormycosis has also been reported in patients with moderate to severe COVID-19, significantly complicating the management of this condition. (Selarka et al., Mucormycosis and COVID-19: An epidemic within a pandemic in India. Mycoses. Oct 2021; 64(10):1253-1260. doi: 10.1111 / myc.13353. Epub July 24, 2021. PMID: 34255907; PMCID: PMC8446956.)

[0005] Mucormycosis includes nasocerebromycosis (symptoms may include facial swelling, headache, nasal or sinus congestion, lesions on the bridge of the nose or inside the mouth, and fever), pulmonary mucormycosis (symptoms may include fever, cough, chest pain, and shortness of breath), gastrointestinal mucormycosis (symptoms may include abdominal pain, nausea and vomiting, and gastrointestinal bleeding), cutaneous mucormycosis (symptoms may include blistering or ulceration, or pain, warming of the skin, excessive redness, or swelling around the wound), and disseminated mucormycosis (where the infection spreads through the bloodstream to affect another part of the body, such as the brain, spleen, heart, and skin; patients with disseminated infection in the brain may experience altered mental status or coma). Mucormycosis is contracted through contact with spores of Mucorales fungi in the environment. For example, nasocerebromycosis and pulmonary mucormycosis can occur through inhalation of fungal spores, while cutaneous mucormycosis can occur after the fungus enters the skin through a lesion. Disseminated mucormycosis can occur secondary to any of the aforementioned forms of mucormycosis and, for example, in patients with neutropenia who have lung infections.

[0006] Mucorales exhibit inherent resistance to most clinically available antifungals, significantly limiting treatment options. Amphotericin B is currently the preferred treatment for mucormycosis, but it has significant nephrotoxicity. Active azole antifungals, such as isavuconazole and posaconazole, are also used. Treatment outcomes with available antifungals are not optimal, leading to frequent treatment failures and deaths. Given the high mortality rate and the limitations of current options, there is a need for new therapies for mucormycosis in this field. Summary of the Invention

[0007] This invention addresses the need for novel treatments for mucormycosis in the relevant field. The invention provides the use of an infumafenidine derivative triterpenoid (or a pharmaceutically acceptable salt or hydrate thereof) of formula (I), alone or in combination with another antifungal agent, in the treatment of mucormycosis (including pulmonary mucormycosis).

[0008] The present invention also provides a method for treating individual mucormycosis (including pulmonary mucormycosis) by administering a compound of formula (I) (or a pharmaceutically acceptable salt or hydrate thereof) alone or in combination with another antifungal agent. Furthermore, the present invention provides the use of a compound of formula (I) (or a pharmaceutically acceptable salt or hydrate thereof) alone or in combination with another antifungal agent in the preparation of a medicament for treating individual mucormycosis (including pulmonary mucormycosis).

[0009] The secondary antifungal agent, when used, can be a polyene, azole, purine or pyrimidine nucleotide inhibitor, chitin inhibitor, orotomide, Gwt1 inhibitor, or immunomodulator. Specific examples of secondary antifungal agents include amphotericin B (polyene), isaconazole, voriconazole, posaconazole and itraconazole (azoles), and olorofim (orotomide and fosmanogepix) (Gwt1 inhibitor). Amphotericin B is a preferred secondary antifungal agent.

[0010] In a preferred embodiment, the triterpenoid antifungal agent SCY-247 may be used alone or in combination with a second antifungal agent to treat mucormycosis, including pulmonary mucormycosis.

[0011] Surprisingly, despite showing low activity against Mucorales in in vitro testing (e.g., MIC > 16 µg / mL), SCY-247 demonstrated efficacy against mucormycosis in the in vivo studies described herein. In the rodent studies described herein, SCY-247 monotherapy improved median survival and percentage survival at all tested doses compared to placebo. Furthermore, in the same study, SCY-247 monotherapy at a dose of 48 mg / kg BID demonstrated superior median survival and percentage survival compared to amphotericin B monotherapy (the standard of care for mucormycosis). Additionally, in the same study, the combination therapy of SCY-247 and amphotericin B at a dose of 32 mg / kg BID achieved a significant 90% overall survival and demonstrated superiority over any tested monotherapy (including amphotericin B monotherapy). Attached Figure Description

[0012] Figure 1 A graph showing the cumulative survival probability in studies of mice with neutropenia inoculated with Rhizopus delemar 99-880 and treated with: SCY-247 alone, a liposomal formulation of amphotericin B (L-AMB), or a combination of SCY-247 and L-AMB. Compared with placebo, both SCY-247 monotherapy and combination therapy improved survival in mice with pulmonary mucormycosis and neutropenia. The combination therapy achieved a 90% overall survival and a median survival of >21 days, which was superior to placebo and any monotherapy, including amphotericin B monotherapy, which is the standard of care. Detailed Implementation

[0013] This invention relates to the use of an infmufentanil derivative triterpenoid (or a pharmaceutically acceptable salt or hydrate thereof) (which is an inhibitor of (1,3)-β-D-glucan synthesis) alone or in combination with another antifungal agent in the treatment of fungal infections caused by molds, particularly mucormycosis. Mucormycosis remains a life-threatening infection, and current treatment options for it are limited and have inconsistent results and / or toxicity issues. According to the invention, the use of the triterpenoid antifungal agent SCY-247 alone or specifically in combination with amphotericin B can provide advantages in the treatment of mucormycosis, including pulmonary mucormycosis.

[0014] Infmufentanil is a hemiacetal triterpenoid glycoside produced by fermentation of *Hormonema* spp., a fungus associated with the living leaves of *Juniperus communis* (US Patent No. 5,756,472; Pelaez et al., *Systematic and Applied Microbiology*, 23:333–343 (2000); Schwartz et al., *JACS*, 122: 4882-4886 (2000); Schwartz RE, *Expert Opinion on Therapeutic Patents*, 11(11): 1761–1772 (2001)). Infmufentanil is one of several triterpenoid glycosides with in vitro antifungal activity. The antifungal mechanism of action of infmufentanil and other antifungal triterpenoid glycosides has been established as the inhibition of fungal cell wall glucan synthesis through their specific action on (1,3)-β-D-glucan synthase (Onishi et al., Antimicrobial Agents and Chemotherapy, 44: 368–377 (2000); Pelles et al. (2000)). 1,3-β-D-glucan synthase remains an attractive target for antifungal drug action due to its presence in many pathogenic fungi and thus providing a broad antifungal spectrum. Furthermore, the infmufentanil derivatives described herein exhibit little or no mechanism-based toxicity due to the absence of a mammalian counterpart to (1,3)-β-D-glucan synthase.

[0015] Various infumafenidine derivatives of triterpenoid antifungal compounds have been disclosed, for example, in WO 2007 / 126900 and WO2007 / 127012. Triterpenoid antifungal agents (or fungerp) are the first antifungal compounds to be developed since 2001.

[0016] This invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof for the treatment of individual mucormycosis:

[0017]

[0018] in:

[0019] X is O or H,H;

[0020] R 1 for

[0021] a) OH;

[0022] b) OC(O)C1-C 12 -alkyl group, which is unsubstituted or has one or two derivatives selected from OR 0 、N(R 0 )2 and CO2R 0 Substituents of the substituents;

[0023] c) OC(O)C1-C6-haloalkyl;

[0024] d) OC(O)C3-C8-cycloalkyl;

[0025] e) O-C1-C6-alkyl, which is unsubstituted or has one or two derivatives selected from OR 0 and N(R) 0 Substitution of )2 by substituents;

[0026] f) OC(O)NHC1-C6-alkyl, which is unsubstituted or phenyl-substituted;

[0027] g) OC(O)OC1-C6-alkyl;

[0028] h) NHC(O)C1-C6-alkyl, which is unsubstituted or phenyl-substituted; or

[0029] i) (O) n CH2C(O)C1-C6-alkyl;

[0030] n is 0 or 1;

[0031] R 2 for

[0032] a) CH2R 4 ,

[0033] b) CH2CHR 5 (CH2) m NR 6 R 7 ,

[0034] c) CH2C(R 8 (R) 9 (CH2) m NR 6 R 7 ,

[0035] d) CH2C(R 10 (R) 11 )R 12 ,

[0036] e) CH2CH(OR 0 CH2OR 0 ,

[0037] f) CHR 13 CHR 5 (CH2) m NR 6 R 7 ,

[0038] g) (CH2) p C(R 8 (R) 9 )NR 6 R 7 ,or,

[0039] h) CH2CHR 5 C(R 8 (R) 9 )NR 6 R 7 ,

[0040] m is 0, 1, or 2;

[0041] p is between 2 and 6;

[0042] R 1 and R 2 Optionally, together they form methylenedioxy or ethylenedioxy groups that are unsubstituted or substituted with one or two substituents selected from C1-C6-alkyl and C1-C6-alkoxy groups;

[0043] R 3 for

[0044] a) C(O)R 14 ;

[0045] b) CH2OH; or

[0046] c) CH2OC(O)C1-C6-alkyl;

[0047] R 14 For OH, OR 15 H, N(R) 0 )2 or C1-C6-alkyl;

[0048] R 15 It is a C1-C6-alkyl group, which is unsubstituted or has one or two derivatives selected from phenyl, OC(O)C1-C6-alkyl, C(O)OR 0 OR 0 C(O)N(R) 0 )2 and C(O)NH2(CH2) 2-4 The NH2 group is substituted, and the phenyl group is optionally substituted with 1 to 3 halogen groups;

[0049] R 4 for

[0050] a) H;

[0051] b) (CH2) 1-6 -R 16 ;

[0052] c) OC1-C6-alkyl;

[0053] d) Aryl group, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from 1 to 3 groups selected from halogens, N(R) 0 2. OR 0 C1-C6-alkyl, CF3, OCF3, CO2R 0 and C(O)N(R) 0 Substitution of )2 by substituents;

[0054] e) A heterocyclic group, wherein the heterocyclic group is a 3- or 6-membered saturated or unsaturated nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, which is linked via a carbon or nitrogen atom on the ring, and optionally substituted at the non-linking carbon or nitrogen atom by 1 to 2 substituents selected from: side-oxygen groups, N(R) ... 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or has one or two derivatives selected from N(R) 0 2. NHC (=NH)NH2, OC (O)C1-C6-alkyl and CO2R 0 Substituents; or

[0055] f) A heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, linked via a ring carbon or nitrogen atom, and optionally substituted at the non-linking ring carbon or nitrogen atom by 1 or 2 substituents selected from: N(R 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are unsubstituted or have one or two derivatives selected from N(R) 0 2. NHC (=NH)NH2, OC (O)C1-C6 alkyl groups and CO2R 0 Substituents of the substituents;

[0056] R 16 for

[0057] a) H;

[0058] b) OH;

[0059] c) NH2;

[0060] d) NHC(O)R 17 ;

[0061] e) NHSO2R 17 ;

[0062] f) NHC(O)NHR 0 ;

[0063] g) NHC(O)CHR 18 NH2;

[0064] h) A heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered saturated or unsaturated nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, which is linked via a carbon or nitrogen atom on the ring, and optionally substituted at the non-linking carbon or nitrogen atom by 1 to 2 substituents selected from: N(R 0 2. Imino, lateral oxygen, OR 0 CO2R 0 CON(R) 0 )2 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or has one or two derivatives selected from N(R) 0 )2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, OR 0 and CO2R 0 Substituents of the substituents;

[0065] i) NH-N(C1-C6-alkyl)2;

[0066] j) NHC(=NH)NHC(=NH)NH2;

[0067] k) NR a (CH2) p NHR a ;

[0068] l) NR a R b ;

[0069] m) N(R b )2;

[0070] n) NHC(=NR d NH2;

[0071] o) NHC(=NR c )NH-C1-C6-alkyl, wherein the alkyl group is unsubstituted or substituted with phenyl, CF3 or NHC(O)C1-C6-alkyl;

[0072] p) NHC(=NR d)NH-C3-C6-cycloalkyl;

[0073] q) NHC(=NR d )NH-phenyl, wherein the phenyl group is unsubstituted or substituted with one or two substituents selected from halogens and CF3;

[0074] r) CO2C1-C6-alkyl;

[0075] s) OCOC1-C6 alkyl;

[0076] t) a heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, connected via a carbon or nitrogen atom on the ring, and optionally substituted at a non-connecting carbon or nitrogen atom by 1 or 2 substituents selected from: N(R 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are unsubstituted or contain one or two derivatives selected from N(R) 0 2. NHC(=NH)NH2, OC(O)C1-C6 alkyl, OR 0 and CO2R 0 Substituents; or

[0077] u) CN;

[0078] p is 1, 2, 3 or 4;

[0079] R a It is H or C(=NH)NH2;

[0080] R b It is a C1-C6 alkyl group, which is unsubstituted or has one or two derivatives selected from N(R) 0 )2 and OR 0 Substituents of the substituents;

[0081] R c For H or CN;

[0082] R d It is H or C3-C6-cycloalkyl;

[0083] R 5 for

[0084] a) C1-C6-alkyl groups, which are unsubstituted or derived from one or two N(R) groups. 0 )2 and OR 0 Substituents of the substituents;

[0085] b) OH;

[0086] c) OC1-C6-alkyl groups that are unsubstituted or phenyl-substituted;

[0087] d) OC(O)C1-C6-alkyl;

[0088] e) C3-C6-cycloalkyl;

[0089] f) aryl, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from 1 to 3 groups selected from halogens, OCF3, CF3, N(R) 0 )2 and OR 0 Substituents of the substituents;

[0090] g) a heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, which is linked via a carbon or nitrogen atom on the ring, and optionally via 1 or 2 heteroatoms selected from N(R) on the non-linking carbon or nitrogen atom. 0 2. OR 0 and C1-C6-alkyl substituents; or

[0091] h) A heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered saturated or unsaturated nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, which is linked via a ring carbon or nitrogen, and optionally via 1 to 2 heteroatoms selected from N (R) at the non-linking ring carbon or nitrogen. 0 2. OR 0 and C1-C6-alkyl substituents;

[0092] R 6 It is an H or C1-C6 alkyl group, wherein the alkyl group is unsubstituted or substituted with a 5- to 6-membered saturated, unsaturated, or aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, which is linked via a ring carbon or nitrogen atom, and optionally substituted with 1 to 2 substituents selected from N(R) at the non-linking ring carbon or nitrogen atom: 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or derived from one or two groups selected from OR 0 、N(R 0 2. NHC(=NH)NH2, OC(O)C1-C6-alkyl, CO2R 0 C(O)N(R) 0 )2 and NHC(O)R 0 Substituents of the substituents;

[0093] R 7 for

[0094] a) H;

[0095] b) C1-C6 alkyl groups, which are unsubstituted or derived from one or two N(R) groups. 0 2. OR 0 CO2R 0 OC(O)C1-C6-alkyl, NHC(O)R 0 C(O)N(R) 0 2. Substitution of phenyl, heteroaryl and heterocyclic groups, wherein the heteroaryl group is defined as in (j) below and the heterocyclic group is defined as in (k) below;

[0096] c) C(O)H;

[0097] d) C(O)C1-C6-haloalkyl;

[0098] e) C(O)C1-C6-alkyl, which is unsubstituted or has one or two derivatives selected from CO2R 0 OR 0 OCH2CO2R 0 、N(R 0 )2、C(O)C1-C6-alkyl、O(CH2)2OC1-C6-alkyl、C(O)N(R 0 2. OC(O)C1-C6 alkyl groups and NHC(O)R 0 Substituents of the substituents;

[0099] f) C(O)OC1-C6-alkyl;

[0100] g) C(O)NH-C1-C6-alkyl;

[0101] h) SO2C1-C6-alkyl;

[0102] i) C3-C6-cycloalkyl;

[0103] j) aryl, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from 1 to 3 alkyl groups selected from halogens, N(R) 0 2. OR 0 C1-C6-alkyl, CF3, OCF3, CO2R 0 and C(O)N(R) 0 Substitution of )2 by substituents;

[0104] k) a heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, connected via a carbon or nitrogen atom on the ring, and optionally substituted at a non-connecting carbon or nitrogen atom by 1 or 2 substituents selected from: N(R 0 2. OR 0 CO2R 0OC(O)C1-C6-alkyl, CON(R) 0 2. NHC(O)R 0 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or has one or two derivatives selected from N(R) 0 2. NHC(=NH)NH2, OC(O)C1-C6 alkyl, OR 0 CO2R 0 C(O)N(R) 0 )2 and NHC(O)R 0 Substituents of the substituents;

[0105] l) A heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered saturated or unsaturated nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, which is linked via a carbon or nitrogen atom on the ring, and optionally substituted at the non-linking carbon or nitrogen atom by 1 to 2 substituents selected from: N(R 0 2. Imino, lateral oxygen, OR 0 CO2R 0 OC(O)C1-C6-alkyl, CON(R) 0 2. NHC(O)R 0 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or has one or two derivatives selected from N(R) 0 )2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, OR 0 CO2R 0 C(O)N(R) 0 )2 and NHC(O)R 0 Substituents of the substituents;

[0106] m) C(=NH)C1-C6-alkyl, wherein the alkyl group is unsubstituted or derived from one or two groups selected from halogens, CF3, N(R) 0 2. OR 0 and substituents of NHC(O)C1-C6-alkyl groups;

[0107] n) C(=NR d NH2;

[0108] o) C(=NH)NH-C1-C6-alkyl, wherein the alkyl group is unsubstituted or derived from 1 to 3 groups selected from halogens, CF3, N(R) 0 2. OR 0 and substituents of NHC(O)C1-C6-alkyl groups;

[0109] p) C(=NH)NH-C3-C6-cycloalkyl;

[0110] q) C(=NH)NH-phenyl, wherein the phenyl group is unsubstituted or substituted with 1 to 3 substituents selected from halogens and CF3; or

[0111] r) C(=NH)NHC(=NH)NH2;

[0112] R 6 and R 7 Optionally, together with the attached nitrogen atom, a 3- to 6-membered saturated, unsaturated, or aromatic ring having 0 to 2 additional heteroatoms selected from N, O, and S is formed, wherein the ring is optionally substituted at the non-connecting carbon or nitrogen atom by 1 to 2 substituents selected from: halogen, N(R) 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are unsubstituted or derived from one or two groups selected from OR 0 and N(R) 0 The ring is substituted with a substituent of )2, wherein two adjacent substituents of the ring optionally together form a fused 5- or 6-membered saturated, unsaturated, or aromatic ring having 0 to 2 heteroatoms selected from N, O, and S; or R 6 and R 9 Optional with R 6 The nitrogen atoms bonded together form a pyrrolidinyl ring;

[0113] R 8 Choose from the following groups

[0114] a) Hydrogen,

[0115] b) C1-C6 alkyl groups that are unsubstituted or have undergone OR treatment. 0 or SO2R 0 replace,

[0116] c) C3-C6-cycloalkyl groups, and

[0117] d) Aryl group, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from 1 to 3 groups selected from halogen groups, OCF3, CF3, N(R) 0 )2 and OR 0 Substituents of the substituents;

[0118] R 9 It is a C1-C6 alkyl group, which is unsubstituted or OR- 0 or SO2R 0 replace;

[0119] R 8 and R 9 Optionally, they can be combined to form a 3- to 6-membered saturated ring having 0 to 1 heteroatoms selected from N, O, or S;

[0120] R 10 Independently select from the following groups

[0121] a) C1-C6 alkyl groups, which are unsubstituted or OR-treated. 0 、N(R 0 2. OC(O)C1-C6 alkyl or CO2R 0 Replacement, and

[0122] b) CO2R 0 ;

[0123] R 11 It is a C1-C6 alkyl group, which is unsubstituted or OR- 0 OC(O)C1-C6 alkyl, OC(O)-phenyl, CO2R 0 or N(R) 0 )2 replaces;

[0124] R 12 It is OH or C1-C6 alkyl, wherein the alkyl is unsubstituted or OC(O)C1-C6 alkyl or OR 0 replace;

[0125] R 13 It is a C1-C4 alkyl group;

[0126] R 17 for

[0127] a) C1-C6 alkyl groups, which are unsubstituted or derived from one or two groups selected from CO2R. 0 OR 0 、N(R 0 Substitution of 2 and OC(O)C1-C6-alkyl groups;

[0128] b) Aryl, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from one or two halogen groups, OR 0 and N(R) 0 Substitution of )2 by substituents; or

[0129] c) C1-C6-haloalkyl;

[0130] R 18 It is an H or C1-C6 alkyl group, wherein the alkyl group is unsubstituted or derived from one or two groups selected from OR. 0 、N(R 0 2. Heteroaryl, heterocyclic, CO2N(R) 0 )2 and CO2R 0 Substituents, including heteroaryl groups such as R 16 As defined in (t) and heterocyclic groups such as R16 As defined in (h); and

[0131] Each R 0 It is independently H or C1-C6-alkyl.

[0132] The present invention also provides a method for treating individual mucormycosis by administering a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof. Furthermore, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating individual mucormycosis.

[0133] The present invention further provides a combination therapy of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof with another antifungal agent for the treatment of mucormycosis. The combination therapy shall include an antifungal agent, when administered together, that, compared to individual monotherapy regimens, increases antifungal efficacy, reduces toxicity, provides faster cure, prevents or avoids the development of resistance, and / or provides broader-spectrum antifungal activity.

[0134] This invention provides a combination of a first antifungal agent and a second antifungal agent, which is a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof. This invention also provides a combination of a first antifungal agent and a second antifungal agent, which is a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, used in a method of treating individual mucormycosis. This invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, combined with a second antifungal agent, in the treatment of individual mucormycosis. This invention also provides a method of treating individual mucormycosis by administering a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, combined with a second antifungal agent. Furthermore, this invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, combined with a second antifungal agent, in the preparation of a medicament for treating individual mucormycosis.

[0135] In any of the foregoing embodiments involving a second antifungal agent, the second antifungal agent may be selected from: polyenes, azoles, purine or pyrimidine nucleotide inhibitors, chitin inhibitors, olotomids, Gwt1 inhibitors, and immunomodulators. In any of the foregoing embodiments involving a second antifungal agent, the second antifungal agent may be selected from: amphotericin B, isaconazole, voriconazole, posaconazole, itraconazole, olorofen, and fossogpi. Amphotericin B is a preferred second antifungal agent.

[0136] Examples of polyenes that can be used as a second antifungal agent in any of the foregoing embodiments include (but are not limited to) amphotericin B, its liposomes and lipid forms, such as ABELCET. ® AMBISOME ® and AMPHOCIL ®Nystatin and its liposomes and lipid forms, and the third-generation polyene SF001 and its liposomes and lipid forms. Examples of azoles that can be used as secondary antifungal agents in any of the foregoing embodiments include (but are not limited to) isaconazole, fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, ravuconazole, detoconazole, clotrimazole, and posaconazole. Examples of purine or pyrimidine nucleotide inhibitors that can be used as secondary antifungal agents in any of the foregoing embodiments include (but are not limited to) flucytosine, polyoxin, and nikkomycin, particularly nikkomycin Z or nikkomycin X. Polyoxin and nikkomycin are also chitin inhibitors; these and other chitin inhibitors can be used as secondary antifungal agents in any of the foregoing embodiments. Examples of ollotomyd compounds that can be used as secondary antifungal agents in any of the foregoing embodiments include (but are not limited to) olorofen. Examples of Gwt1 inhibitor compounds that can be used as a second antifungal agent in any of the foregoing embodiments include (but are not limited to) fossogpi. Examples of immunomodulators that can be used as a second antifungal agent in any of the foregoing embodiments include (but are not limited to) interferons (e.g., IL-1, IL-2, IL-3, and IL-8), defensins, tacrolimus, and granulocyte colony-stimulating factor (G-CSF).

[0137] SCY-247, which has the structure shown below, is a second-generation fungerp:

[0138]

[0139] Chemical formula: C 36 H 59 NO6

[0140] Precision mass: 601.43

[0141] Molecular weight: 601.87

[0142] The structure of SCY-247 is contained in formula (I). SCY-247 is orally bioavailable and offers a significant advantage over echinocandin (which is also an inhibitor of 1,3-β-D-glucan synthase) because echinocandin requires non-enteral administration.

[0143] This invention provides the use of SCY-247 or a pharmaceutically acceptable salt or hydrate thereof in the treatment of individual mucormycosis. This invention also provides a method of treating individual mucormycosis by administering SCY-247 or a pharmaceutically acceptable salt or hydrate thereof. Furthermore, this invention provides the use of SCY-247 or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating individual mucormycosis.

[0144] In a preferred embodiment, the present invention provides a combination of the following: a first antifungal agent, SCY-247 having the following structure.

[0145]

[0146] Or its pharmaceutically acceptable salts or hydrates; and a second antifungal agent.

[0147] This invention also provides a combination of a first antifungal agent and a second antifungal agent, comprising SCY-247 or a pharmaceutically acceptable salt or hydrate thereof, used in a method for treating individual mucormycosis. This invention also provides the use of the combination of SCY-247 or a pharmaceutically acceptable salt or hydrate thereof and a second antifungal agent in treating individual mucormycosis. This invention also provides a method for treating individual mucormycosis by administering SCY-247 or a pharmaceutically acceptable salt or hydrate thereof and a second antifungal agent. Furthermore, this invention provides the use of the combination of SCY-247 or a pharmaceutically acceptable salt or hydrate thereof and a second antifungal agent in the preparation of a medicament for treating individual mucormycosis.

[0148] In any of the foregoing embodiments involving SCY-247 (or its pharmaceutically acceptable salts or hydrates) and a second antifungal agent, the second antifungal agent may be selected from: polyenes, azoles, purine or pyrimidine nucleotide inhibitors, chitin inhibitors, olotomid, Gwt1 inhibitors, and immunomodulators. In any of the foregoing embodiments involving SCY-247 (or its pharmaceutically acceptable salts or hydrates) and a second antifungal agent, the second antifungal agent may be selected from: amphotericin B, isaconazole, voriconazole, posaconazole, itraconazole, olorofen, and fossogpi. Amphotericin B is a preferred second antifungal agent.

[0149] Examples of polyenes that can be used as a second antifungal agent in any of the foregoing embodiments involving SCY-247 (or its pharmaceutically acceptable salts or hydrates) include (but are not limited to) amphotericin B, its liposomes and lipid forms, such as ABELCET. ® AMBISOME ® and AMPHOCIL ®Nystatin and its liposomes and lipid forms, and the third-generation polyene SF001 and its liposomes and lipid forms. Examples of azoles that can be used as secondary antifungal agents in any of the foregoing embodiments involving SCY-247 (or its pharmaceutically acceptable salts or hydrates) include (but are not limited to) isaconazole, fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, rivconazole, detoconazole, clotrimazole, and posaconazole. Examples of purine or pyrimidine nucleotide inhibitors that can be used as secondary antifungal agents in any of the foregoing embodiments involving SCY-247 (or its pharmaceutically acceptable salts or hydrates) include (but are not limited to) flucytosine, polyoxin, and huaguangmycin, particularly huaguangmycin Z or huaguangmycin X. Polyoxin and huaguangmycin are also chitin inhibitors; these and other chitin inhibitors can be used as secondary antifungal agents in any of the foregoing embodiments involving SCY-247 (or its pharmaceutically acceptable salts or hydrates). Examples of ollotomede compounds that can be used as a secondary antifungal agent in any of the foregoing embodiments involving SCY-247 (or a pharmaceutically acceptable salt or hydrate thereof) include (but are not limited to) ollorofen. Examples of Gwt1 inhibitor compounds that can be used as a secondary antifungal agent in any of the foregoing embodiments involving SCY-247 (or a pharmaceutically acceptable salt or hydrate thereof) include (but are not limited to) fostigpi. Examples of immunomodulators that can be used as a secondary antifungal agent in any of the foregoing embodiments involving SCY-247 (or a pharmaceutically acceptable salt or hydrate thereof) include (but are not limited to) interferons (e.g., IL-1, IL-2, IL-3, and IL-8), defensins, tacrolimus, and granulocyte colony-stimulating factor (G-CSF).

[0150] Mucormycosis infections that can be treated according to the present invention include nasoencephalomycosis, pulmonary mucormycosis, gastrointestinal mucormycosis, cutaneous mucormycosis, and disseminated mucormycosis.

[0151] For the purpose of treating fungal infections, compounds of formula (I) (including SCY-247) or their pharmaceutically acceptable salts or hydrates and a second antifungal agent may be administered individually in any manner that produces contact between the respective active agent and the site of action of the active agent. Compounds of formula (I) (including SCY-247) or their pharmaceutically acceptable salts or hydrates and a second antifungal agent may be administered individually or in combination of therapeutic agents in a manner commonly used for use in combination with pharmaceuticals. They may be administered alone, but according to typical practice, may be administered together with a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice. They may be administered simultaneously or sequentially via any acceptable route of administration suitable for the desired purpose for part or the entire duration of a prolonged antifungal regimen. For example, compounds of formula (I) (including SCY-247) or their pharmaceutically acceptable salts or hydrates, along with a second antifungal agent, may be administered intravenously, orally, or topically; or one intravenously and the other orally; or one orally and the other topically; or in any combination of routes of administration suitable for the fungal infection being treated. For mucormycosis, the preferred routes of administration are oral and / or intravenous. If the first and second antifungal agents are administered simultaneously, this includes both the first and second antifungal agents being administered together in a single dose unit and the first and second antifungal agents being administered in separate dose units. Compounds of formula (I) (including SCY-247) or their pharmaceutically acceptable salts or hydrates and a second antifungal agent may be administered in unit dose form of a pharmaceutical composition containing an effective amount of the active agent and conventionally nontoxic, pharmaceutically acceptable carriers, adjuvants, and mediators, for example, via one or more of the following routes: oral, non-enteric (including subcutaneous, intravenous, intramuscular, intralesional, or infusion techniques), by inhalation (e.g., via nebulizer, nasal or buccal inhalation spray, self-dose inhaler aerosol, and dry powder inhaler), ocular, topical, transdermal, or rectal. The administration pattern of the first and / or second antifungal agent may be changed during treatment; for example, the first antifungal agent may be administered intravenously to the individual for a period of time, such as the first 2 to 6 weeks of treatment, and then the first antifungal agent in the form of an oral formulation (e.g., tablets) may be administered to the individual for another period of time, such as the 7th to 12th week of treatment. The first and second antifungal agents can be administered in combination for an initial period (e.g., 2 to 6 weeks), followed by administration of only the first antifungal agent for a subsequent period (e.g., up to 6 more weeks, for a total of up to 12 weeks, during which the first antifungal agent is administered).

[0152] Liquid dosage forms (e.g., suspensions, slurries, elixirs, etc.) suitable for oral administration can be prepared according to techniques known in the relevant art and can use common media such as water, glycols, oils, and alcohols. Solid dosage forms (e.g., powders, pills, capsules, and tablets) suitable for oral administration can be prepared according to techniques known in the relevant art and can use solid excipients such as starch, sugar, kaolin, lubricants, binders, and disintegrants. Non-enteral compositions can be prepared according to techniques known in the relevant art and typically use sterile water as a carrier and optionally other components (e.g., dissolving agents). Injectable solutions can be prepared according to methods known in the relevant art, wherein the carrier comprises a saline solution, a glucose solution, or a solution containing a mixture of saline and glucose.

[0153] Further descriptions of methods suitable for preparing pharmaceutical compositions and ingredients suitable for use in said compositions are provided in [the relevant section]. Remington's Pharmaceutical Sciences 20th edition, edited by AR Gennaro, Mack Publishing Co., 2000.

[0154] Compounds of formula (I) (including SCY-247) or their pharmaceutically acceptable salts or hydrates may be administered, for example, in dose ranges from 0.001 to 1000 mg / kg of mammalian (e.g., human) body weight daily, in a single dose or in divided doses (e.g., orally or intravenously). One example of a dose range is 0.01 to 500 mg / kg body weight daily, orally or intravenously, in a single dose or in divided doses. Another example of a dose range is 0.1 to 100 mg / kg body weight daily, orally or intravenously, in a single dose or in divided doses. For oral administration, compositions containing compound (I) (including SCY-247) or its pharmaceutically acceptable salts or hydrates may be provided in the form of tablets, capsules, solutions, or suspensions containing, for example, 1.0 to 1000 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, and 1000 mg of the active ingredient for symptomatic dose adjustment in the patient to be treated. For intravenous administration, compositions containing compound (I) (including SCY-247) or its pharmaceutically acceptable salts or hydrates may be provided in the form of, for example, 1.0 to 500 mg of the active ingredient, in the form of solutions, suspensions, or other acceptable pharmaceutical forms. For local administration, compositional (I) compounds (including SCY-247) or their pharmaceutically acceptable salts or hydrates may be provided in, for example, creams, solutions, ointments, foams, powders, lacquers, emulsions, or other pharmaceutically acceptable forms containing, for example, 0.001 to 200 mg of active ingredient per gram of product. Specific dose levels and frequencies for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of said compound, age, weight, general health, sex, diet, administration pattern and time, excretion rate, drug combination, severity of the specific condition, and the host having previously received therapy.

[0155] The second antifungal agent may be administered, for example, in a dose range of 0.001 to 1000 mg / kg of mammalian (e.g., human) body weight per day, in a single dose or in divided doses, more preferably in a dose range of 0.01 to 100 mg / kg (e.g., orally or intravenously). An example of a dose range is 1 to 100 mg / kg body weight per day, orally or intravenously, in a single dose or in divided doses. Another example of a dose range includes posaconazole, administered orally or intravenously in a single or divided dose range of 2 to 20 mg / kg per day. Another example of a dose range includes isaconazole, administered orally or intravenously in a single or multiple dose range of 2 to 40 mg / kg per day. Another example of a dose range includes amphotericin B, administered intravenously in a range of 0.1 to 10 mg / kg per day or orally in a single or multiple dose range of 5 to 50 mg / kg per day. For oral administration, compositions containing a second antifungal agent may be provided in the form of tablets, suspensions, solutions, or capsules containing, for example, 1.0 to 1000 mg of active ingredient, particularly 50, 75, 100, 150, 200, 250, 300, 375, 400, 500, and 1000 mg of active ingredient, for symptomatic dose adjustment in the patient to be treated. For intravenous administration, compositions containing a second antifungal agent may be provided in the form of solutions, suspensions, or other acceptable pharmaceutical forms containing, for example, 1.0 to 500 mg of active ingredient. For topical administration, compositions containing a second antifungal agent may be provided in the form of creams, solutions, ointments, foams, powders, liniments, lotions, or other pharmaceutically acceptable forms containing, for example, 0.001 to 200 mg of active ingredient per gram of product. The specific dose level and frequency for any particular patient can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability of the compound and the duration of its action, age, weight, general health, sex, diet, administration pattern and time, excretion rate, drug combination, severity of the specific condition and the host having received the therapy.

[0156] In a preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof is administered orally. In other preferred embodiments, SCY-247 or a pharmaceutically acceptable salt or hydrate thereof is administered orally.

[0157] In other preferred embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof is administered intravenously. In other preferred embodiments, SCY-247 or a pharmaceutically acceptable salt or hydrate thereof is administered intravenously.

[0158] In a preferred embodiment, the second antifungal agent is administered orally. In other preferred embodiments, the second antifungal agent is administered intravenously.

[0159] In a preferred embodiment, the second antifungal agent is amphotericin B. For intravenous administration, amphotericin B can be formulated as, for example, amphotericin B deoxycholate, liposome formulation, or liquid complex formulation. For oral administration, amphotericin B can be formulated as, for example, solid lipid nanoparticles or polymer nanoparticles.

[0160] In a preferred embodiment, a pharmaceutically acceptable salt of SCY-247 is administered to an individual to provide a total daily dose of 150 to 1500 mg of SCY-247, and amphotericin B is administered to the individual to provide a total daily dose of 20 to 600 mg of amphotericin B. In some such preferred embodiments, SCY-247 is administered at a total daily dose of 150 mg, or 250 mg, or 500 mg, or 750 mg, or 1000 mg, or 1500 mg; the total daily dose may be based on once-daily administration or may be administered in divided doses, such as BID (twice-daily) or TID (three times-daily), or may be administered less frequently (e.g., three times, twice, or once a week), particularly for the treatment of pulmonary mucormycosis. In some of these preferred embodiments, a pharmaceutically acceptable salt of SCY-247 is administered via QD (once daily) or BID to provide 150 to 750 mg daily, or 250 to 750 mg daily, or 250 to 1000 mg daily of compound (I).

[0161] In other preferred embodiments, for treating an individual with pulmonary mucormycosis, SCY-247 or a pharmaceutically acceptable saline or hydrate thereof is administered orally, providing a total daily dose of 250 mg to 1000 mg of SCY-247, and liposomal amphotericin B is administered intravenously, providing a total daily dose of 50 to 350 mg of amphotericin B. In other preferred embodiments, for treating an individual with pulmonary mucormycosis, SCY-247 or a pharmaceutically acceptable saline or hydrate thereof and amphotericin B are administered for 2 to 12 weeks.

[0162] In other preferred embodiments, for treating an individual with pulmonary mucormycosis, SCY-247 or a pharmaceutically acceptable saline or hydrate thereof is administered orally, providing a total daily dose of 150 mg to 750 mg of SCY-247, and liposomal amphotericin B is administered intravenously, providing a total daily dose of 60 to 300 mg of amphotericin B. In other preferred embodiments, for treating an individual with pulmonary mucormycosis, SCY-247 or a pharmaceutically acceptable saline or hydrate thereof and amphotericin B are administered for 4 weeks.

[0163] In a preferred embodiment, SCY-247 (or a pharmaceutically acceptable salt or hydrate thereof) and amphotericin B are administered as a combination therapy for treating an individual’s fungal infection (e.g., mucormycosis), and the dose of amphotericin B used in the combination therapy is less than the dose of amphotericin B already used in a monotherapy regimen for the fungal infection.

[0164] Compounds of formula (I) (including SCY-247) and their pharmaceutically acceptable salts or hydrates may be prepared according to the synthetic method disclosed in U.S. Patent No. 7,863,465, the contents of which are incorporated herein by reference in their entirety.

[0165] In the embodiments illustrated above, the description of compounds of formula (I) includes the indicated substitutions only to the extent that the substituents provide a stable compound as defined.

[0166] As used herein, the term "alkyl" refers to any straight-chain or branched alkyl group having a number of carbon atoms within a specified range. Thus, for example, "C 1-6 "Alkyl" (or "C1-C6 alkyl") refers to all hexylalkyl and pentylalkyl isomers, as well as n-, iso-, secondary and tert-butyl, n- and isopropyl, ethyl and methyl. As another example, "C1-C6 alkyl"... 1-4 "Alkyl" refers to n-, iso-, secondary and tert-butyl, n- and isopropyl, ethyl and methyl.

[0167] The term "alkoxy" refers to -O-alkyl, where alkyl is as defined above.

[0168] The term "cycloalkyl" refers to any cyclic ring of an alkane having a number of carbon atoms within a specified range. Therefore, for example, "C..." 3-6 "Cycloalkyl" (or "C3-C6 cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0169] The term "halogen" (or "halogen group") refers to fluorine, chlorine, bromine, and iodine (or fluorine group, chlorine group, bromine group, and iodine group).

[0170] The term "haloalkyl" refers to an alkyl group as defined above, wherein one or more of the hydrogen atoms have been substituted with a halogen (i.e., F, Cl, Br, and / or I). Thus, for example, "C1-6 haloalkyl" (or "C1-C6 haloalkyl") refers to a C1 to C6 straight-chain or branched alkyl group as defined above, having one or more halogen substituents. Suitable haloalkyl groups include the series (CH2). 0-5 CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, etc.).

[0171] The term "silyl alkyl" refers to an alkyl group as defined above, wherein one or more of the carbon atoms have been replaced by silicon atoms.

[0172] Unless explicitly stated otherwise, all scopes referenced herein are inclusive. For example, a description of a heterocycle containing “1 to 4 heteroatoms” means that the ring may contain 1, 2, 3, or 4 heteroatoms. It should also be understood that any scope referenced herein includes all subscopes within that scope. Thus, for example, a description of a heterocycle containing “1 to 4 heteroatoms” is intended to include, as an aspect thereto, heterocycles containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, and so on.

[0173] Any of the various cycloalkyl and heterocyclic / heteroaryl rings and ring systems defined herein can be attached to the remainder of a compound at any ring atom (i.e., any carbon atom or any heteroatom), provided that a stable compound is produced. Suitable 5- or 6-membered heteroaromatic rings include (but are not limited to) pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiopheneyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxtriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 3- to 6-membered heterocyclic groups include (but are not limited to) acridinel, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolidinyl, imidazolyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, tetrahydropyranyl, tetrahydrothiaranyl, and dioxalyl.

[0174] A "stable" compound is one that can be prepared and isolated and whose structure and properties remain or are likely to remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., individual therapeutic administration).

[0175] Due to the choice of substituents and substituent patterns, certain compounds of formula (I) may have an asymmetric center and may exist as a mixture of stereoisomers or as individual diastereomers or enantiomers. Unless otherwise indicated, the use of all isomers of these compounds (whether isolated or in mixtures) is within the scope of this invention. The use of tautomers of the compounds as depicted is also included within the scope of this invention.

[0176] When any variable appears more than once in any component or in equation (I), its definition at each occurrence is independent of its definition at each other occurrence. Furthermore, combinations of substituents and / or variables are permitted only if such combinations produce stable compounds.

[0177] The term "substituted" includes both mono- and poly-substituted substitutions by a specified substituent, provided that such mono- and poly-substituted substitutions (including poly-substituted substitutions at the same site) are chemically permissible. Unless the contrary is expressly stated, substitution by a specified substituent is permitted on any atom of a ring (e.g., aryl, cycloalkyl, heteroaryl, or heterocyclic) provided that such cyclic substitution is chemically permissible and produces a stable compound.

[0178] Compounds of formula (I) may be administered suitably as pharmaceutically acceptable salts or hydrates. The term "pharmaceutically acceptable salt" refers to a salt having approximately the same efficacy as the parent compound and suitable for administration to a patient. Suitable salts include acid addition salts, which can be formed, for example, by mixing a solution of a compound of formula (I) with a solution of a pharmaceutically acceptable acid. Many compounds of formula (I) carry an acidic moiety, in which case suitable pharmaceutically acceptable salts may include alkali metal salts, alkaline earth metal salts, and salts formed with suitable organic ligands (e.g., quaternary ammonium salts). Furthermore, in the presence of an acid (-COOH) or alcohol group, pharmaceutically acceptable esters may be used to adjust the solubility or hydrolytic properties of the compound.

[0179] The term “administration” and its variations (e.g., “administering” of a compound) means the administration of a compound or a prodrug of a compound to an individual in need of treatment. When a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof is administered in combination with a second antifungal agent, “administration” and its variations shall each be understood to include the simultaneous and sequential administration of the compound (or a pharmaceutically acceptable salt or hydrate thereof) and the second antifungal agent.

[0180] As used herein, the term "composition" is intended to cover products containing the specified ingredients, and any products that are produced directly or indirectly as a result of combining the specified ingredients.

[0181] "Pharmaceutical acceptable" means that the components of a drug composition must be compatible with each other and harmless to the recipient.

[0182] As used herein, the term “individual” (or “patient” as used herein) refers to an animal, preferably a mammal, and most preferably a human, that has been used as the subject of treatment, observation or experimentation.

[0183] The term "synergistic effect" refers to the effect provided by a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof or its hydrate with a second antifungal agent to treat a condition, said effect being better, more beneficial, or more significant than the additive effect of individual therapies. The synergistic effect of the therapy combination may enable the use of one or more of the individual therapies at lower doses and / or at lower frequencies of administration to an individual with the condition; this ability to use lower doses and / or administer the therapy at lower frequencies reduces the toxicity associated with administration of the therapy to the individual without diminishing the efficacy of the therapy in treating the condition. Furthermore, the synergistic effect may enhance the efficacy of the agent in treating the condition. Finally, the synergistic effect of the therapy combination may allow for the avoidance or reduction of adverse or undesirable side effects associated with the use of any one therapy alone.

[0184] As used herein, the term "effective amount" means the amount of an active compound that elicits a biological or medical response in a tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or other clinician. In one embodiment, an "effective amount" may be a therapeutically effective amount that relieves symptoms of the disease or symptom being treated. The term may also refer to an inhibitory effective amount of an infmufenquinol derivative sufficient to inhibit (1,3)-β-D-glucan synthase and thereby elicit the sought response. The term may also refer to an amount of a second antifungal agent (e.g., mycotoxin) sufficient to inhibit fungal growth. The term may also refer to an amount (e.g., a therapeutically effective amount or an inhibitory effective amount) of an infmufenquinol derivative and a second antifungal agent sufficient to inhibit fungal growth and thereby elicit the sought response when administered in combination. When the active compound is administered in salt or hydrate form, references to the amount of the drug administered refer to the free acid or free base form of the compound.

[0185] When “treat / treating / treatment” and its variants are mentioned, it generally refers to treatment that eliminates or improves one or more signs or symptoms associated with a fungal infection, or eradicates the fungus causing the infection, or any combination of these results after its administration.

[0186] The antifungal activity of a compound can be determined by various assays known in the relevant field, such as by measuring its inhibitory activity against yeast glucan synthesis (IC50) in a broth microdilution assay. 50 Minimum Inhibitory Concentration (MIC) 100 or minimum significant inhibition (MIC) 80The minimum effective concentration (MEC) against filamentous molds and dermatophytes is used to confirm the antifungal activity, or it is confirmed by measuring the in vivo antifungal activity in a mouse model. Generally, compounds of formula (I) have been found to provide MECs against Aspergillus fumigatus in the range of <0.5 to 8 µg / mL and MECs against Mucor at >16 µg / mL.

[0187] Example

[0188] The following examples are for illustrative purposes only and are not intended to limit the scope or spirit of the invention.

[0189] Example 1

[0190] An immunodeficient mouse model was used in a study to evaluate the activity of SCY-247 alone and in combination with liposomal amphotericin B (L-AMB), the current standard of care for mucormycosis. Although SCY-247 has shown low potency against mucormycosis in in vitro testing, in this study, SCY-247 surprisingly demonstrated in vivo efficacy against mucormycosis when used alone, and even more so when used in combination with amphotericin B.

[0191] Preparation of SCY-247 for administration in mice

[0192] SCY-247 was prepared in 0.5% (w / v) methylcellulose (400 CPS) in sterile water for injection and stirred for at least 30 minutes using a magnetic stir plate and stirring rod, then adjusted to pH 6.5 ± 0.3 (Table 1). The formulation was stored in a refrigerator protected from light, set to maintain a temperature of 2 to 8°C, and used within 24 hours of preparation. The solution or suspension was allowed to acclimate to ambient room temperature before administration. These storage conditions were selected for further stability studies. The mediator control formulation of the 0.5% (w / v) methylcellulose solution was stored similarly to the SCY-247 formulation. A formulation of liposomal amphotericin B (L-AMB) was used as a positive control.

[0193] Table 1. SCY-247 Dosage Formulation

[0194]

[0195] Group 2 was administered only with the mediator control (0.5% (w / v) methylcellulose).

[0196] b: All groups are presented in Table 2.

[0197] c: Groups 4 and 7 were administered SCY-247; Group 7 also received L-AMB.

[0198] SCY-247 dosing

[0199] The SCY-247 dose formulation was administered orally twice daily (BID) (approximately every 12 hours) at a dose volume of 10 mL / kg for 7 days. The dosage was based on the most recently recorded average body weight. The dose formulation was allowed to equilibrate to approximately room temperature and stirred for at least 30 minutes using a magnetic stir plate and stir bar before and throughout the administration period. The SCY-247 formulation was a suspension requiring continuous stirring during the administration period. The purity of SCY-247 was determined by HPLC. SCY-247 from one batch was administered orally at doses of 20, 40, and 60 mg / kg BID, which, after correction for purity, correspond to doses of SCY-247 of 16, 32, and 48 mg / kg BID, respectively. These corrected actual SCY-247 doses (i.e., 16, 32, and 48 mg / kg) are used in the description of the methods and results of the experiments.

[0200] mouse strains

[0201] Outcrossed male ICR mice weighing approximately 25 grams were used. The mice were housed in captivity at a rate of 5 mice per cage, with free access to food and water.

[0202] Immune status

[0203] Neutropenia was induced in mice on days -2, +3, and +8 relative to infection by intraperitoneal administration of 200 mg / kg cyclophosphamide in sterile irrigation water and subcutaneous (SQ) administration of 500 mg / kg cortisone acetate (CA) in 0.1 ml 0.05% Tween 80 (ultrasound treatment for 30 to 60 seconds prior to use).

[0204] To prevent super-infection and death in immunosuppressed mice, mice were given enrofloxacin (Baytril) at 50 ppm in drinking water on day -3 relative to infection. ® The patient was given antibacterial prophylaxis with a drug from Bayer, and then switched to daily treatment with ceftazidime (5 mg) from day 0 to day +13.

[0205] isolates and intratracheal inoculation

[0206] Rhizopus delemar 99-880, isolated from the brain of a patient with mucormycosis, was obtained from the Fungus Testing Laboratory at UT Health San Antonio. This strain had its genome sequenced and was a standard strain for virulence and therapeutic studies of mucormycosis. The organisms were grown on potato dextrose agar (PDA, Becton Dickinson) plates at 37°C for 4 to 5 days. Sporangiospores were collected in endotoxin-free Dulbecco's phosphate-buffered saline (PBS) containing 0.01% Tween 80, washed with PBS, and counted using a hemocytometer to prepare 1 x 10⁻⁶ cells / mL. 7 The final concentration was [number of spores / ml]. After sedation with isoflurane gas while simultaneously pulling the tongue forward and to the side with forceps, Fisherbrand was used. TM The gel loading tip will hold 25 μl of fungal spores (2.5 x 10⁻⁶) contained in PBS. 5 (Spores) were injected into the trachea via the vocal cords. Five mice were killed immediately after inoculation (within 2 to 3 minutes), and their lungs were subsequently homogenized and quantitatively cultured to confirm inoculum delivery to the lungs. For SCY-247, MIC 100 The MIC of L-AMB (defined as the concentration that causes 100% growth inhibition) is >16 µg / mL. 100 The value was 0.0315 µg / mL.

[0207] Mouse assessment

[0208] Throughout the experiment, animals were monitored at least twice daily to prevent and minimize unnecessary pain and suffering. Any animal that became moribund before the endpoint was euthanized. Moribund animals were identified using the following criteria:

[0209] 1. Fur with wrinkles / dull texture

[0210] 2. Hunchback posture

[0211] 3. Weight loss (e.g., >20%)

[0212] 4. Hypothermia (feels very cold to the touch)

[0213] 5. Over- / under-ventilation

[0214] 6. Unable to eat or drink

[0215] Animals exhibiting >1 of these criteria will be euthanized by isoflurane anesthesia followed by cervical dislocation.

[0216] treat

[0217] All antifungal treatments were initiated 24 hours after infection. Mice were administered SCY-247 orally (PO) for 7 days at doses of 16, 32, and 48 mg / kg twice daily (BID) (Table 3). A placebo control group consisting of a mediator used to administer SCY-247 was also included, administered orally via PO. Other mouse groups received: L-AMB at 10 mg / kg / day, intravenously (IV) for 4 days; or a combination of L-AMB (10 mg / kg IV) and SCY-247 (32 mg / kg BID PO) for 4 days, followed by SCY-247 alone (32 mg / kg BID PO) for 3 days. Treatment studies consisted of survival experiments and tissue fungal load assays of target organs in the lungs and brain (measured by qPCR). The number of mice in each treatment group and arm is listed in Table 2.

[0218] Table 2. Treatment groups and number of mice in each group in the survival and tissue fungal load experiments.

[0219]

[0220] Total number of mice required = 140

[0221] Result measurement

[0222] Two primary outcome measures were used to confirm the efficacy of SCY-247 compared to L-AMB in treating neutropenic mice infected with Rhizopus delbrueckii. These were:

[0223] 1. Survive Mice were monitored at least twice daily until day 21, or at least 14 days after treatment was discontinued in the treatment study, to allow for adequate rinsing out of the antifungal agent. To prevent and minimize unnecessary pain or suffering, any animal that became moribund (according to the above criteria) before the endpoint was euthanized as described above.

[0224] 2. Tissue load – Tissue fungal load was determined using qPCR to count colony-forming units in the lungs (primary target organ) and brain (secondary target organ). Tissue was collected in the fungal load arm on day +4 (the day before placebo mice began to die from infection). Organ collection was performed 8 hours after the last treatment, administered in the early morning of day +4.

[0225] Data Analysis

[0226] Survival rates were plotted using Kaplan-Meier analysis, and differences in median survival time and percentage survival were analyzed using log-rank and chi-square tests, respectively. For comparisons involving more than two groups, ANOVA with Tukey's post-test for multiple comparisons was used for normally distributed data, and the Kruskal-Wallis test with Dunn's post-test for multiple comparisons was used for non-normally distributed data. A p-value <0.05 was considered statistically significant for all comparisons.

[0227] result

[0228] SCY-247 monotherapy and combination therapy are effective in treating pulmonary mucormycosis in rodents caused by Rhizopus delbrueckii.

[0229] The efficacy of SCY-247 in treating murine mucormycosis was evaluated in survival studies, as described above, either alone or in combination with L-AMB. In these studies, all monotherapy treatments with SCY-247 (16, 32, or 48 mg / kg BID) and L-AMB improved survival compared to placebo-treated mice, with overall survival rates of 20%, 40%, 50%, and 40%, respectively, compared to 0% in placebo-treated mice. Furthermore, 32 and 48 mg / kg (BID) of SCY-247 resulted in enhanced median survival of 14.5 and 18 days, respectively, compared to 8.5 days with placebo. The combination therapy of 32 mg / kg (BID) of SCY-247 + L-AMB achieved an overall survival rate of 90% and a median survival of >21 days, which was superior to placebo and to any monotherapy. Figure 1 Therefore, both SCY-247 monotherapy and combination therapy improved the survival of neutropenic mice with pulmonary mucormycosis. Table 3 shows the log-rank P-values ​​for the percentage survival rates of each group. A P-value <0.05 was considered significant.

[0230] Table 3. Log-rank (Mantel-Cox) test (P-value)

[0231]

[0232]

[0233] SCY-247 monotherapy and combination therapy with L-AMB reduced tissue fungal load in mice infected with Rhizopus delbrueckii.

[0234] After demonstrating the efficacy of SCY-247, alone or in combination with L-AMB, in prolonging mouse survival as described above, the effects of treatment on lung and brain fungal load in mice infected with *Rhizopus delbrueckii* were evaluated. In this model, the lungs and brain were the primary and secondary target organs. Mice were infected via the tracheal route and treated as described above. On day +4 relative to infection, mice were sacrificed, and tissues were collected, homogenized, and fungal load was determined by qPCR. Consistent with survival studies, single-dose treatment with SCY-247 at 32 or 48 mg / kg resulted in a reduction of lung and brain fungal load by approximately 0.7 to 1.0 log compared to placebo-treated mice, similar to L-AMB at 10 mg / kg, qd. Importantly, and consistent with the synergistic effects shown in survival studies, the combination of SCY-247 (32 mg / kg, BID) + L-AMB (10 mg / kg, qd) reduced the fungal load in lung and brain tissues by approximately 2.0 to 3.0 log compared to placebo and by approximately 1.5 log compared to monotherapy (Table 4).

[0235] Table 4. Mann-Whitney Test

[0236]

[0237]

[0238]

[0239] SCY-247 monotherapy (32 and 48 mg / kg BID) or combination therapy with L-AMB reduced tissue fungal load in immunosuppressed mice infected with Rhizopus delbrueckii.

[0240] Assessment of intratracheal infection with Rhizopus delbrueckii 99-880 (4.1 x 10⁻⁶) 3 Fungal load in the lungs and brain tissues of mice (1 spore / mouse). Mice were killed on day +4 relative to infection. P < 0.05 was considered significant.

[0241] SCY-247 monotherapy (32 and 48 mg / kg BID) is as effective as the standard of care for L-AMB.

[0242] SCY-247 monotherapy at 32 or 48 mg / kg (BID) was as effective as the standard of care with L-AMB at 10 mg / kg / day in prolonging median survival, improving overall survival, and reducing tissue fungal load in mice with neutropenia infected with Rhizopus delbrueckii. SCY-247 showed a synergistic effect against mucormycosis in rodents when combined with L-AMB.

[0243] Example 2

[0244] Another study could be conducted to further investigate the synergistic effect of combination therapy of SCY-247 and amphotericin B in the treatment of mucormycosis. In this study, amphotericin B will be tested in combination with SCY-247 at different doses.

[0245] The recommended first-line treatment for mucormycosis is a liposomal formulation of amphotericin B, but the nephrotoxicity of amphotericin B limits the duration of treatment (meaning prolonged treatment is not possible) and dosage (meaning higher doses are not feasible). The combination of SCY-247 and amphotericin B allows for the administration of lower doses of amphotericin B, thus reducing toxicity issues while maintaining acceptable efficacy. This synergistic effect can be investigated using an immunodeficient mouse model of pulmonary mucormycosis.

[0246] Preparation of SCY-247 for mouse administration: SCY-247 was prepared in 0.5% (w / v) methylcellulose (400 CPS) in sterile water for injection and stirred for at least 30 minutes, then adjusted to pH 6.5 ± 0.3. A formulation of the 0.5% (w / v) methylcellulose solution was used as a mediator control. A formulation of liposomal amphotericin B (L-AMB) was used as a positive control.

[0247] SCY-247 Dosage: The SCY-247 dosage formulation will be administered orally twice daily (BID) (approximately every 12 hours) for 7 days at a dose volume of 10 mL / kg. SCY-247 will be administered orally to provide a dose of approximately 32 mg / kg BID of SCY-247.

[0248] Mouse strain and immunological status: Outcrossed male ICR mice weighing approximately 25 grams were used in this study. Neutropenia was induced in mice on days -2, +3, and +8 relative to infection by intraperitoneal administration of 200 mg / kg cyclophosphamide in sterile irrigation water and subcutaneous (SQ) administration of 500 mg / kg cortisone acetate (CA) in 0.1 ml of 0.05% Tween 80. Another immunosuppressive regimen known in the art could be used. Mice were given antibacterial prophylaxis to prevent bacterial co-infection and death in immunosuppressed mice.

[0249] Inoculation: Rhizopus delbrueckii or other Mucor species will be used for intratracheal inoculation.

[0250] Measurements: Survival rate and colony-forming units in lung tissue will be used to assess the therapeutic effect.

[0251] Treatment: All antifungal treatments will begin 24 hours after infection. Mice will receive SCY-247 orally (PO) for 7 days at approximately 32 mg / kg twice daily (BID). A placebo control group consisting of the mediator used to administer SCY-247 will also be included. Other mouse groups will receive: L-AMB intravenously (IV) for 4 days at doses ranging from 1 to 10 mg / kg / day; or a combination of L-AMB and SCY-247 (32 mg / kg BID PO) for 4 days, followed by SCY-247 alone (32 mg / kg BID PO) for another 3 days. Treatment studies will consist of survival experiments and tissue fungal load assays of target organs (measured by qPCR). The number of mice in each treatment group and arm will be approximately 10 per active substance treatment group and approximately 5 per mediator control group.

[0252] Data Analysis: Survival rates will be plotted using Kaplan-Meier analysis, and differences in median survival time and percentage survival will be analyzed using log-rank tests and chi-square tests, or other statistically comparable methods known in the relevant fields. For all comparisons, a p-value < 0.05 will be considered statistically significant.

[0253] Results: The results of this study confirm that comparable or better therapeutic effects were observed when amphotericin B at doses below 10 mg / kg / day was combined with SCY-247, compared to the therapeutic effects achieved by high doses of amphotericin B (10 mg / kg / day). This indicates that combination therapy with SCY-247 and amphotericin B can provide a less toxic treatment regimen while maintaining efficacy against diseases associated with high mortality rates.

[0254] While the invention has been particularly shown and described with reference to its preferred embodiments, those skilled in the art will understand from this disclosure that various changes in form and detail may be made herein without departing from the scope of the invention as covered by the appended claims.

Claims

1. A method for treating mucormycosis in an individual in need, the method comprising administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof: in: X is O or H,H; R 1 for a) OH; b) OC(O)C1-C 12 -alkyl group, which is unsubstituted or has one or two derivatives selected from OR 0 、N(R 0 )2 and CO2R 0 Substituents of the substituents; c) OC(O)C1-C6-haloalkyl; d) OC(O)C3-C8-cycloalkyl; e) O-C1-C6-alkyl, which is unsubstituted or has one or two derivatives selected from OR 0 and N(R) 0 Substitution of )2 by substituents; f) OC(O)NHC1-C6-alkyl, which is unsubstituted or phenyl-substituted; g) OC(O)OC1-C6-alkyl; h) NHC(O)C1-C6-alkyl, which is unsubstituted or phenyl-substituted; or i) (O) n CH2C(O)C1-C6-alkyl; n is 0 or 1; R 2 for a) CH2R 4 , b) CH2CHR 5 (CH2) m NR 6 R 7 , c) CH2C(R 8 )(R 9 )(CH2) m NR 6 R 7 , d) CH2C(R 10 )(R 11 )R 12 , e) CH2CH(OR 0 )CH2OR 0 , f) CHR 13 CHR 5 (CH2) m NR 6 R 7 , g) (CH2) p C(R 8 (R) 9 )NR 6 R 7 ,or h) CH2CHR 5 C(R 8 )(R 9 )NR 6 R 7 , m is 0, 1, or 2; p is between 2 and 6; R 1 and R 2 Optionally, together they form methylenedioxy or ethylenedioxy groups that are unsubstituted or substituted with one or two substituents selected from C1-C6-alkyl and C1-C6-alkoxy groups; R 3 for a) C(O)R 14 ; b) CH2OH; or c) CH2OC(O)C1-C6-alkyl; R 14 For OH, OR 15 H, N(R) 0 )2 or C1-C6-alkyl; R 15 It is a C1-C6-alkyl group, which is unsubstituted or has one or two derivatives selected from phenyl, OC(O)C1-C6-alkyl, C(O)OR 0 OR 0 C(O)N(R) 0 )2 and C(O)NH2(CH2) 2-4 The NH2 group is substituted, and the phenyl group is optionally substituted with 1 to 3 halogen groups; R 4 for a) H; b) (CH2) 1-6 -R 16 ; c) OC1-C6-alkyl; d) Aryl group, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from 1 to 3 hydroxyl groups selected from halogens, N(R) 0 2. OR 0 C1-C6-alkyl, CF3, OCF3, CO2R 0 and C(O)N(R) 0 Substitution of )2 by substituents; e) A heterocyclic group, wherein the heterocyclic group is a 3- or 6-membered saturated or unsaturated nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, which is linked via a carbon or nitrogen atom on the ring, and optionally substituted at the non-linking carbon or nitrogen atom by 1 to 2 substituents selected from: side-oxygen groups, N(R) ... 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or has one or two derivatives selected from N(R) 0 2. NHC (=NH)NH2, OC (O)C1-C6-alkyl and CO2R 0 Substituents; or f) A heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, linked via a ring carbon or nitrogen atom, and optionally substituted at the non-linking ring carbon or nitrogen atom by 1 or 2 substituents selected from: N(R 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are unsubstituted or have one or two derivatives selected from N(R) 0 2. NHC (=NH)NH2, OC (O)C1-C6 alkyl groups and CO2R 0 Substituents of the substituents; R 16 for a) H; b) OH; c) NH2; d) NHC(O)R 17 ; e) NHSO2R 17 ; f) NHC(O)NHR 0 ; g) NHC(O)CHR 18 NH2; h) A heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered saturated or unsaturated nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, which is linked via a carbon or nitrogen atom on the ring, and optionally substituted at the non-linking carbon or nitrogen atom by 1 to 2 substituents selected from: N(R 0 2. Imino, lateral oxygen, OR 0 CO2R 0 CON(R) 0 )2 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or has one or two derivatives selected from N(R) 0 )2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, OR 0 and CO2R 0 Substituents of the substituents; i) NH-N(C1-C6-alkyl)2; j) NHC(=NH)NHC(=NH)NH2; k) NR a (CH2) p NHR a ; l) NR a R b ; m) N(R b )2; n) NHC(=NR d )NH2; o) NHC(=NR c )NH-C1-C6-alkyl, wherein the alkyl group is unsubstituted or substituted with phenyl, CF3 or NHC(O)C1-C6-alkyl; p) NHC(=NR d )NH-C3-C6-cycloalkyl; q) NHC(=NR d )NH-phenyl, wherein the phenyl group is unsubstituted or substituted with one or two substituents selected from halogens and CF3; r) CO2C1-C6-alkyl; s) OCOC1-C6 alkyl; t) a heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, which is linked via a carbon or nitrogen atom on the ring, and optionally substituted at a non-linking carbon or nitrogen atom by 1 or 2 substituents selected from: N(R 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are unsubstituted or have one or two derivatives selected from N(R) 0 2. NHC(=NH)NH2, OC(O)C1-C6 alkyl, OR 0 and CO2R 0 Substituents; or u) CN; p is 1, 2, 3 or 4; R a It is H or C(=NH)NH2; R b It is a C1-C6 alkyl group, which is unsubstituted or has one or two derivatives selected from N(R) 0 )2 and OR 0 Substituents of the substituents; R c For H or CN; R d It is H or C3-C6-cycloalkyl; R 5 for a) C1-C6-alkyl groups, which are unsubstituted or derived from one or two N(R) groups. 0 )2 and OR 0 Substituents of the substituents; b) OH; c) OC1-C6-alkyl groups that are unsubstituted or phenyl-substituted; d) OC(O)C1-C6-alkyl; e) C3-C6-cycloalkyl; f) aryl, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from 1 to 3 groups selected from halogens, OCF3, CF3, N(R) 0 )2 and OR 0 Substituents of the substituents; g) a heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, which is linked via a carbon or nitrogen atom on the ring, and optionally via 1 or 2 heteroatoms selected from N(R) on the non-linking carbon or nitrogen atom. 0 2. OR 0 and C1-C6-alkyl substituents; or h) A heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered saturated or unsaturated nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, which is linked via a ring carbon or nitrogen, and optionally via 1 to 2 heteroatoms selected from N (R) at the non-linking ring carbon or nitrogen. 0 2. OR 0 and C1-C6-alkyl substituents; R 6 It is an H or C1-C6 alkyl group, wherein the alkyl group is unsubstituted or substituted with a 5- to 6-membered saturated, unsaturated, or aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, which is linked via a ring carbon or nitrogen atom, and optionally substituted with 1 to 2 substituents selected from N(R) at the non-linking ring carbon or nitrogen atom: 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or derived from one or two groups selected from OR 0 、N(R 0 2. NHC(=NH)NH2, OC(O)C1-C6-alkyl, CO2R 0 C(O)N(R) 0 )2 and NHC(O)R 0 Substituents of the substituents; R 7 for a) H; b) C1-C6 alkyl groups, which are unsubstituted or have one or two derivatives selected from N(R) 0 2. OR 0 CO2R 0 OC(O)C1-C6-alkyl, NHC(O)R 0 C(O)N(R) 0 2. Substitution of phenyl, heteroaryl and heterocyclic groups, wherein the heteroaryl group is defined as in (j) below and the heterocyclic group is defined as in (k) below; c) C(O)H; d) C(O)C1-C6-haloalkyl; e) C(O)C1-C6-alkyl, which is unsubstituted or has one or two derivatives selected from CO2R 0 OR 0 OCH2CO2R 0 、N(R 0 )2、C(O)C1-C6-alkyl、O(CH2)2OC1-C6-alkyl、C(O)N(R 0 2. OC(O)C1-C6 alkyl groups and NHC(O)R 0 Substituents of the substituents; f) C(O)OC1-C6-alkyl; g) C(O)NH-C1-C6-alkyl; h) SO2C1-C6-alkyl; i) C3-C6-cycloalkyl; j) aryl, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from 1 to 3 alkyl groups selected from halogens, N(R) 0 2. OR 0 C1-C6-alkyl, CF3, OCF3, CO2R 0 and C(O)N(R) 0 Substitution of )2 by substituents; k) a heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered aromatic ring having 1, 2, or 3 heteroatoms selected from N, O, or S, connected via a carbon or nitrogen atom on the ring, and optionally substituted at a non-connecting carbon or nitrogen atom by 1 or 2 substituents selected from: N(R 0 2. OR 0 CO2R 0 OC(O)C1-C6-alkyl, CON(R) 0 2. NHC(O)R 0 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or has one or two derivatives selected from N(R) 0 2. NHC(=NH)NH2, OC(O)C1-C6 alkyl, OR 0 CO2R 0 C(O)N(R) 0 )2 and NHC(O)R 0 Substituents of the substituents; l) A heterocyclic group, wherein the heterocyclic group is a 5- or 6-membered saturated or unsaturated nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, which is linked via a carbon or nitrogen atom on the ring, and optionally substituted at the non-linking carbon or nitrogen atom by 1 to 2 substituents selected from: N(R 0 2. Imino, lateral oxygen, OR 0 CO2R 0 OC(O)C1-C6-alkyl, CON(R) 0 2. NHC(O)R 0 and C1-C6-alkyl, wherein the C1-C6-alkyl is unsubstituted or has one or two derivatives selected from N(R) 0 )2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, OR 0 CO2R 0 C(O)N(R) 0 )2 and NHC(O)R 0 Substituents of the substituents; m) C(=NH)C1-C6-alkyl, wherein the alkyl group is unsubstituted or derived from one or two groups selected from halogens, CF3, N(R) 0 2. OR 0 and substituents of NHC(O)C1-C6-alkyl groups; n) C(=NR d )NH2; o) C(=NH)NH-C1-C6-alkyl, wherein the alkyl group is unsubstituted or derived from 1 to 3 groups selected from halogens, CF3, N(R) 0 2. OR 0 and substituents of NHC(O)C1-C6-alkyl groups; p) C(=NH)NH-C3-C6-cycloalkyl; q) C(=NH)NH-phenyl, wherein the phenyl group is unsubstituted or substituted with 1 to 3 substituents selected from halogens and CF3; or r) C(=NH)NHC(=NH)NH2; R 6 and R 7 Optionally, together with the attached nitrogen atom, a 3- to 6-membered saturated, unsaturated, or aromatic ring having 0 to 2 additional heteroatoms selected from N, O, and S is formed, wherein the ring is optionally substituted at the non-connecting carbon or nitrogen atom by 1 to 2 substituents selected from: halogen, N(R) 0 2. OR 0 CO2R 0 CON(R) 0 )2 and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are unsubstituted or derived from one or two groups selected from OR 0 and N(R) 0 The ring is substituted with a substituent of )2, wherein two adjacent substituents of the ring optionally together form a fused 5- or 6-membered saturated, unsaturated, or aromatic ring having 0 to 2 heteroatoms selected from N, O, and S; or R 6 and R 9 Optional with R 6 The nitrogen atoms bonded together form a pyrrolidinyl ring; R 8 Choose from the following groups a) Hydrogen, b) C1-C6 alkyl groups that are unsubstituted or have undergone OR treatment. 0 or SO2R 0 replace, c) C3-C6-cycloalkyl groups, and d) Aryl group, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from 1 to 3 groups selected from halogen groups, OCF3, CF3, N(R) 0 )2 and OR 0 Substituents of the substituents; R 9 It is a C1-C6 alkyl group, which is unsubstituted or OR- 0 or SO2R 0 replace; R 8 and R 9 Optionally, they can be combined to form a 3- to 6-membered saturated ring having 0 to 1 heteroatoms selected from N, O, or S; R 10 Independently select from the following groups a) C1-C6 alkyl groups, which are unsubstituted or OR-treated. 0 、N(R 0 2. OC(O)C1-C6 alkyl or CO2R 0 Replacement, and b) CO2R 0 ; R 11 It is a C1-C6 alkyl group, which is unsubstituted or OR- 0 OC(O)C1-C6 alkyl, OC(O)-phenyl, CO2R 0 or N(R) 0 )2 replaces; R 12 It is OH or C1-C6 alkyl, wherein the alkyl is unsubstituted or OC(O)C1-C6 alkyl or OR 0 replace; R 13 It is a C1-C4 alkyl group; R 17 for a) C1-C6 alkyl groups, which are unsubstituted or derived from one or two groups selected from CO2R. 0 OR 0 、N(R 0 Substitution of 2 and OC(O)C1-C6-alkyl groups; b) aryl, wherein the aryl group is phenyl or naphthyl, and the aryl group is unsubstituted or derived from one or two halogen groups, OR 0 and N(R) 0 Substitution of )2 by substituents; or c) C1-C6-haloalkyl; R 18 It is H or C1-C6-alkyl, wherein the alkyl group is unsubstituted or substituted with one or two substituents selected from the following: OR 0 、N(R 0 2. Heteroaryl, heterocyclic, CO2N(R) 0 )2 and CO2R 0 Among them, heteroaryl groups such as R 16 As defined in (t) and heterocyclic groups such as R 16 As defined in (h); and Each R 0 It is independently H or C1-C6-alkyl.

2. The method of claim 1, further comprising administering to the individual a second antifungal agent selected from: polyenes, azoles, purine or pyrimidine nucleotide inhibitors, chitin inhibitors, orotomide, Gwt1 inhibitors, and immunomodulators.

3. The method according to claim 2, wherein the second antifungal agent is amphotericin B, isavuconazole, voriconazole, posaconazole, itraconazole, olorofim, or fosmanogepix.

4. The method according to claim 2, wherein the second antifungal agent is amphotericin B.

5. A method for treating mucormycosis in an individual in need, the method comprising administering the individual the compound SCY-247: Or its pharmaceutically acceptable salts or hydrates.

6. The method of claim 5, further comprising administering to the individual a second antifungal agent selected from: polyenes, azoles, purine or pyrimidine nucleotide inhibitors, chitin inhibitors, ollotomede, Gwt1 inhibitors, and immunomodulators.

7. The method according to claim 6, wherein the second antifungal agent is amphotericin B, isaconazole, voriconazole, posaconazole, itraconazole, ololofen, or fossogpi.

8. The method according to claim 6, wherein the second antifungal agent is amphotericin B.

9. A combination of drugs as follows: (a) The first antifungal agent is compound SCY-247: Or its pharmaceutically acceptable salts or hydrates; and (b) A second antifungal agent selected from polyene, azole, purine or pyrimidine nucleotide inhibitors, chitin inhibitors, olotomid, Gwt1 inhibitors and immunomodulators.

10. The pharmaceutical combination according to claim 9, wherein the second antifungal agent is amphotericin B, isaconazole, voriconazole, posaconazole, itraconazole, ololofen, or fossogpi.

11. The pharmaceutical combination according to claim 9, wherein the second antifungal agent is amphotericin B.

12. A method for treating pulmonary mucormycosis in an individual in need, the method comprising administering the following substances to the individual: (a) A first antifungal agent, which is the compound SCY-247: Or its pharmaceutically acceptable salts or hydrates; and (b) A second antifungal agent selected from polyene, azole, purine or pyrimidine nucleotide inhibitors, chitin inhibitors, olotomid, Gwt1 inhibitors and immunomodulators.

13. The method according to claim 12, wherein the second antifungal agent is amphotericin B, isaconazole, voriconazole, posaconazole, itraconazole, ololofen, or fossogpi.

14. The method according to claim 12, wherein the second antifungal agent is amphotericin B.

15. The method of claim 12, wherein the first antifungal agent is a pharmaceutically acceptable salt of SCY-247 and the second antifungal agent is amphotericin B.

16. The method of claim 15, wherein the first antifungal agent is administered orally.

17. The method of claim 15, wherein the first antifungal agent is administered intravenously.

18. The method of claim 15, wherein the first antifungal agent is administered intravenously, and the second antifungal agent is administered intravenously.

19. The method of claim 15, wherein the first antifungal agent is administered intravenously for an initial period and then orally for a subsequent period.

20. The method of claim 12, wherein the first antifungal agent and the second antifungal agent are administered simultaneously.

21. The method of claim 12, wherein the first antifungal agent and the second antifungal agent are administered sequentially.

22. The method of claim 12, wherein the individual is a human being.

23. The method of claim 15, wherein SCY-247 is provided in a total daily dose of 250 mg to 750 mg and amphotericin B is provided in a total daily dose of 50 mg to 350 mg.

24. The method of claim 12, wherein the first antifungal agent is administered for 2 to 12 weeks, and the second antifungal agent is amphotericin B and is administered for 2 to 6 weeks.

25. A method for preparing a medicament for treating mucormycosis, comprising using the compound SCY-247: Or its pharmaceutically acceptable salts or hydrates.

26. A compound SCY-247: Or its pharmaceutically acceptable use as a salt or hydrate, It is used to prepare medicines for treating mucormycosis.

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