Triterpenoid antifungals for use in the treatment of mucormycosis

Abstract

Enfumafungin derivative triterpenoid antifungal compounds are used to treat mucormycosis. The enfumafungin derivative triterpenoids (or pharmaceutically acceptable salts or hydrates thereof) are inhibitors of (1,3)-β-D-glucan synthesis and are useful alone or in combination with a second antifungal agent in the treatment of mucormycosis, including pulmonary mucormycosis.

Description

Docket No.035680.2301-WO02 TITLE OF THE INVENTION TRITERPENOID ANTIFUNGALS FOR THE TREATMENT OF MOLD INFECTIONS

[0001] This invention was made with United States of America government supportunder Contract No. HHSN272201700039I / 75N93022F00001 awarded by the National Institute of Allergy and Infectious Diseases. The United States government has certain rights in this invention. FIELD OF THE INVENTION

[0002] The present invention relates to the use of triterpenoid antifungals to treatfungal infections caused by molds. More particularly, the invention relates to the use of enfumafungin derivative triterpenoids (or pharmaceutically acceptable salts or hydrates thereof) that are inhibitors of (1,3)-β-D-glucan synthesis resulting in a deficiency in (1,3)-β- D-glucan (a fungal cell structure building block), alone or in combination with another antifungal agent, in the treatment of fungal infections caused by molds, especially mucormycosis. Mucormycosis remains a life-threatening infection with suboptimal treatment options. In accordance with the present invention, the use of the triterpenoid antifungal SCY- 247, alone or particularly in combination with amphotericin B, can provide advantages in the treatment of mucormycosis, including pulmonary mucormycosis. BACKGROUND OF THE INVENTION

[0003] Fungal infections caused by molds are a significant healthcare problem withhigh associated mortality. Several molds, including those in the Mucorales order (formerly known as Zygomycetes), Aspergillus species, Lomentospora species, Fusarium species, Scopulariopsis species, Trichophyton species, and Scedosporium species, can cause systemicfungal infections. Among these, the diseases caused by fungi of the Mucorales order, knownas mucormycosis (formerly zygomycosis), are among the most deadly and difficult to treat despite the availability of antifungal agents with activity against the causative pathogens. The mortality associated with mucormycosis ranges from 40% to 78% in 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 Apr;27(4):538-549. doi: 10.1016 / j.cmi.2020.12.035. Epub 2021 Jan 5. PMID: 33418022.) The most common fungi inDocket No.035680.2301-WO02 the Mucorales order causing human disease include Rhizopus species and species of Mucor, Lichtheimia (previously Absidia), Apophysomyces, Rhizomucor, and Cunninghamella genus.

[0004] There are many risk factors that predispose patients to mucormycosis,including uncontrolled diabetes, neutropenia, hematological malignancies, organ transplantation, trauma and burn, and use of immuno-suppressants such as corticosteroids. Mucormycosis has also been reported in patients suffering from 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.2021 Oct;64(10):1253-1260. doi: 10.1111 / myc.13353. Epub 2021 Jul 24. PMID: 34255907; PMCID: PMC8446956.)

[0005] Mucormycosis infections include rhinocerebral mucormycosis (symptoms ofwhich may include facial swelling, headache, nasal or sinus congestion, lesions on the nasal bridge or inside the mouth, and fever), pulmonary mucormycosis (symptoms of which may include fever, cough, chest pain, and shortness of breath), gastrointestinal mucormycosis (symptoms of which may include abdominal pain, nausea and vomiting, and gastrointestinal bleeding), cutaneous mucormycosis (symptoms of which may include blisters or ulcers, or pain, warmth, excessive redness, or swelling around a wound), and disseminated mucormycosis (wherein 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 can develop mental status changes or coma). Mucormycosis is contracted through contact with Mucorales fungal spores in the environment. For example, rhinocerebral mucormycosis and pulmonary mucormycosis can develop through inhalation of the fungal spores, and cutaneous mucormycosis can develop after the fungus enters the skin through an injury in the skin. Disseminated mucormycosis can follow any of the forms of mucormycosis described above and, for example, develops in neutropenic patients with a pulmonary infection.

[0006] Mucorales are innately resistant to most clinically available antifungal agents,significantly limiting the therapeutic options. Amphotericin B is the currently-preferred therapeutic option for mucormycosis, but it has significant renal toxicity. Mold-active azole antifungals such as isavuconazole and posaconazole are also used. Treatment outcomes with the available antifungals are not optimal, leading to frequent treatment failures and mortality. In view of high mortality and the difficulties with current options, there is a need in the art for new therapies to treat mucormycosis.Docket No.035680.2301-WO02 SUMMARY OF THE INVENTION

[0007] The present invention addresses the need in the art for new mucormycosistherapies. The present invention provides the use of enfumafungin derivative triterpenoids of Formula (I) (or pharmaceutically acceptable salts or hydrates thereof) alone or in combination with another antifungal agent in the treatment of mucormycosis, including pulmonary mucormycosis.

[0008] The present invention also provides methods of treating mucormycosis,including pulmonary mucormycosis, in a subject by administering the compound of Formula (I) (or a pharmaceutically acceptable salt or hydrate thereof) alone or in combination with another antifungal agent. Further, 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 the treatment of mucormycosis, including pulmonary mucormycosis, in a subject.

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

[0010] In preferred embodiments, the triterpenoid antifungal SCY-247 can be usedalone or in combination with a second antifungal agent to treat mucormycosis, including pulmonary mucormycosis.

[0011] Unexpectedly, although SCY-247 has shown low activity (e.g., MIC > 16µg / mL) against Mucorales when tested in vitro, it showed efficacy against mucormycosis in in vivo studies described herein. In a murine study described herein, SCY-247 monotherapy at all tested dosages improved median survival and percent survival as compared with placebo. Further, in the study, SCY-247 monotherapy dosed at 48 mg / kg BID demonstrated advantages in median survival and percent survival over amphotericin B monotherapy, which is the standard of care for mucormycosis. Moreover, in the study, combination therapy of SCY-247 dosed at 32 mg / kg BID and amphotericin B resulted in a remarkable 90% overall survival and demonstrated advantages over any of the tested monotherapies, including amphotericin B monotherapy.Docket No.035680.2301-WO02 BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 is a graph showing cumulative survival probability from a study ofneutropenic mice inoculated with R. delemar 99-880 and treated with: SCY-247 only, a liposomal formulation of amphotericin B (L-AMB), or SCY-247 in combination with L- AMB. SCY-247 monotherapy and combination therapy each improved the survival of neutropenic mice with pulmonary mucormycosis, compared with the placebo group. The combination therapy resulted in 90% overall survival and a median survival time of >21 days, which was better than placebo as well as any of the monotherapies, including amphotericin B monotherapy which is the standard of care. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention relates to the use of enfumafungin derivativetriterpenoids (or pharmaceutically acceptable salts or hydrates thereof) that are inhibitors of (1,3)-β-D-glucan synthesis, alone or in combination with another antifungal agent, in the treatment of fungal infections caused by molds, especially mucormycosis. Mucormycosis remains a life-threatening infection, for which the current treatment options are limited and have inconsistent outcomes and / or toxicity problems. In accordance with the present invention, the use of the triterpenoid antifungal SCY-247, alone or particularly in combination with amphotericin B, can provide advantages in the treatment of mucormycosis, including pulmonary mucormycosis.

[0014] Enfumafungin is a hemiacetal triterpene glycoside that is produced infermentations of a Hormonema spp. associated with living leaves of Juniperus communis (U.S. Pat. No.5,756,472; Pelaez et al., Systematic and Applied Microbiology, 23:333–343 (2000); Schwartz et al., JACS, 122: 4882–4886 (2000); Schwartz, R.E., Expert Opinion on Therapeutic Patents, 11(11): 1761–1772 (2001)). Enfumafungin is one of the several triterpene glycosides that have in vitro antifungal activities. The mode of the antifungal action of enfumafungin and other antifungal triterpenoid glycosides was determined to be the inhibition of fungal cell wall glucan synthesis by their specific action on (1,3)-β-D-glucan synthase (Onishi et al., Antimicrobial Agents and Chemotherapy, 44: 368–377 (2000); Pelaez et al., (2000)). 1,3-β-D-glucan synthase remains an attractive target for antifungal drug action because it is present in many pathogenic fungi and therefore affords a broad antifungal spectrum. In addition, because there is no mammalian counterpart to (1,3)-β-D-glucan synthase, the enfumafungin derivatives described herein have little or no mechanism-based toxicity.Docket No.035680.2301-WO02

[0015] Various enfumafungin derivative triterpenoid antifungal compounds havebeen disclosed, e.g., in WO 2007 / 126900 and WO 2007 / 127012. Triterpenoid antifungals, or fungerps, are the first new class of antifungal compounds since 2001.

[0016] The present invention provides the use of a compound of Formula (I), or apharmaceutically acceptable salt or hydrate thereof: X R3wherein:X is O or H,H; R1is a) OH; b) OC(O)C1-C12-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from OR0, N(R0)2, and CO2R0; c) OC(O)C1-C6-haloalkyl; d) OC(O)C3-C8-cycloalkyl; e) O-C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from OR0and N(R0)2; f) OC(O)NHC1-C6-alkyl, unsubstituted or substituted with phenyl; g) OC(O)OC1-C6-alkyl; h) NHC(O)C1-C6-alkyl, unsubstituted or substituted with phenyl; or i) (O)nCH2C(O)C1-C6-alkyl; n is 0 or 1; R2is a) CH2R4, b) CH2CHR5(CH2)mNR6R7, c) CH2C(R8)(R9)(CH2)mNR6R7, d) CH2C(R10)(R11)R12, e) CH2CH(OR0)CH2OR0, f) CHR13CHR5(CH2)mNR6R7, g) (CH2)pC(R8)(R9)NR6R7, or, h) CH2CHR5C(R8)(R9)NR6R7, m is 0, 1 or 2;Docket No.035680.2301-WO02 p is 2 to 6; R1and R2are optionally taken together to form a methylenedioxy or ethylenedioxy, unsubstituted or substituted with 1 or 2 substituents selected from C1-C6-alkyl and C1-C6-alkoxy; R3is a) C(O)R14; b) CH2OH; or c) CH2OC(O)C1-C6-alkyl; R14is OH, OR15, H, N(R0)2, or C1-C6-alkyl; R15is C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from phenyl, OC(O)C1-C6-alkyl, C(O)OR0, OR0, C(O)N(R0)2, and C(O)NH2(CH2)2-4NH2and wherein said phenyl is optionally substituted with 1 to 3 halo groups; R4is a) H; b) (CH2)1-6-R16; c) OC1-C6-alkyl; d) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 3 substituents selected from halo, N(R0)2, OR0, C1-C6-alkyl, CF3, OCF3, CO2R0, and C(O)N(R0)2; e) heterocyclyl, wherein heterocyclyl is a 3- or 6-membered, saturated or unsaturated non-aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from oxo, N(R0)2, OR0, CO2R0, CON(R0)2, and C1-C6-alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6-alkyl and CO2R0; or f) heteroaryl, wherein heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a ring carbon or nitrogen, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 or 2 substituents selected from N(R0)2, OR0, CO2R0, CON(R0)2, and C1-C6 alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6 alkyl and CO2R0; R16is a) H; b) OH; c) NH2; d) NHC(O)R17;Docket No.035680.2301-WO02 e) NHSO2R17; f) NHC(O)NHR0; g) NHC(O)CHR18NH2; h) heterocyclyl, wherein heterocyclyl is a 5- or 6-membered, saturated or unsaturated non-aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from N(R0)2, imino, oxo, OR0, CO2R0, CON(R0)2, and C1-C6-alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, OR0, and CO2R0; i) NH-N(C1-C6-alkyl)2; j) NHC(=NH)NHC(=NH)NH2; NRaalkyl, wherein said alkyl is unsubstituted or substituted (O)C1-C6-alkyl;cycloalkyl; q) NHC(=NRd)NH-phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents selected from halo and CF3; r) CO2C1-C6-alkyl; s) OCOC1-C6alkyl; t) heteroaryl, wherein heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 or 2 substituents selected from N(R0)2, OR0, CO2R0, CON(R0)2, and C1-C6 alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6 alkyl, OR0, and CO2R0; or u) CN; p is 1, 2, 3 or 4; Rais H or C(=NH)NH2; Rbis C1-C6alkyl, unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2and OR0; Rcis H or CN; Rdis H or C3-C6-cycloalkyl;Docket No.035680.2301-WO02 R5is a) C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2 and OR0; b) OH; c) OC1-C6-alkyl, unsubstituted or substituted with phenyl; d) OC(O)C1-C6-alkyl; e) C3-C6-cycloalkyl; f) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 3 substituents selected from halo, OCF3, CF3, N(R0)2and OR0; g) heteroaryl, wherein heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 or 2 substituents selected from N(R0)2, OR0, and C1-C6-alkyl; or h) heterocyclyl, wherein heterocyclyl is a 5- or 6-membered, saturated or unsaturated non-aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a ring carbon or nitrogen, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from N(R0)2, OR0, and C1-C6-alkyl; R6is H or C1-C6-alkyl, wherein said alkyl 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, attached through a ring carbon or nitrogen, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from N(R0)2, OR0, CO2R0, CON(R0)2and C1-C6-alkyl unsubstituted or substituted with one or two substituents selected from OR0, N(R0)2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, CO2R0, C(O)N(R0)2, and NHC(O)R0; R7is a) H; b) C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, OR0, CO2R0, OC(O)C1-C6-alkyl, NHC(O)R0, C(O)N(R0)2, phenyl, heteroaryl, and heterocyclyl, wherein heteroaryl is as defined below in (j) and heterocyclyl is as defined below in (k); c) C(O)H; d) C(O)C1-C6-haloalkyl; e) C(O)C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from CO2R0, OR0, OCH2CO2R0, N(R0)2, C(O)C1-C6-alkyl, O(CH2)2OC1-C6- alkyl, C(O)N(R0)2, OC(O)C1-C6alkyl, and NHC(O)R0;Docket No.035680.2301-WO02 f) C(O)OC1-C6-alkyl; g) C(O)NH-C1-C6-alkyl; h) SO2C1-C6-alkyl; i) C3-C6-cycloalkyl; j) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 3 substituents selected from halo, N(R0)2, OR0, C1-C6-alkyl, CF3, OCF3, CO2R0, and C(O)N(R0)2; k) heteroaryl, wherein heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 or 2 substituents selected from N(R0)2, OR0, CO2R0, OC(O)C1-C6-alkyl, CON(R0)2, NHC(O)R0, and C1-C6- alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6 alkyl, OR0, CO2R0, C(O)N(R0)2 and NHC(O)R0; l) heterocyclyl, wherein heterocyclyl is a 5- or 6-membered, saturated or unsaturated non-aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from N(R0)2, imino, oxo, OR0, CO2R0, OC(O)C1-C6-alkyl, CON(R0)2, NHC(O)R0, and C1-C6-alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, OR0, CO2R0, C(O)N(R0)2and NHC(O)R0; m) C(=NH)C1-C6-alkyl, wherein said alkyl is unsubstituted or substituted with 1 or 2 substituents selected from halo, CF3, N(R0)2, OR0, and NHC(O)C1-C6- alkyl; n) C(=NRd)NH2; o) C(=NH)NH-C1-C6-alkyl, wherein said alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halo, CF3, N(R0)2, OR0, and NHC(O)C1-C6- alkyl; p) C(=NH)NH-C3-C6-cycloalkyl; q) C(=NH)NH-phenyl, wherein phenyl is unsubstituted or substituted with 1 to 3 substituents selected from halo and CF3; or r) C(=NH)NHC(=NH)NH2; R6and R7are optionally taken together with the attached nitrogen atom to form a 3- to 6-membered saturated, unsaturated or aromatic ring having 0-2 additional heteroatoms selected from N, O and S, wherein said ring is optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2Docket No.035680.2301-WO02 substituents selected from halo, N(R0)2, OR0, CO2R0, CON(R0)2, and C1-C6 alkyl unsubstituted or substituted with 1 or 2 substituents selected from OR0and N(R0)2, and wherein two adjacent substituents of said ring are optionally taken together to form a fused 5- or 6-membered saturated, unsaturated, or aromatic ring having 0-2 heteroatoms selected from N, O and S; or R6and R9are optionally taken together, with the nitrogen atom R6is attached to, to form a pyrrolidinyl ring; R8is selected from the group consisting of a) hydrogen, b) C1-C6-alkyl, unsubstituted or substituted with OR0or SO2R0, c) C3-C6-cycloalkyl, and d) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 3 substituents selected from halo, OCF3, CF3, N(R0)2and OR0; R9is C1-C6-alkyl, unsubstituted or substituted with OR0or SO2R0; R8and R9are optionally taken together to form a 3- to 6-membered saturated ring having 0-1 heteroatom selected from N, O or S; R10is independently selected from the group consisting of a) C1-C6-alkyl unsubstituted or substituted with OR0, N(R0)2, OC(O)C1-C6 alkyl or CO2R0, and b) CO2R0; R11is C1-C6alkyl unsubstituted or substituted with OR0, OC(O)C1-C6alkyl, OC(O)- phenyl, CO2R0, or N(R0)2; R12is OH or C1-C6alkyl, wherein said alkyl is unsubstituted or substituted with OC(O)C1-C6alkyl or OR0; R13is C1-C4-alkyl; R17is a) C1-C6-alkyl, unsubstituted or substituted with 1 to 2 substituents selected from CO2R0, OR0, N(R0)2, and OC(O)C1-C6-alkyl; b) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 2 substituents selected from halo, OR0and N(R0)2; or c) C1-C6-haloalkyl; R18is H or C1-C6-alkyl, wherein said alkyl is unsubstituted or substituted with 1 to 2 substituents selected from OR0, N(R0)2, heteroaryl, heterocyclyl, CO2N(R0)2, and CO2R0, wherein heteroaryl is as defined in R16(t) and heterocyclyl is as defined in R16(h); and each R0is independently H or C1-C6-alkyl, in a subject for the treatment of mucormycosis.Docket No.035680.2301-WO02

[0017] The present invention also provides methods of treating mucormycosis in asubject by administering the compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof. Further, 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 the treatment of mucormycosis in a subject.

[0018] The present invention further provides combination therapies of the compoundof Formula (I) or a pharmaceutically acceptable salt or hydrate thereof, and another antifungal agent, for the treatment of mucormycosis. Combination therapy should include antifungal agents that when administered together can increase antifungal efficacy, reduce toxicity, cure faster, prevent or avoid the emergence of resistance, and / or provide broader- spectrum antifungal activity in comparison with the respective monotherapy regimens.

[0019] The present invention provides a combination of a first antifungal agent that isa compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof, and a second antifungal agent. The present invention also provides a combination of a first antifungal agent that is a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof and a second antifungal agent, for use in a method of treating mucormycosis in a subject. The present invention also provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof in combination with a second antifungal agent, in a subject for the treatment of mucormycosis. The present invention also provides methods of treating mucormycosis in a subject by administering the compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof in combination with a second antifungal agent. Further, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof in combination with a second antifungal agent, in the preparation of a medicament for the treatment of mucormycosis in a subject.

[0020] In any of the foregoing embodiments involving a second antifungal agent, thesecond antifungal agent may be selected from: polyenes, azoles, purine or pyrimidine nucleotide inhibitors, chitin inhibitors, orotomides, Gwt1 inhibitors, and immunomodulating agents. In any of the foregoing embodiments involving a second antifungal agent, the second antifungal agent may be selected from: amphotericin B, isavuconazole, voriconazole, posaconazole, itraconazole, olorofim, and fosmanogepix. Amphotericin B is a preferred second antifungal agent.Docket No.035680.2301-WO02

[0021] Examples of polyenes that may be used as the second antifungal agent in anyof the foregoing embodiments include but are not limited to amphotericin B, liposomal and lipid forms thereof such as ABELCET®, AMBISOME®, and AMPHOCIL®, nystatin, and liposomal and lipid forms thereof, and the third-generation polyene SF001, and liposomal and lipid forms thereof. Examples of azoles that may be used as the second antifungal agent in any of the foregoing embodiments include but are not limited to isavuconazole, fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, ravuconazole, detoconazole, clotrimazole, and posaconazole. Examples of purine or pyrimidine nucleotide inhibitors that may be used as the second antifungal agent in any of the foregoing embodiments include but are not limited to flucytosine, polyoxins, and nikkomycins, in particular nikkomycin Z or nikkomycin X. Polyoxins and nikkomycins are chitin inhibitors as well; these and other chitin inhibitors may be used as the second antifungal agent in any of the foregoing embodiments. Examples of orotomide compounds that may be used as the second antifungal agent in any of the foregoing embodiments include but are not limited to olorofim. Examples of Gwt1 inhibitors compounds that may be used as the second antifungal agent in any of the foregoing embodiments include but are not limited to fosmanogepix. Examples of immunomodulators that may be used as the 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), defensines, tacrolimus, and granulocyte-colony stimulating factor (G-CSF).

[0022] SCY-247, which has the structure shown below, is a second generationfungerp:Exact Mass: 601.43 Molecular Weight: 601.87 The structure of SCY-247 is encompassed within Formula (I). SCY-247 is orally bioavailable, which provides an important advantage over echinocandins (which are alsoDocket No.035680.2301-WO02 inhibitors of 1,3-β-D-glucan synthase) because echinocandins require parenteral administration.

[0023] The present invention provides the use of SCY-247 or a pharmaceuticallyacceptable salt or hydrate thereof in a subject for the treatment of mucormycosis. The present invention also provides methods of treating mucormycosis in a subject by administering SCY-247 or a pharmaceutically acceptable salt or hydrate thereof. Further, the present invention provides the use of SCY-247 or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for the treatment of mucormycosis in a subject.

[0024] In preferred embodiments, the present invention provides a combination of afirst antifungal agent that is SCY-247 which has the following structureor a pharmaceutically acceptable salt or hydrate thereof, and a second antifungal agent.

[0025] The present invention also provides a combination of a first antifungal agentthat is SCY-247 or a pharmaceutically acceptable salt or hydrate thereof and a second antifungal agent, for use in a method of treating mucormycosis in a subject. The present invention also provides the use of SCY-247 or a pharmaceutically acceptable salt or hydrate thereof in combination with a second antifungal agent, in a subject for the treatment of mucormycosis. The present invention also provides methods of treating mucormycosis in a subject by administering SCY-247 or a pharmaceutically acceptable salt or hydrate thereof in combination with a second antifungal agent. Further, the present invention provides the use of SCY-247 or a pharmaceutically acceptable salt or hydrate thereof in combination with a second antifungal agent, in the preparation of a medicament for the treatment of mucormycosis in a subject.

[0026] In any of the foregoing embodiments involving SCY-247 (or apharmaceutically acceptable salt or hydrate thereof) and a second antifungal agent, the second antifungal agent may be selected from: polyenes, azoles, purine or pyrimidineDocket No.035680.2301-WO02 nucleotide inhibitors, chitin inhibitors, orotomides, Gwt1 inhibitors, and immunomodulating agents. In any of the foregoing embodiments involving SCY-247 (or a pharmaceutically acceptable salt or hydrate thereof) and a second antifungal agent, the second antifungal agent may be selected from: amphotericin B, isavuconazole, voriconazole, posaconazole, itraconazole, olorofim, and fosmanogepix. Amphotericin B is a preferred second antifungal agent.

[0027] Examples of polyenes that may be used as the second antifungal agent in anyof the foregoing embodiments involving SCY-247 (or a pharmaceutically acceptable salt or hydrate thereof) include but are not limited to amphotericin B, liposomal and lipid forms thereof such as ABELCET®, AMBISOME®, and AMPHOCIL®, nystatin, and liposomal and lipid forms thereof, and the third-generation polyene SF001, and liposomal and lipid forms thereof. Examples of azoles that may be used as the second 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 isavuconazole, fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, ravuconazole, detoconazole, clotrimazole, and posaconazole. Examples of purine or pyrimidine nucleotide inhibitors that may be used as the second 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 flucytosine, polyoxins, and nikkomycins, in particular nikkomycin Z or nikkomycin X. Polyoxins and nikkomycins are chitin inhibitors as well; these and other chitin inhibitors may be used as the second antifungal agent in any of the foregoing embodiments involving SCY-247 (or a pharmaceutically acceptable salt or hydrate thereof). Examples of orotomide compounds that may be used as the second 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 olorofim. Examples of Gwt1 inhibitors compounds that may be used as the second 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 fosmanogepix. Examples of immunomodulators that may be used as the second 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), defensines, tacrolimus, and granulocyte-colony stimulating factor (G-CSF).Docket No.035680.2301-WO02

[0028] Mucormycosis infections that can be treated according to the present inventioninclude rhinocerebral mucormycosis, pulmonary mucormycosis, gastrointestinal mucormycosis, cutaneous mucormycosis, and disseminated mucormycosis.

[0029] For the purpose of treating fungal infections, compounds of Formula (I),including SCY-247, or pharmaceutically acceptable salts or hydrates thereof, and second antifungal agents can each be administered in any way that produces contact of the respective active agent with the active agent’s site of action. Compounds of Formula (I), including SCY-247, or pharmaceutically acceptable salts or hydrates thereof, and second antifungal agents can be administered in conventional ways available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or as a combination of therapeutic agents. They can be administered alone, but in accordance with a typical practice can be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. They can be administered concurrently or sequentially for a portion of or for the entire duration of the antifungal regimen via any acceptable administration route appropriate for the intended purpose. For example, a compound of Formula (I), including SCY-247, or a pharmaceutically acceptable salt or hydrate thereof, and a second antifungal agent can both be given intravenously, orally, or topically; or one intravenously and other orally; or one orally and other topically; or in any combination of administration routes as would be appropriate for the fungal infection being treated. In the case of mucormycosis, the preferred route of administration is orally and / or intravenously. If administration of the first antifungal agent and the second antifungal agent is concurrent, this includes providing the first antifungal agent and the second antifungal agent together in a single dosage unit, and providing the first antifungal agent and the second antifungal agent in separate dosage units. Compounds of Formula (I), including SCY-247, or pharmaceutically acceptable salts or hydrates thereof, and second antifungal agents can be administered, for example, by one or more of the following routes: orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intralesional injection or infusion techniques), by inhalation (e.g., by nebulizer, nasal or buccal inhalation spray, aerosols from metered dose inhalator, and dry powder inhalator), ocularly, topically, transdermally, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the active agent and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. The mode of administration of the first antifungal agent and / or the second antifungal agent may be changed duringDocket No.035680.2301-WO02 treatment; for example, the first antifungal agent may be administered intravenously to a subject for a period of time such as for the first 2 to 6 weeks of treatment, and then the first antifungal agent in an oral formulation such as a tablet may be administered to the subject for a further period of time such as the 7th through 12th weeks of treatment. The first antifungal agent and the second antifungal agent may be administered in combination for an initial period of time (e.g., for 2 to 6 weeks), and then only the first antifungal agent may be administered for a subsequent period of time (e.g., up to another 6 weeks, for a total of up to 12 weeks during which the first antifungal agent is administered).

[0030] Liquid preparations suitable for oral administration (e.g., suspensions, syrups,elixirs and the like) can be prepared according to techniques known in the art and can employ the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose.

[0031] Further description of methods suitable for use in preparing pharmaceuticalcompositions and of ingredients suitable for use in said compositions is provided in Remington’s Pharmaceutical Sciences, 20thedition, edited by A. R. Gennaro, Mack Publishing Co., 2000.

[0032] The compounds of Formula (I), including SCY-247, or pharmaceuticallyacceptable salts or hydrates thereof can be administered, e.g., orally or intravenously, in a dosage range of, for example, 0.001 to 1000 mg / kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. An example of a dosage range is 0.01 to 500 mg / kg body weight per day orally or intravenously in a single dose or in divided doses. Another example of a dosage range is 0.1 to 100 mg / kg body weight per day orally or intravenously in single or divided doses. For oral administration, compositions comprising a compound of Formula (I), including SCY-247, or pharmaceutically acceptable salts or hydrates thereof can be provided in the form of tablets or capsules or solutions or suspensions containing, for example, 1.0 to 1000 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, and 1000 milligrams of theDocket No.035680.2301-WO02 active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. For intravenous administration, compositions comprising a compound of Formula (I), including SCY-247, or pharmaceutically acceptable salts or hydrates thereof can be provided in the form of (e.g.) solutions, suspensions or other acceptable pharmaceutical forms containing, for example, 1.0 to 500 milligrams of the active ingredient. For topical administration, compositions comprising a compound of Formula (I), including SCY-247, or pharmaceutically acceptable salts or hydrates thereof can be provided as (e.g.) a cream, solution, ointment, foam, powder, lacquer, emulsion or other pharmaceutically acceptable forms containing, for example, 0.001 to 200 milligrams of the active ingredient per gram of product. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0033] The second antifungal agent can be administered (e.g., orally or intravenously)in a dosage range of, for example, 0.001 to 1000 mg / kg of mammal (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. An example of a dosage 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 dosage range includes posaconazole administered at a range from 2 to 20 mg / kg per day orally or intravenously in single or divided doses. Another example of a dosage range includes isavuconazole administered at a range from 2 to 40 mg / kg per day orally or intravenously in single or divided doses. Another example of a dosage range includes amphotericin B administered at a range from 0.1 to 10 mg / kg per day intravenously or 5 to 50 mg / kg per day orally in single or divided doses. For oral administration, compositions comprising a second antifungal agent can be provided in the form of (e.g.) tablets, suspensions, solutions or capsules containing, for example, 1.0 to 1000 milligrams of the active ingredient, particularly 50, 75, 100, 150, 200, 250, 300, 375, 400, 500, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. For intravenous administration, compositions comprising a second antifungal agent can be provided in the form of (e.g.) solutions, suspensions or other acceptable pharmaceutical forms containing, for example, 1.0 to 500 milligrams of the active ingredient. For topical administration, compositions comprising a second antifungal agent can be provided as (e.g.) a cream,Docket No.035680.2301-WO02 solution, ointment, foam, powder, lacquer, emulsion or other pharmaceutically acceptable forms containing, for example, 0.001 to 200 milligrams of the active ingredient per gram of product. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0034] In preferred embodiments, the compound of Formula (I) or a pharmaceuticallyacceptable salt or hydrate thereof is administered orally. In other preferred embodiments, SCY-247 or a pharmaceutically acceptable salt or hydrate thereof is administered orally.

[0035] In other preferred embodiments, the compound of Formula (I) or apharmaceutically 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.

[0036] In preferred embodiments, the second antifungal agent is administered orally.In other preferred embodiments, the second antifungal agent is administered intravenously.

[0037] In preferred embodiments, the second antifungal agent is amphotericin B. Forintravenous administration, amphotericin B may be formulated, for example, as amphotericin B deoxycholate, in a liposomal formulation, or in a lipid complex formulation. For oral administration, amphotericin B may be formulated, for example, as solid lipid nanoparticles or polymeric nanoparticles.

[0038] In preferred embodiments, a pharmaceutically acceptable salt of SCY-247 isadministered to a subject to provide a total daily dose of 150 to 1500 mg of SCY-247, and amphotericin B is administered to the subject to provide a total daily dose of 20 to 600 mg of the amphotericin B. In certain such preferred embodiments, a total daily dose of 150 mg, or a total daily dose of 250 mg, or a total daily dose of 500 mg, or a total daily dose of 750 mg, or a total daily dose of 1000 mg, or a total daily dose of 1500 mg of SCY-247 is administered; the total daily dose may be administered on a once-daily basis or it may be divided such as for BID (twice daily) dosing or TID (thrice daily) dosing or it may be administered less frequently such as three-times-a-week, twice-a-week or once-a-week particularly for treatment of pulmonary mucormycosis. In certain such preferred embodiments, a pharmaceutically acceptable salt of SCY-247 is administered QD (once daily) or BID toDocket No.035680.2301-WO02 provide 150 to 750 mg, or to provide 250 to 750 mg, or to provide 250 to 1000 mg, of the compound of Formula (I) per day.

[0039] In other preferred embodiments, for treatment of pulmonary mucormycosis ina subject, SCY-247 or a pharmaceutically acceptable salt or hydrate thereof is administered orally and provides a total daily dose of from 250 mg to 1000 mg of SCY-247, and liposomal amphotericin B is administered intravenously and provides a total daily dose of 50 to 350 mg of amphotericin B. In preferred other embodiments, for treatment of pulmonary mucormycosis in a subject, SCY-247 or a pharmaceutically acceptable salt or hydrate thereof and amphotericin B are administered for 2 to 12 weeks.

[0040] In other preferred embodiments, for treatment of pulmonary mucormycosis ina subject, SCY-247 or a pharmaceutically acceptable salt or hydrate thereof is administered orally and provides a total daily dose of from 150 mg to 750 mg of SCY-247, and liposomal amphotericin B is administered intravenously and provides a total daily dose of 60 to 300 mg of amphotericin B. In preferred other embodiments, for treatment of pulmonary mucormycosis in a subject, SCY-247 or a pharmaceutically acceptable salt or hydrate thereof and amphotericin B are administered for 4 weeks.

[0041] In preferred embodiments, SCY-247 (or a pharmaceutically acceptable salt orhydrate thereof) and amphotericin B are administered in a combination therapy for treating a fungal infection such as mucormycosis in a subject, and the dosage of amphotericin B used in the combination therapy is less than the dosage of amphotericin B that would have been used in an amphotericin B monotherapy regimen for the fungal infection.

[0042] Compounds of Formula (I), including SCY-247, and pharmaceuticallyacceptable salts or hydrates thereof can be made according to the synthesis methods disclosed in U.S. Patent No.7,863,465, the contents of which are hereby incorporated by reference in their entirety.

[0043] In the description of the compounds of Formula (I) in the embodiments setforth above, indicated substitutions are included only to the extent that the substituents provide stable compounds consistent with the definition.

[0044] As used herein, the term “alkyl” refers to any linear or branched chain alkylgroup having a number of carbon atoms in the specified range. Thus, for example, “C1-6alkyl” (or “C1-C6alkyl”) refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-,Docket No.035680.2301-WO02 iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. As another example, “C1-4alkyl” refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

[0045] The term “alkoxy” refers to an –O-alkyl group wherein alkyl is as definedabove.

[0046] The term “cycloalkyl” refers to any cyclic ring of an alkane having a numberof carbon atoms in the specified range. Thus, for example, “C3-6cycloalkyl” (or “C3-C6cycloalkyl”) refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine and iodine(alternatively referred to as fluoro, chloro, bromo, and iodo).

[0048] The term “haloalkyl” refers to an alkyl group as defined above in which one ormore of the hydrogen atoms have been replaced with a halogen (i.e., F, Cl, Br and / or I). Thus, for example, “C1-6haloalkyl” (or “C1-C6haloalkyl”) refers to a C1to C6linear or branched alkyl group as defined above with one or more halogen substituents. Suitable haloalkyls include the series (CH2)0-5CF3(i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoro-n-propyl, etc.).

[0049] The term “silylalkyl” refers to an alkyl group as defined above in which one ormore of the carbon atoms have been replaced with a silicon atom.

[0050] Unless expressly stated to the contrary, all ranges cited herein are inclusive.For example, a heterocyclic ring described as containing from “1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings 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 forth.

[0051] Any of the various cycloalkyl and heterocyclic / heteroaryl rings and ringsystems defined herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results. Suitable 5- or 6-membered heteroaromatic rings include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, andDocket No.035680.2301-WO02 thiadiazolyl. Suitable 3- to 6-membered heterocyclyls include, but are not limited to, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl.

[0052] A “stable” compound is a compound that can be prepared and isolated andwhose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0053] As a result of the selection of substituents and substituent patterns, certain ofthe compounds of Formula (I) can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. Unless otherwise indicated, use of all isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention. Also included within the scope of the present invention is the use of tautomeric forms of the compounds as depicted.

[0054] When any variable occurs more than one time in any constituent or in Formula(I), its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0055] The term “substituted” includes mono- and poly-substitution by a namedsubstituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., an aryl, a cycloalkyl, a heteroaryl, or a heterocyclyl) provided such ring substitution is chemically allowed and results in a stable compound.

[0056] The compounds of Formula (I) may be administered in the form ofpharmaceutically acceptable salts or hydrates as appropriate. The term “pharmaceutically acceptable salt” refers to a salt that possesses the approximate effectiveness of the parent compound and is suitable for administration to a patient. Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of a compound of Formula (I) with a solution of a pharmaceutically acceptable acid. Many of the compounds of FormulaDocket No.035680.2301-WO02 (I) carry an acidic moiety, in which case suitable pharmaceutically acceptable salts thereof can include alkali metal salts, alkaline earth metal salts, and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

[0057] The term “administration” and variants thereof (e.g., “administering” acompound) mean providing a compound or a prodrug of the compound to the subject in need of treatment. When a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof is provided in combination with a second antifungal agent, “administration” and its variants are each understood to include concurrent provision and sequential provision of the compound (or pharmaceutically acceptable salt or hydrate thereof) and the second antifungal agent.

[0058] As used herein, the term “composition” is intended to encompass a productcomprising the specified ingredients, as well as any product that results, directly or indirectly, from combining the specified ingredients.

[0059] By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

[0060] The term “subject” (alternatively referred to herein as “patient”) as used hereinrefers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0061] The term “synergistic” refers to the effect of a compound of Formula (I) or apharmaceutically acceptable salt thereof or hydrate thereof provided in combination with a second antifungal agent to treat a disorder, which effect is better or more beneficial or more pronounced than the additive effects of the individual therapies. A synergistic effect of a combination of therapies may permit the use of lower dosages of one or more of the individual therapies and / or less frequent administration of the therapies to a subject with a disorder; such ability to use lower dosages of a therapy and / or to administer the therapy less frequently reduces the toxicity associated with the administration of the therapy to a subject without reducing the efficacy of the therapy in the treatment of a disorder. In addition, a synergistic effect can result in improved efficacy of agents in the treatment of a disorder.Docket No.035680.2301-WO02 Finally, a synergistic effect of a combination of therapies may permit avoidance or reduction of adverse or unwanted side effects associated with the use of either therapy alone.

[0062] The term “effective amount” as used herein means an amount of activecompound that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician. In one embodiment, the “effective amount” can be a therapeutically effective amount that alleviates the symptoms of the disease or condition being treated. The term can also refer to an inhibition effective amount of the enfumafungin derivative sufficient to inhibit (1,3)-β-D- glucan synthase and thereby elicit the response being sought. The term can also refer to the amount of the second antifungal agent, such as a mold-active azole, sufficient to inhibit the growth of the mold. The term can also refer to the amount of the enfumafungin derivative and the second antifungal agent that when administered in combination is sufficient to inhibit the growth of mold, and thereby elicit the response being sought (e.g., a therapeutically effective amount, or an inhibition effective amount). When an active compound is administered in a salt form or a hydrate form, references to the amount of drug administered are to the free acid or free base form of the compound.

[0063] References to “treat,” “treating,” “treatment,” and variants thereof, generallyrefer to a treatment that, after it is administered, results in resolution or improvement of one or more signs or symptoms associated with a fungal infection, or that results in eradication of the fungi responsible for an infection, or any combination of these outcomes.

[0064] Antifungal activity of compounds can be demonstrated by various assaysknown in the art, for example, by their glucan synthesis inhibitory activity (IC50), minimum inhibitory concentration (MIC100) or minimum prominent inhibition (MIC80) against yeasts and minimum effective concentration (MEC) against filamentous molds and dermatophytes in a broth microdilution assay, or in vivo antifungal activity in mouse models. The compounds of Formula (I) were generally found to give an MEC against Aspergillus fumigatus in the range of <0.5-8 µg / mL and an MEC against Mucorales of >16 µg / mL. EXAMPLES

[0065] The following examples serve only to illustrate the invention and its practice.The examples are not to be construed as limitations on the scope or spirit of the invention.Docket No.035680.2301-WO02 EXAMPLE 1

[0066] A study was conducted to evaluate the activity of SCY-247 alone and incombination with liposomal amphotericin B (L-AMB), the current standard of care for mucormycosis, using a immunocompromised mice model. Although it has shown low potency against Mucorales when tested in vitro, SCY-247 in this study surprisingly demonstrated efficacy against mucormycosis in vivo when used alone, and even more so when used in combination with amphotericin B. Preparation of SCY-247 for Dosing in Mice

[0067] SCY-247 was prepared in 0.5% (w / v) methyl cellulose (400 CPS) in sterilewater for injection and stirred using a magnetic stir plate and stir bar for at least 30 minutes then adjusted to pH 6.5^0.3 (Table 1). Formulations were stored protected from light in a refrigerator set to maintain a temperature of 2 to 8oC and used within 24 hr of preparation. Solutions or suspensions were allowed to acclimate to ambient room temperature before administration. These storage conditions were selected while stability studies were ongoing. A vehicle control formulation of 0.5% (w / v) methyl cellulose solution was stored similarly with the SCY-247 formulation. A pharmaceutical preparation of liposomal amphotericin B (L-AMB) was used as the positive control. Table 1. SCY-247 dose formulation Groupa,bDose Level Dose Concentration (mg / kg) (mg / mL) ellulose) only.b: groups are presented n abe . c: Groups 4 and 7 were administered SCY-247; Group 7 also received L-AMB. SCY-247 Dose Administration

[0068] Dose formulations of SCY-247 were administered twice daily (BID) (~q12hr)by oral gavage for 7 days at a dose volume of 10 mL / kg. Doses were based on the most recently recorded mean body weights. Dose formulations were allowed to equilibrate to approximately room temperature and stirred using a magnetic stir plate and stir bar for at least 30 minutes prior to and throughout dosing. SCY-247 formulations were suspensions necessitating constant stirring during the administration period. Purity of SCY-247 was tested by HPLC method. SCY-247 from a batch was administered orally at doses of 20, 40,Docket No.035680.2301-WO02 and 60 mg / kg BID, which corresponded respectively to doses of 16, 32, and 48 mg / kg BID of SCY-247 when corrected for purity. The actual SCY-247 dose amounts after such correction (i.e., 16, 32, and 48 mg / kg) are used in the description of the methods and the results of this experiment. Mouse Strain

[0069] Outbred male ICR mice weighing ~25 grams were used. Mice were housed 5per cage and had access to food and water ad libitum. Immune Status

[0070] Mice were rendered neutropenic by administration of 200 mg / kgcyclophosphamide given intraperitoneally in sterile irrigation water and 500 mg / kg cortisone acetate (CA) subcutaneously (SQ) in 0.1 ml of 0.05% Tween 80 (sonicated for 30-60 sec before use) on Day -2, +3, and +8, relative to infection.

[0071] To prevent bacterial super-infection and deaths in the immunosuppressedmice, mice received antibacterial prophylaxis consisting of enrofloxacin at 50 ppm enrofloxacin (Baytril®; Bayer) in drinking water on Day -3, then switched to daily treatment of ceftazidime (5 mg) starting on Day 0 through Day + 13 relative to infection. Isolate and Intratracheal Inoculation

[0072] Rhizopus delemar 99-880 isolated from the brain of a patient withmucormycosis was obtained from the Fungus Testing Laboratory, UT Health San Antonio. This strain had its genome sequenced and is the standard strain for virulence and treatment studies for mucormycosis. The organism was grown on potato dextrose agar (PDA, Becton Dickinson) plates for 4-5 days at 37oC. The sporangiospores were collected in endotoxin free Dulbecco’s phosphate buffered saline (PBS) containing 0.01% Tween 80, washed withPBS, and counted with a hemocytometer to prepare a final concentration of 1 x 107spores / ml. After sedation with isoflurane gas and while pulling the tongue anteriorly to the side with forceps, twenty-five ^l of fungal spores (2.5 x 105spores) in PBS was injected through the vocal cords into the trachea with a FisherbrandTMGel-Loading Tip. Immediately after inoculation (within 2-3 min), five mice were sacrificed, after which their lungs were homogenized and quantitatively cultured to confirm delivery of the inoculum to the lungs.For SCY-247, the MIC100 value (defined as the concentration that resulted in 100% growthinhibition) was > 16 µg / mL. The MIC100 value for L-AMB was 0.0315 µg / mL.Docket No.035680.2301-WO02 Mouse Assessment

[0073] Throughout the course of the experiments, animals were monitored at leasttwice daily to prevent and minimize unnecessary pain and distress. Any animal that appeared moribund prior to the scheduled endpoint was euthanized. Moribund animals were identified by the following criteria: 1. Ruffled / matted fur 2. Hunched posture 3. Weight loss (e.g., >20%) 4. Hypothermia (cool to touch) 5. Hyper- / hypoventilation 6. Inability to eat or drink Any animal demonstrating > 1 of these criteria was euthanized by isoflurane anesthesia followed by cervical dislocation. Treatment

[0074] All antifungal treatment started 24 h post infection. Mice were administeredSCY-247 at 16, 32, and 48 mg / kg twice daily (BID) by oral (PO) gavage for a period of 7 days (Table 3). A placebo control group consisting of the vehicle used to administer SCY- 247 was also included and was given via oral gavage. Other groups of mice received: L- AMB at 10 mg / kg / day given intravenously (IV) for 4 days; or a combination of L-AMB (10 mg / kg IV) and SCY-247 (32 mg / kg BID PO gavage) for 4 days followed by only SCY-247 (32 mg / kg BID PO gavage) for a further 3 days. Treatment studies consisted of a survival experiment and a tissue fungal burden experiment (determined by qPCR) of target organs of lung and brain. The number of mice in each treatment group and arm are listed in Table 2. Table 2. Treatment groups and number of mice per group in the survival and tissue fungal burden experiments. Group Group Survival Tissue fungal number experiment burdenDocket No.035680.2301-WO02 Outcome Measures

[0075] Two primary outcome measures were used to demonstrate the efficacy of theSCY-247 compared to L-AMB in treating neutropenic mice infected with R. delemar. These were: 1. Survival – Mice were monitored at least two times daily until day 21, at least 14 daysafter therapy had been discontinued in the treatment studies to allow for adequate washout of the antifungal agents. To prevent and minimize unnecessary pain or distress, any animal that appeared moribund (by the criteria described above) prior to the scheduled endpoint was humanely euthanized as described above. 2. Tissue Burden – Tissue fungal burden was measured using enumeration of colony-forming units in lungs (primary target organ) and brains (secondary target organ) using qPCR. In the fungal burden arm, tissues were collected on Day +4, the day before placebo mice started dying from infection. Organ collection was done 8 h after the last treatment that was administered the morning of Day +4. Data Analysis

[0076] Survival was plotted by Kaplan-Meier analysis, and differences in the mediansurvival time and percent survival were analyzed by the log-rank test and chi-square test, respectively. For comparisons involving more than two groups, ANOVA with Tukey’s post- test for multiple comparisons for normally distributed data or the Kruskal-Wallis Test with Dunn’s post-test for multiple comparisons for non-normally distributed data was used. A p-value < 0.05 was considered statistically significant for all comparisons.RESULTS SCY-247 monotherapy and combination therapy were effective in treating murine pulmonary mucormycosis due to R. delemar

[0077] The efficacy of SCY-247 in treating murine mucormycosis was assessed viathe survival study of SCY-247 alone or in combination with L-AMB, as described above. In the study, all monotherapy treatments of SCY-247 (16, 32, or 48 mg / kg BID) and L-AMB improved survival over placebo-treated mice, with overall survival of 20%, 40%, 50%, 40%, respectively, versus 0% for placebo-treated mice. Further, SCY-247 at 32 and 48 mg / kg, BID, led to enhanced median survival time of 14.5 and 18 days, respectively, vs.8.5 days for placebo. Combination therapy of SCY-247 of 32 mg / kg, BID + L-AMB, resulted in 90% overall survival and a median survival time of >21 days, which was better than placebo, and better than any of the monotherapies (FIG.1). Thus, both SCY-247 monotherapy and combination therapy improved the survival of neutropenic mice with pulmonaryDocket No.035680.2301-WO02 mucormycosis. Table 3 shows log rank P values for percent of survival comparisons across the groups. P values of <0.05 were considered significant. Table 3. Log-rank (Mantel-Cox) test (P values) Log-rank SCY-247 SCY-247 SCY-2 Cox) Place 47 SCY-247 LAMB (Mantel- bo 32mg / kg+ 16 k 32 k 48 k 10 k 1 1 7 4 bur en o m ce n ec e w . eemar.

[0078] Following the demonstration of efficacy of SCY-247 in prolonging survival ofmice when given alone or in combination with L-AMB as described above, the effect of treatment on the lung and brain fungal burden of mice infected with R. delemar was assessed. Lungs and brain are the primary and secondary target organs in this model. Mice were infected by intratracheal route and treated as described above. Mice were sacrificed on Day +4 relative to infection and tissues were collected, homogenized and the fungal burden determined by qPCR. Consistent with the survival studies, SCY-247 at 32 or 48 mg / kg BID monotherapy was as effective as 10 mg / kg, qd of L-AMB in reducing lung and brain fungal burden by ~0.7-1.0-log compared to placebo-treated mice. Importantly and consistent with the synergy shown in the survival studies, combination of SCY-247 (32 mg / kg, BID) + L- AMB (10 mg / kg, qd) reduced tissue fungal burden of lung and brain by ~2.0-3.0-log when compared to placebo and by ~1.5-log versus monotherapies (Table 4).Docket No.035680.2301-WO02 Table 4. Mann-Whitney Test SCY-247 SCY-247 SCY-247 SCY-247 LAMB Placebo 16mg / kg 32mg / kg 48mg / kg 10mg / kg 32mg / kg+SCY-247 Placebo SCY-247 SCY-247 SCY-247 LAMB 32mg / kg+SCY-247 monotherapy (32 and 48 mg / kg BID) or combination therapy with L-AMB reduced tissue fungal burden of immunosuppressed mice infected with R. delemar

[0079] Tissue fungal burden of lung and brain of mice infected intratracheally with R.delemar 99-880 (4.1 x 103 spores / mouse) was assessed. Mice were sacrificed on Day +4,relative to infection. P values of <0.05 were considered significant.Docket No.035680.2301-WO02 SCY-247 monotherapy (32 and 48 mg / kg BID) was as effective as the standard of care of L-AMB

[0080] SCY-247 monotherapy at 32 or 48 mg / kg, BID was as effective as thestandard of care of L-AMB given at 10 mg / kg / day in prolonging median survival, enhancing overall survival, and reducing tissue fungal burden of neutropenic mice infected with R. delemar. SCY-247 demonstrated synergy when combined with L-AMB against murine mucormycosis caused by R. delemar. EXAMPLE 2

[0081] Another study can be conducted to further investigate the synergistic effects ofa combination therapy of SCY-247 and amphotericin B for the treatment of mucormycosis. In the study, amphotericin B would be tested at different doses in combination with SCY- 247.

[0082] The recommended first line treatment for mucormycosis is liposomalformulations of amphotericin B, but nephrotoxicity of amphotericin B limits both the duration of treatment (meaning prolonged treatment is not possible) and the dosage amount (meaning that treatment with higher dosage amounts is not possible). The combination of SCY-247 with amphotericin B could allow the administration of lower doses of amphotericin B, hence reducing toxicity issues while maintaining acceptable efficacy. This synergistic effect can be investigated using a immunocompromised murine model of pulmonary mucormycosis.

[0083] Preparation of SCY-247 for Dosing in Mice: SCY-247 would be preparedin 0.5% (w / v) methyl cellulose (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 0.5% (w / v) methyl cellulose solution would be used as vehicle control. A pharmaceutical preparation of liposomal amphotericin B (L-AMB) would be used as the positive control.

[0084] SCY-247 Dose Administration: Dose formulations of SCY-247 would beadministered twice daily (BID) (~q12hr) by oral gavage for 7 days at a dose volume of 10 mL / kg. SCY-247 would be administered orally to provide doses of SCY-247 of approximately 32 mg / kg BID.

[0085] Mouse Strain and Immune Status: Outbred male ICR mice weighing ~25grams would be used in the study. Mice would be rendered neutropenic by administration ofDocket No.035680.2301-WO02 200 mg / kg cyclophosphamide given intraperitoneally in sterile irrigation water and 500 mg / kg cortisone acetate (CA) subcutaneously (SQ) in 0.1 ml of 0.05% Tween 80 on Day -2, +3, and +8, relative to infection. Another immunosuppressive regimen known in the art could be used. To prevent bacterial super-infection and deaths in the immunosuppressed mice, mice would receive antibacterial prophylaxis.

[0086] Inoculation: Rhizopus delemar or other Mucorales species would be used forintratracheal inoculation.

[0087] Measurements: Survival and colony-forming units in lung tissue would beused as an assessment of treatment effect.

[0088] Treatment: All antifungal treatment would be started 24 h post infection.Mice would receive SCY-247 at approximately 32 mg / kg twice daily (BID) by oral (PO) gavage for a period of 7 days. A placebo control group consisting of the vehicle used to administer SCY-247 would also be included. Other groups of mice would receive: L-AMB at doses ranging from 1 to 10 mg / kg / day given intravenously (IV) for 4 days; or a combination of L-AMB and SCY-247 (32 mg / kg BID PO gavage) for 4 days followed by only SCY-247 (32 mg / kg BID PO gavage) for a further 3 days. Treatment studies would consist of a survival experiment and a tissue fungal burden experiment (determined by qPCR) of target organs. The number of mice in each treatment group and arm would be ~10 per active treatment group and ~ 5 per vehicle control.

[0089] Data Analysis: Survival would be plotted by Kaplan-Meier analysis, anddifferences in the median survival time and percent survival would be analyzed by the log- rank test and chi-square test, respectively, or comparable statistical methods known in the art.A p-value < 0.05 would be considered statistically significant for all comparisons.

[0090] RESULTS: The results of the study could demonstrate that a comparable orbetter treatment effect is observed when doses lower than 10mg / kg per day of amphotericin B are administered in combination with SCY-247, as compared to the treatment effect achieved by a high dose of amphotericin B (10mg / kg / day). This would indicate that, with the combination therapy of SCY-247 and amphotericin B, it is possible to provide a less toxic treatment regimen while maintaining efficacy against a disease associated with high mortality.

[0091] While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood in light of the presentDocket No.035680.2301-WO02 disclosure by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

Docket No.035680.2301-WO02 WHAT IS CLAIMED IS:

1. A method of treating mucormycosis in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof: X R3wherein:X is O or H,H; R1is a) OH; b) OC(O)C1-C12-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from OR0, N(R0)2, and CO2R0; c) OC(O)C1-C6-haloalkyl; d) OC(O)C3-C8-cycloalkyl; e) O-C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from OR0and N(R0)2; f) OC(O)NHC1-C6-alkyl, unsubstituted or substituted with phenyl; g) OC(O)OC1-C6-alkyl; h) NHC(O)C1-C6-alkyl, unsubstituted or substituted with phenyl; or i) (O)nCH2C(O)C1-C6-alkyl; n is 0 or 1; R2is a) CH2R4, b) CH2CHR5(CH2)mNR6R7, c) CH2C(R8)(R9)(CH2)mNR6R7, d) CH2C(R10)(R11)R12, e) CH2CH(OR0)CH2OR0, f) CHR13CHR5(CH2)mNR6R7, g) (CH2)pC(R8)(R9)NR6R7, or, h) CH2CHR5C(R8)(R9)NR6R7, m is 0, 1 or 2; p is 2 to 6;Docket No.035680.2301-WO02 R1and R2are optionally taken together to form a methylenedioxy or ethylenedioxy, unsubstituted or substituted with 1 or 2 substituents selected from C1-C6-alkyl and C1-C6-alkoxy; R3is a) C(O)R14; b) CH2OH; or c) CH2OC(O)C1-C6-alkyl; R14is OH, OR15, H, N(R0)2, or C1-C6-alkyl; R15is C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from phenyl, OC(O)C1-C6-alkyl, C(O)OR0, OR0, C(O)N(R0)2, and C(O)NH2(CH2)2-4NH2and wherein said phenyl is optionally substituted with 1 to 3 halo groups; R4is a) H; b) (CH2)1-6-R16; c) OC1-C6-alkyl; d) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 3 substituents selected from halo, N(R0)2, OR0, C1-C6-alkyl, CF3, OCF3, CO2R0, and C(O)N(R0)2; e) heterocyclyl, wherein heterocyclyl is a 3- or 6-membered, saturated or unsaturated non-aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from oxo, N(R0)2, OR0, CO2R0, CON(R0)2, and C1-C6-alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6-alkyl and CO2R0; or f) heteroaryl, wherein heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a ring carbon or nitrogen, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 or 2 substituents selected from N(R0)2, OR0, CO2R0, CON(R0)2, and C1-C6 alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6 alkyl and CO2R0; R16is a) H; b) OH; c) NH2; d) NHC(O)R17; e) NHSO2R17;Docket No.035680.2301-WO02 f) NHC(O)NHR0; g) NHC(O)CHR18NH2; h) heterocyclyl, wherein heterocyclyl is a 5- or 6-membered, saturated or unsaturated non-aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from N(R0)2, imino, oxo, OR0, CO2R0, CON(R0)2, and C1-C6-alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, OR0, and CO2R0; i) NH-N(C1-C6-alkyl)2; j) NHC(=NH)NHC(=NH)NH2; k) NRa(CH2)pNHRa; alkyl, wherein said alkyl is unsubstituted or substituted (O)C1-C6-alkyl;cycloalkyl; q) NHC(=NRd)NH-phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents selected from halo and CF3; r) CO2C1-C6-alkyl; s) OCOC1-C6alkyl; t) heteroaryl, wherein heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 or 2 substituents selected from N(R0)2, OR0, CO2R0, CON(R0)2, and C1-C6 alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6 alkyl, OR0, and CO2R0; or u) CN; p is 1, 2, 3 or 4; Rais H or C(=NH)NH2; Rbis C1-C6alkyl, unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2and OR0; Rcis H or CN; Rdis H or C3-C6-cycloalkyl; R5isDocket No.035680.2301-WO02 a) C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2 and OR0; b) OH; c) OC1-C6-alkyl, unsubstituted or substituted with phenyl; d) OC(O)C1-C6-alkyl; e) C3-C6-cycloalkyl; f) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 3 substituents selected from halo, OCF3, CF3, N(R0)2and OR0; g) heteroaryl, wherein heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 or 2 substituents selected from N(R0)2, OR0, and C1-C6-alkyl; or h) heterocyclyl, wherein heterocyclyl is a 5- or 6-membered, saturated or unsaturated non-aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a ring carbon or nitrogen, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from N(R0)2, OR0, and C1-C6-alkyl; R6is H or C1-C6-alkyl, wherein said alkyl 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, attached through a ring carbon or nitrogen, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from N(R0)2, OR0, CO2R0, CON(R0)2and C1-C6-alkyl unsubstituted or substituted with one or two substituents selected from OR0, N(R0)2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, CO2R0, C(O)N(R0)2, and NHC(O)R0; R7is a) H; b) C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, OR0, CO2R0, OC(O)C1-C6-alkyl, NHC(O)R0, C(O)N(R0)2, phenyl, heteroaryl, and heterocyclyl, wherein heteroaryl is as defined below in (j) and heterocyclyl is as defined below in (k); c) C(O)H; d) C(O)C1-C6-haloalkyl; e) C(O)C1-C6-alkyl, unsubstituted or substituted with 1 or 2 substituents selected from CO2R0, OR0, OCH2CO2R0, N(R0)2, C(O)C1-C6-alkyl, O(CH2)2OC1-C6- alkyl, C(O)N(R0)2, OC(O)C1-C6alkyl, and NHC(O)R0; f) C(O)OC1-C6-alkyl;Docket No.035680.2301-WO02 g) C(O)NH-C1-C6-alkyl; h) SO2C1-C6-alkyl; i) C3-C6-cycloalkyl; j) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 3 substituents selected from halo, N(R0)2, OR0, C1-C6-alkyl, CF3, OCF3, CO2R0, and C(O)N(R0)2; k) heteroaryl, wherein heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 or 2 substituents selected from N(R0)2, OR0, CO2R0, OC(O)C1-C6-alkyl, CON(R0)2, NHC(O)R0, and C1-C6- alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6alkyl, OR0, CO2R0, C(O)N(R0)2and NHC(O)R0; l) heterocyclyl, wherein heterocyclyl is a 5- or 6-membered, saturated or unsaturated non-aromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S, attached through a carbon or nitrogen on the ring, and optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from N(R0)2, imino, oxo, OR0, CO2R0, OC(O)C1-C6-alkyl, CON(R0)2, NHC(O)R0, and C1-C6-alkyl unsubstituted or substituted with 1 or 2 substituents selected from N(R0)2, NHC(=NH)NH2, OC(O)C1-C6-alkyl, OR0, CO2R0, C(O)N(R0)2and NHC(O)R0; m) C(=NH)C1-C6-alkyl, wherein said alkyl is unsubstituted or substituted with 1 or 2 substituents selected from halo, CF3, N(R0)2, OR0, and NHC(O)C1-C6- alkyl; n) C(=NRd)NH2; o) C(=NH)NH-C1-C6-alkyl, wherein said alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halo, CF3, N(R0)2, OR0, and NHC(O)C1-C6- alkyl; p) C(=NH)NH-C3-C6-cycloalkyl; q) C(=NH)NH-phenyl, wherein phenyl is unsubstituted or substituted with 1 to 3 substituents selected from halo and CF3; or r) C(=NH)NHC(=NH)NH2; R6and R7are optionally taken together with the attached nitrogen atom to form a 3- to 6-membered saturated, unsaturated or aromatic ring having 0-2 additional heteroatoms selected from N, O and S, wherein said ring is optionally substituted on a ring carbon or nitrogen that is not the point of attachment, with 1 to 2 substituents selected from halo, N(R0)2, OR0, CO2R0, CON(R0)2, and C1-C6alkylDocket No.035680.2301-WO02 unsubstituted or substituted with 1 or 2 substituents selected from OR0and N(R0)2, and wherein two adjacent substituents of said ring are optionally taken together to form a fused 5- or 6-membered saturated, unsaturated, or aromatic ring having 0-2 heteroatoms selected from N, O and S; or R6and R9are optionally taken together, with the nitrogen atom R6is attached to, to form a pyrrolidinyl ring; R8is selected from the group consisting of a) hydrogen, b) C1-C6-alkyl, unsubstituted or substituted with OR0or SO2R0, c) C3-C6-cycloalkyl, and d) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 3 substituents selected from halo, OCF3, CF3, N(R0)2and OR0; R9is C1-C6-alkyl, unsubstituted or substituted with OR0or SO2R0; R8and R9are optionally taken together to form a 3- to 6-membered saturated ring having 0-1 heteroatom selected from N, O or S; R10is independently selected from the group consisting of a) C1-C6-alkyl unsubstituted or substituted with OR0, N(R0)2, OC(O)C1-C6 alkyl or CO2R0, and b) CO2R0; R11is C1-C6alkyl unsubstituted or substituted with OR0, OC(O)C1-C6alkyl, OC(O)- phenyl, CO2R0, or N(R0)2; R12is OH or C1-C6alkyl, wherein said alkyl is unsubstituted or substituted with OC(O)C1-C6alkyl or OR0; R13is C1-C4-alkyl; R17is a) C1-C6-alkyl, unsubstituted or substituted with 1 to 2 substituents selected from CO2R0, OR0, N(R0)2, and OC(O)C1-C6-alkyl; b) aryl, wherein aryl is phenyl or naphthyl and aryl is unsubstituted or substituted with 1 to 2 substituents selected from halo, OR0and N(R0)2; or c) C1-C6-haloalkyl; R18is H or C1-C6-alkyl, wherein said alkyl is unsubstituted or substituted with 1 to 2 substituents selected from OR0, N(R0)2, heteroaryl, heterocyclyl, CO2N(R0)2, and CO2R0, wherein heteroaryl is as defined in R16(t) and heterocyclyl is as defined in R16(h); and each R0is independently H or C1-C6-alkyl.

2. The method according to claim 1, further comprising administering to the subject a second antifungal agent selected from a polyene, an azole, a purine or pyrimidine nucleotide inhibitor, a chitin inhibitor, an orotomide, a Gwt1 inhibitor, and an immunomodulating agent.Docket No.035680.2301-WO02 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 of treating mucormycosis in a subject in need thereof, the method comprising administering to the subject the compound SCY-247:or a pharmaceutically acceptable salt or hydrate thereof.

6. The method according to claim 5, further comprising administering to the subject a second antifungal agent selected from a polyene, an azole, a purine or pyrimidine nucleotide inhibitor, a chitin inhibitor, an orotomide, a Gwt1 inhibitor, and an immunomodulating agent.

7. The method according to claim 6, wherein the second antifungal agent is amphotericin B, isavuconazole, voriconazole, posaconazole, itraconazole, olorofim, or fosmanogepix.

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

9. A pharmaceutical combination of: (a) a first antifungal agent that is the compound SCY-247:Docket No.035680.2301-WO02 or a pharmaceutically acceptable salt or hydrate thereof; and (b) a second antifungal agent selected from a polyene, an azole, a purine or pyrimidine nucleotide inhibitor, a chitin inhibitor, an orotomide, a Gwt1 inhibitor, and an immunomodulating agent.

10. The pharmaceutical combination according to claim 9, wherein the second antifungal agent is amphotericin B, isavuconazole, voriconazole, posaconazole, itraconazole, olorofim, or fosmanogepix.

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

12. A method of treating pulmonary mucormycosis in a subject in need thereof, the method comprising administering to the subject: (a) a first antifungal agent that is the compound SCY-247:or a pharmaceutically acceptable salt or hydrate thereof; and (b) a second antifungal agent selected from a polyene, an azole, a purine or pyrimidine nucleotide inhibitor, a chitin inhibitor, an orotomide, a Gwt1 inhibitor, and an immunomodulating agent.

13. The method according to claim 12, wherein the second antifungal agent is amphotericin B, isavuconazole, voriconazole, posaconazole, itraconazole, olorofim, or fosmanogepix.

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

15. The method according to claim 12, wherein the first antifungal agent is a pharmaceutically acceptable salt of SCY-247 and the second antifungal agent is amphotericin B.Docket No.035680.2301-WO02 16. The method according to claim 15, wherein the first antifungal agent is administered orally.

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

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

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

20. The method according to claim 12, wherein the first antifungal agent and the second antifungal agent are administered concurrently.

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

22. The method according to claim 12, wherein the subject is a human.

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

24. The method according to 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. Preparation of a medicament for treating mucormycosis comprising the use of the compound SCY-247:or a orDocket No.035680.2301-WO02 26. Use of the compound SCY-247: or ain the preparation of a medicament for treating mucormycosis.

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