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WO2025226861A1 - Inhibiteurs de cycline - Google Patents

Inhibiteurs de cycline

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Publication number
WO2025226861A1
WO2025226861A1 PCT/US2025/026045 US2025026045W WO2025226861A1 WO 2025226861 A1 WO2025226861 A1 WO 2025226861A1 US 2025026045 W US2025026045 W US 2025026045W WO 2025226861 A1 WO2025226861 A1 WO 2025226861A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
independently
compound
heterocycloalkyl
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/026045
Other languages
English (en)
Inventor
Andrew T. BOCKUS
Breena F. WALTON
Constantine Kreatsoulas
James B. Aggen
Justin A. SHAPIRO
Megan DEMART
Nathan J. Dupper
Sik Fai Siegfried LEUNG
Chinmay Bhatt
Samuel Metobo
Kai Yang
Ming Hsun Ho
Rajinder Singh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Circle Pharma Inc
Original Assignee
Circle Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Circle Pharma Inc filed Critical Circle Pharma Inc
Publication of WO2025226861A1 publication Critical patent/WO2025226861A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • cyclins including Cyclins D, E, A and B
  • CDKs cognate cyclin dependent kinases
  • CDKs cyclin dependent kinases
  • Disruptions of the normal regulatory functions of cyclin-CDK complexes are common drivers of oncogenesis and the rapid proliferation of cancer cells.
  • the central role of cyclins and CDKs in the cell cycle makes these proteins and their complexes attractive targets for treating proliferative disorders and cancer.
  • CDK inhibitors target the kinase 15 activity of CDKs
  • Alternative approaches could include disrupting the association of cyclins with CDKs or the interaction of a particular cyclin-CDK complex with its substrates or regulators.
  • CDK inhibitors have been developed and proven successful in certain 20 cancers, they are currently limited by their relative lack of selectivity, small therapeutic window, and ultimately the development of resistance. As such, there is a need to develop agents that offer alternative approaches to inhibiting the function of cyclin-CDK complexes as a means to modulate the cell cycle. Such agents could provide new tools in the treatment of proliferative diseases.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating a 20 disease or disorder mediated at least in part by cyclin activity, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the disorder or condition.
  • the present disclosure provides a method of treating a 25 cancer mediated at least in part by cyclin A, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer.
  • the present invention provides intermediates useful in the 30 preparation of compounds of Formula (I).
  • cyclin and CDKs that regulate these substrates therefore play key roles in regulating the cell cycle, including Cyclins D, A, E and B, and CDKs 1, 2, 4 and 6.
  • certain substrates including p21, p27, Rb, E2F and CDC6, first bind to the cyclin- CDK complex via a conserved RxL motif within the substrate (Adams et al. Mol Cell Biol. 15 1996.16(12):6223-33.) and bind to a region with the cyclin that is referred to as an RxL binding domain or a “hydrophobic patch” (Brown et al.
  • the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term “about” means within a standard deviation using measurements generally acceptable in the art. In some embodiments, about means a range extending to +/- 10% of the specified value. In some embodiments, about means the 30 specified value. 7 PATENT Attorney Docket No.052687-508001WO [0015] “Alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated.
  • Alkyl can include any number of carbons, such as C1-2, C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C5-6.
  • C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, 5 butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.
  • Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.
  • Alkylene refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent 10 hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group.
  • a straight chain alkylene can be the bivalent radical of –(CH 2 ) n – , where n is 1, 2, 3, 4, 5 or 6.
  • Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.
  • Alkylene groups can be substituted or 15 unsubstituted.
  • Alkenyl refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond.
  • Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C 6 .
  • Alkenyl groups can have any suitable number of double bonds, including, but not 20 limited to, 1, 2, 3, 4, 5 or more.
  • alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.
  • Alkenyl groups can be substituted or unsubstituted.
  • Alkenylene refers to a straight or branched hydrocarbon having at least 2 carbon atoms, one double bond, and linking at least two other groups, i.e., a divalent hydrocarbon radical. Alkenylene can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 3-6 , C 3-7 , C 4 , C 4-5 , C 4-6 , C 4-7 , C 6-7 , C 5 , C 6 and C 7.
  • the two moieties linked to the alkenylene can be linked to the same atom or different atoms of the30 alkenylene group.
  • Representative alkenylene groups include, but are not limited to, (E)-hex- 2-enylene, (Z)-hex-2-enylene, (E)-hept-2-enylene, (Z)-hept-2-enylene, (E)-hept-3-enylene, 8 PATENT Attorney Docket No.052687-508001WO and (Z)-hept-3-enylene.
  • Alkenylene moieties can be in the E or Z isomer.
  • Alkenylene groups can be substituted or unsubstituted.
  • Alkynyl refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl can include any number of carbons, such 5 as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C 6 .
  • alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.
  • Alkynyl groups can be substituted or 10 unsubstituted.
  • Alkoxy refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-.
  • alkyl group alkoxy groups can have any suitable number of carbon atoms, such as C 1-6 .
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, 15 tert-butoxy, pentoxy, hexoxy, etc.
  • the alkoxy groups can be substituted or unsubstituted.
  • Alkoxyalkyl refers to alkyl group connected to an oxygen atom that is further connected to an second alkyl group, the second alkyl group being the point of attachment to the remainder of the molecule: alkyl-O-alkyl.
  • the alkyl portion can have any suitable number of carbon atoms, such as C2-6.
  • Alkoxyalkyl groups include, for example, 20 methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc.
  • the alkoxy groups can be substituted or unsubstituted.
  • Halo or “halogen” refers to fluorine, chlorine, bromine and iodine.
  • Haloalkyl refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms.
  • alkyl group haloalkyl groups can have any 25 suitable number of carbon atoms, such as C1-6.
  • haloalkyl includes trifluoromethyl, flouromethyl, etc.
  • perfluoro can be used to define a compound or radical where all the hydrogens are replaced with fluorine.
  • perfluoromethyl refers to 1,1,1-trifluoromethyl.
  • Haloalkoxy refers to an alkoxy group where some or all of the hydrogen atoms 30 are substituted with halogen atoms.
  • haloalkoxy groups can have any suitable number of carbon atoms, such as C 1-6 .
  • the alkoxy groups can be substituted with 1, 9 PATENT Attorney Docket No.052687-508001WO 2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated.
  • Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.
  • Cycloalkyl refers to a saturated or partially unsaturated, monocyclic, spirocyclic, 5 fused or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C 3-6 , C 4-6 , C 5-6 , C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12.
  • Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] 10 bicyclooctane, decahydronaphthalene and adamantane.
  • Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring, but cycloalkyl groups are not aromatic.
  • Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobuteneyl, cyclopenteneyl, cyclohexeneyl, cyclohexadieneyl (1,3- and 1,4-isomers), cyclohepteneyl, cycloheptadieneyl, cycloocteneyl, 15 cyclooctadieneyl (1,3-, 1,4- and 1,5-isomers), norborneneyl, and norbornadieneyl.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexeneyl, cyclohexadieneyl (1,3- and 1,4-isomers).
  • exemplary groups include, but are not limited to bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, 20 bicyclo[4.2.0]octanyl, and octahydro-1H-indenyl.
  • exemplary groups include, but are not limited to bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, and bicyclo[2.1.1]hexane.
  • exemplary groups include, but are not limited to spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonanyl, spiro[2.5]octane, and spiro[2.4]heptane.
  • Cycloalkyl groups can be 25 substituted or unsubstituted.
  • Heterocycloalkyl refers to a saturated or partially unsaturated, monocyclic, spirocyclic, fused or bridged polycyclic ring assembly having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S.
  • the heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O) 2 -.
  • Heterocycloalkyl groups can include any number of ring 30 atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members.
  • heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, 10 PATENT Attorney Docket No.052687-508001WO piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), tetrahydropyridine, oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thi
  • Heterocycloalkyl groups can be unsubstituted or substituted.
  • the heterocycloalkyl groups can be linked via any position on the ring.
  • aziridine can be 1- or 2-aziridine
  • azetidine can be 1- or 2- azetidine
  • pyrrolidine can be 1-, 2- or 3-pyrrolidine
  • piperidine can be 1-, 2-, 3- or 4-piperidine
  • pyrazolidine can be 1-, 10 2-, 3-, or 4-pyrazolidine
  • imidazolidine can be 1-, 2-, 3- or 4-imidazolidine
  • piperazine can be 1-, 2-, 3- or 4-piperazine
  • tetrahydrofuran can be 1- or 2-tetrahydrofuran
  • oxazolidine can be 2-, 3-, 4- or 5-oxazolidine
  • isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine
  • thiazolidine can be 2-, 3-, 4- or 5-thiazolidine,
  • heterocycloalkyl is a monocyclic heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms
  • representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxzoalidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane and dithiane.
  • Heterocycloalkyl can also be monocyclic 20 heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.
  • Aryl refers to an aromatic ring system having any suitable number of ring atoms 25 and any suitable number of rings.
  • Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members.
  • Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group.
  • Representative aryl groups include phenyl, naphthyl and biphenyl.
  • Other aryl groups include benzyl, having a methylene 30 linking group.
  • Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl.
  • aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. 11 PATENT Attorney Docket No.052687-508001WO Some other aryl groups have 6 ring members, such as phenyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 12 ring atoms, where from 1 to 6 of the ring atoms are a heteroatom 5 such as N, O or S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O) 2 -.
  • Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 5 to 8, 5 to 9, 5 to 10, 5 to 12, or 9 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, 5, or 6, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5, or 3 to 6.
  • Heteroaryl groups 10 can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
  • the heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, 15 isothiazole, oxazole, and isoxazole.
  • heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran.
  • Other heteroaryl groups include 20 heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.
  • the heteroaryl groups can be linked via any position on the ring.
  • pyrrole includes 1-, 2- and 3-pyrrole
  • pyridine includes 2-, 3- and 4-pyridine
  • imidazole includes 1-, 2-, 4- and 5-imidazole
  • pyrazole includes 1-, 3-, 4- and 5-pyrazole
  • triazole 25 includes 1-, 4- and 5-triazole
  • tetrazole includes 1- and 5-tetrazole
  • pyrimidine includes 2-, 4-, 5- and 6- pyrimidine
  • pyridazine includes 3- and 4-pyridazine
  • 1,2,3-triazine includes 4- and 5-triazine
  • 1,2,4-triazine includes 3-, 5- and 6-triazine
  • 1,3,5-triazine includes 2-triazine
  • thiophene includes 2- and 3-thiophene
  • furan includes 2- and 3-furan
  • thiazole includes 2-, 4- and 5-thiazole
  • isothiazole includes 3-, 4- and
  • heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, 5 pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran.
  • N, O or S such as pyrrole, pyridine, imidazole, pyrazole, triazole, 5 pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-
  • heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, 10 pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroatoms such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, 10 pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine.
  • heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 15 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • “Pharmaceutically acceptable excipient” refers to a substance that aids the 20 formulation and/or administration of an active agent to a subject.
  • compositions useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.
  • Subject refers to animals such as mammals, including, but not limited to, primates 25 (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human.
  • administering refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release 30 device e.g., a mini-osmotic pump, to the subject. 13 PATENT Attorney Docket No.052687-508001WO [0037] “Therapeutically effective amount” refers to a dose that produces therapeutic effects for which it is administered.
  • Treatment refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any 10 objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition.
  • the present disclosure provides a compound of Formula (I): (I) wherein R 3 is 20 (a) C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, or C 1-8 haloalkyl, each substituted with 0, 1, 2, 3, 4, or 5 R 3a , (b) C 3-12 cycloalkyl substituted with 0, 1, 2, 3, 4, or 5 R 3b , or (c) heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 25 4, or 5 R 3c ; 14 PATENT Attorney Docket No.052687-508001WO (g) heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring A comprises 13 to 21 ring atoms.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring A comprises 14 to 20 ring atoms.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring A comprises 16 to 18 ring atoms.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring A comprises 13 ring atoms.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring A comprises 14 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A 10 comprises 15 ring atoms. In some embodiment ring A comprises 16 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 17 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 18 ring atoms.
  • the compound, or the 15 pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring A comprises 19 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 20 ring atoms. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring A comprises 21 ring atoms.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (a) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C1-6 haloalkyl substituted with 0, 1, 2, 3, 4, or 5 R 3a .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), 25 wherein R 3 is (a) C1-6 alkyl or C1-6 haloalkyl substituted with 0, 1, or 2 R 3a .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (a) C1-6 alkyl substituted with 0, 1, or 2 R 3a .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (a) C1-6 haloalkyl substituted with 0, 1, or 2 R 3a .
  • R 3 can be combined with any of the embodiments described herein for R 3a .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 3a is –OH or C1-6 alkoxy.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 3a is –OH. These embodiments of R 3a can be 5 combined with any of the relevant embodiments described herein for R 3 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (b) C3-12 cycloalkyl substituted with 0, 1, 2, or 3 R 3b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (b) C3-7 cycloalkyl substituted with 0, 10 1, 2, or 3 R 3b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (b) C5-6 cycloalkyl substituted with 0, 1, or 2 R 3b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (b) C3-4 cycloalkyl substituted with 0, 1, or 2 R 3b .
  • R 3 can be combined with any of the embodiments 15 described herein for R 3b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 3b is halo, C 1-4 haloalkyl, or cyano.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 3b is halo or C 1-4 haloalkyl. In some embodiments, 20 the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R 3b is fluoro or trifluoromethyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (c) heterocycloalkyl having 3 to 6 ring 25 members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 4, or 5 R 3c .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (c) heterocycloalkyl having 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, or 2 R 3c .
  • R 3 can be combined with any of the relevant embodiments described herein for R 3c .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3c is halo or C1-4 haloalkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 3c is fluoro or trifluoromethyl.
  • R 3c is fluoro or trifluoromethyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (g) heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 R 3g .
  • the compound, or the 10 pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is (g) heteroaryl having 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heteroaryl is substituted with 0, 1, or 2 R 3g .
  • R 3 can be combined with any of the relevant embodiments described herein for R 3g .
  • the compound, or the pharmaceutically acceptable salt 15 thereof is the compound of Formula (I), wherein R 3g is halo or C 1-4 haloalkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 3g is chloro, fluoro, or trifluoromethyl. These embodiments of R 3g can be combined with any of the embodiments described herein for R 3 .
  • the compound, or the pharmaceutically acceptable salt 20 thereof is the compound of Formula (I), wherein R 3 is , [0050] Any of the embodiments described herein for residue 3 can be combined with any of the embodiments described herein for residues 4, 5, 6, 7, and 8.
  • any of the 25 embodiments of R 3 as described herein can be combined with any of the embodiments described herein for R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b R 6d , L 6a , Y 6 , L 6b , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , and ring A.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 4a , R 4b , and R 4c are each independently H or C1-6 alkyl; 5 alternatively, R 4c and R 4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, or 2 R 4a1 ; and each R 4a1 is independently halo.
  • R 4a , R 4b , and R 4c are each independently H or C1-6 alkyl; 5 alternatively, R 4c and R 4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, or 2 R 4a1 ; and each R 4a1 is independently hal
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 4a , R 4b , and R 4c are each independently H or C 1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein 15 R 4b is H or C 1-6 alkyl; and R 4c and R 4a together with the carbon and nitrogen to which each is attached combine to form a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein the heterocycloalkyl is substituted with 0, 1, 2, or 3 R 4a1 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 4a and R 4b are each H; and R 4c is ethyl; alternatively, R 4c and R 4a together with the carbon and nitrogen to which each is attached 25 combine to form a pyrrolidinyl, substituted with 0, 1, or 2 fluoro.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 4b is H; and R 4c and R 4a together with the carbon and nitrogen to which each is attached combine to form 30 a pyrrolidinyl, substituted with 0, 1, or 2 R 4a1 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 4a1 is C1-6 alkyl or halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R 4a1 is halo. In some embodiments, the compound, or the 5 pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R 4a1 is fluoro.
  • R 4a1 can be combined with any of the relevant embodiments described herein for R 4 .
  • the embodiments described herein for R 4a , R 4b and R 4c can be present in any combination.
  • any of the embodiments of R 4a , R 4b and R 4c as described herein can be combined with any of the embodiments described herein for R 3 , R 5a , R 5b , R 5c , R 6a , R 6b R 6d , L 6a , Y 6 , L 6b , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , and ring A.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 5a is H or C 1-6 alkyl; R 5b and R 5c are each independently H, C1-6 alkyl, –C1-6 alkyl–OH, C2-6 alkoxyalkyl, C1-6 haloalkyl, C 3-6 cycloalkyl, or C 1-4 alkyl–C 3-6 cycloalkyl, wherein each cycloalkyl is 20 substituted with 0, 1, 2, or 3 R 5b5 ; and each R 5b5 is independently C 1-4 alkyl, halo, or C 1-4 haloalkyl.
  • R 5a is H or C 1-6 alkyl
  • R 5b and R 5c are each independently H, C1-6 alkyl, –C1-6 alkyl–OH, C2-6 alkoxyalkyl, C1-6 haloalkyl, C 3-6 cycloalkyl, or C 1-4 alkyl–C 3-6 cycloalkyl,
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 5a is H or C 1-6 alkyl; and 25 R 5b and R 5c are each independently H, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkyl–C3-6 cycloalkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 5a is H or C1-6 alkyl; R 5b is H; and 30 R 5c is C3-6 cycloalkyl or C1-4 alkyl–C3-6 cycloalkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 5a and R 5b are each H; and R 5c is H, methyl, ethyl . 5
  • the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 5a and R 5b are each H; and R 5c is methyl .
  • the em o iments described herein for R 5a , R 5b and R 5c can be present in any 10 combination.
  • any of the embodiments of R 5a , R 5b and R 5c as described herein can be combined with any of the embodiments described herein for R 3 , R 4a , R 4b , R 4c , R 6a , R 6b R 6d , L 6a , Y 6 , L 6b , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , and ring A.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 6a is H, C 1-4 alkyl, or –C 1-4 alkyl–C 3-6 cycloalkyl; and R 6b and R 6d are each independently H or C1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula 20 (I), wherein R 6a is H or C1-4 alkyl; R 6b is H; and R 6d is C1-4 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 6a is H or C1-4 alkyl; and R 6b and R 6d are each H.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 6a , R 6b , and R 6d are each H.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 6a is H, methyl, n-propyl, o ; R 6b is H; and R 6d is H, methyl, ethyl, isopropyl, or 24 PATENT Attorney Docket No.052687-508001WO –CD 3 .
  • R 6a , R 6b and R 6d can be combined with any of the embodiments described herein for L 6a , Y 6 , and L 6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein 5 R 6a is H, methyl, n-propyl, or ; R 6b is H; and R 6d is H or methyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6a is C 1-5 alkylene substituted with 0, 1, 2, 10 or 3 R L6a .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6a is C 2-5 alkenylene substituted with 0, 1, 2, or 3 R L6a .
  • L 6a is C 2-5 alkenylene substituted with 0, 1, 2, or 3 R L6a .
  • the compound, or the pharmaceutically acceptable salt 15 thereof is the compound of Formula (I), wherein L 6a is substituted with 0 R L6a .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6a is substituted with 1 R L6a .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6a is substituted with 2 R L6a .
  • the compound, or the 20 pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6a is substituted with 3 R L6a .
  • L 6a and R L6a can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d , Y 6 , and L 6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R L6a is C1-4 alkyl, –OH, or halo.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R L6a is C1-4 alkyl or halo. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each R L6a is C1-4 alkyl.
  • R L6a can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d , L 6a , Y 6 , and L 6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6b is C1-5 alkylene substituted with 0, 1, 2, 25 PATENT Attorney Docket No.052687-508001WO or 3 R L6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6b is C2-5 alkenylene substituted with 0, 1, 2, or 3 R L6b .
  • L 6b can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d , L 6a , and Y 6 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6b is substituted with 0 R L6b . In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L 6b is substituted with 1 R L6b . In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), 10 wherein L 6b is substituted with 2 R L6b . In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein L 6b is substituted with 3 R L6b .
  • the compound, or the pharmaceutically acceptable salt 15 thereof is the compound of Formula (I), wherein each R L6b is C 1-4 alkyl, –OH, or halo.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R L6b is C 1-4 alkyl or halo.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R L6b is C 1-4 alkyl.
  • R L6b can be combined with any of the 20 embodiments described herein for R 6a , R 6b , R 6d , L 6a , Y 6 , and L 6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein Y 6 is a bond and L 6a and L 6b combine to form C8-10 alkylene substituted with 0, 1, 2, or 3 R L6a and 0, 1, 2, or 3 R L6b .
  • This embodiment of Y 6 can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d , R L6a , 25 and R L6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein Y 6 is a bond and L 6a and L 6b combine to form C8-10 alkenylene substituted with 0, 1, 2, or 3 R L6a and 0, 1, 2, or 3 R L6b .
  • This embodiment of Y 6 can be combined with any of the embodiments described herein for R 6a , 30 R 6b , R 6d , R L6a , and R L6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein Y 6 is a bond and L 6a is substituted with at 26 PATENT Attorney Docket No.052687-508001WO least one R L6a , and an R L6a and R 6b on adjacent carbon atoms combine to form a C 3-6 cycloalkyl.
  • This embodiment of Y 6 can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d , L 6a , and L 6b .
  • the compound, or the pharmaceutically acceptable salt 5 thereof is the compound of Formula (I), wherein Y 6 is O, NH, S, S(O), or S(O)2. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Y 6 is O, S, S(O), or S(O)2.
  • Y 6 can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d , L 6a , and L 6b .
  • the compound, or the pharmaceutically acceptable salt 10 thereof is the compound of Formula (I), wherein L 6a is C 1-5 alkylene substituted with 0, 1, 2, or 3 R L6a ; L 6b is C1-5 alkylene substituted with 0, 1, 2, or 3 R L6b , Y 6 is a bond, O, S, S(O), or S(O) 2 , wherein when Y 6 is a bond, L 6a is substituted with at least one R L6a , and an R L6a and R 6b on adjacent carbon atoms combine to form a C3-6 cycloalkyl.
  • L 6a is C 1-5 alkylene substituted with 0, 1, 2, or 3 R L6a
  • L 6b is C1-5 alkylene substituted with 0, 1, 2, or 3 R L6b
  • Y 6 is a bond, O, S, S(O), or S(O) 2 , wherein when Y 6 is a bond, L 6a is substituted with at least one R L6a , and an R
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein L 6a is C2-5 alkenylene substituted with 0, 1, 2, or 3 R L6a ; 20 L 6b is C 1-5 alkylene substituted with 0, 1, 2, or 3 R L6b ; Y 6 is a bond, O, NH, S, S(O), or S(O)2, wherein when Y 6 is a bond, L 6a is substituted with at least one R L6a , and an R L6a and R 6b on adjacent carbon atoms combine to form a C 3-6 cycloalkyl.
  • Formula (I) wherein L 6a is C2-5 alkenylene substituted with 0, 1, 2, or 3 R L6a ; 20 L 6b is C 1-5 alkylene substituted with 0, 1, 2, or 3 R L6b ; Y 6 is a bond, O, NH, S, S(O), or S(O)2, wherein when Y 6 is a bond, L 6a is substituted with
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein an R L6a and R 6b on adjacent atoms combine to form a C 3-6 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, or 2 R 6e .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein an R L6a and R 6b on adjacent atoms combine to form 30 cyclopropyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein an R L6a and R 6a on non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the 5 heterocycloalkyl is substituted with 0, 1, or 2 R 6e .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein an R L6a and R 6a on non-adjacent atoms combine to form a piperidinyl.
  • R L6a and R 6a can be combined with any of the embodiments described herein for R 6b , R 6d , L 6a , Y 6 , and L 6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein two R L6b moieties on the same atom or on adjacent atoms combine to form a C 3-6 cycloalkyl or a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the cycloalkyl and heterocycloalkyl is substituted with 15 0, 1, or 2 R 6e .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein two R L6b moieties on the same atom or on adjacent atoms combine to form cyclopropyl, cyclopenyl, or tetrahydrofuran.
  • R L6b can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d , L 6a , Y 6 , and L 6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein an R L6b and R 6d on adjacent or non-adjacent atoms combine to form a heterocycloalkyl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R 6e .
  • the compound, 25 or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein n R L6b and R 6d on adjacent or non-adjacent atoms combine to form azetidinyl, pyrrolidinyl, oxazolidinyl, or morpholinyl substituted with 0, 1, or 2, R 6e .
  • R L6b and R 6d can be combined with any of the embodiments described herein for R 6a , R 6b , R 6d , L 6a , Y 6 , and L 6b .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 6e is independently C1-4 alkyl, halo, or C 1-4 haloalkyl.
  • the compound, or the pharmaceutically acceptable 28 PATENT Attorney Docket No.052687-508001WO salt thereof is the compound of Formula (I), wherein each R 6e is independently C 1-4 alkyl or halo.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 6e is independently methyl or fluoro. In some embodiments, each R 6e is independently methyl.
  • R 6e can be combined 5 with any of the embodiments described herein for R 6a , R 6b , R 6d , L 6a , Y 6 , and L 6b .
  • the compound, or the pharmaceutically acceptable salt 10 29 PATENT Attorney Docket No.052687-508001WO 6 b can be combined with any of the [0085]
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein the moiet is 5 .
  • L 6a , Y 6 , L 6b , and R 6b can be described herein for R 6a an 6d d R .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein the moiet is .
  • the moiet is a compound of Formula (I), wherein the moiet is 5 , .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein the moie is 5 , .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein the moiet is 31 PATENT Attorney Docket No.052687-508001WO Y 6 , a.
  • the compound, or the pharmaceutically acceptable salt is 5 [0090]
  • the embodiments described herein for R a , R R , L a , Y , and L can be present in any combination.
  • the embodiments described herein for residue 6 can be present in combination with any of the embodiments described herein for residues 3, 4, 5, 7, and 8.
  • any of the embodiments of R 6a , R 6b R 6d , L 6a , Y 6 , and L 6b as described 10 herein, can be combined with any of the embodiments described herein for R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , and ring A.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 7a and R 7b are each independently H or C1- 15 6 alkyl; and R 7c is C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkyl–OH, or –C1-6 alkyl–C3-6 cycloalkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 7a and R 7b are each independently H or C 1- 6 alkyl; and R 7c is C1-6 alkyl, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl.
  • R 7a and R 7b are each independently H or C 1- 6 alkyl; and R 7c is C1-6 alkyl, C3-6 cycloalkyl, or –C1-6 alkyl–C3-6 cycloalkyl.
  • the compound, or the pharmaceutically acceptable salt 5 thereof is the compound of Formula (I), wherein R 7a and R 7b are each H; and R 7c is C1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 7a and R 7b are each H; and R 7c is isobutyl, O H . 10 ompound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R 7a and R 7b are each H; and R 7c is isobutyl.
  • the embodiments described herein for R 7a , R 7b and R 7c can be present in any combination.
  • any of the embodiments of R 7a , R 7b and R 7c as described herein can be combined with any of the embodiments described herein for R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b R 6d , L 6a , Y 6 , L 6b , R 8a , R 8b , R 8d , R 8e , ring B, m8, R 8f , and ring A.
  • the compound, or the pharmaceutically acceptable salt 20 thereof is the compound of Formula (I), wherein R 8a , R 8b , R 8d , and R 8e are each independently H or C1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 8a is H or methyl; and R 8b , R 8d and R 8e are each H.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring B is phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N, O, or S.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring B is phenyl.
  • the compound, 33 PATENT Attorney Docket No.052687-508001WO or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring B is biphenyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N, O, or S.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, wherein each heteroatom is N.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein ring B is pyrid-3-yl.
  • the compound, or the pharmaceutically acceptable salt 10 thereof is the compound of Formula (I), wherein ring B is phenyl or pyridyl. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein ring B is phenyl or pyrid-3-yl. These embodiments of ring B can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, R 8f , and R 8f3 . 15 [0100] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the subscript m8 is 1, 2, or 3.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein the subscript m8 is 0. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), 20 wherein the subscript m8 is 1. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the subscript m8 is 2. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein the subscript m8 is 3. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), 25 wherein the subscript m8 is 4.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein the subscript m8 is 5. These embodiments of m8 can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , R 8f , R 8f3 , and ring B.
  • the compound, or the pharmaceutically acceptable salt 30 thereof is the compound of Formula (I), wherein the moiety 34 PATENT Attorney Docket No.052687-508001WO .
  • R 8a , 8 b , R 8d , R 8 R e , R 8f , R 8f3 , m8 and ring B are described herein for R 8a , 8 b , R 8d , R 8 R e , R 8f , R 8f3 , m8 and ring B.
  • the compound, or the pharmaceutically acceptable salt 5 thereof is the compound of Formula (I), wherein the moiety .
  • the compound, or the pharmaceutically acceptable salt 10 thereof is the compound of Formula (I), wherein the moiety .
  • at least one R 8f is halo.
  • At least one 15 R 8f is fluoro or chloro.
  • R 8f can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f3 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f is independently C 1-6 alkyl, C 2-6 35 PATENT Attorney Docket No.052687-508001WO alkenyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, halo, C 1-6 haloalkyl, cyano, or –X 8f –cyano.
  • R 8f can be 15 combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f3 .
  • R 8f can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f3 .
  • the compound, or the pharmaceutically acceptable salt 30 thereof is the compound of Formula (I), wherein each X 8f is independently C 1-6 alkylene.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each X 8f is independently C 2-6 alkenylene.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each X 8f is independently –O–C1-6 alkylene.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each X 8f is independently O.
  • the 5 compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each X 8f is independently S.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each X 8f is independently C1-6 alkylene or O.
  • R 8f can be combined with any of the embodiments 20 described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f3 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f is independently C1-4 alkyl, C2-4 alkenyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, halo, C 1-4 haloalkyl, cyano, or –C 1-2 alkyl–cyano.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f is independently halo, C3-6 cycloalkyl, –O–C 3-6 cycloalkyl, heterocycloalkyl, –C 2-4 alkenyl–heterocycloalkyl, –O– heterocycloalkyl, phenyl, –O–phenyl, heteroaryl, or –O–heteroaryl, wherein each 10 heterocycloalkyl has 3 to 6 ring members and 1 to 2 heteroatoms, each independently N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein each cycloalkyl
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f is independently halo, C3-6 cycloalkyl, –O–C 3-6 cycloalkyl, heteroaryl, or –O–heteroaryl, wherein each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, wherein each cycloalkyl, and heteroaryl is substituted with 0, 1, 2, or 3 R 8f3 .
  • R 8f can 20 be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f3 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f is independently halo, heterocycloalkyl, –O–heterocycloalkyl, phenyl, or –O–phenyl, wherein each heterocycloalkyl 25 has 3 to 6 ring members and 1 to 2 heteroatoms, each independently N, O, or S, wherein each heterocycloalkyl and phenyl is substituted with 0, 1, 2, or 3 R 8f3 .
  • the compound, or the pharmaceutically acceptable salt 30 thereof is the compound of Formula (I), wherein each R 8f is independently halo, heterocycloalkyl, or –O–heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 ring members and 1 to 2 heteroatoms, each independently N, O, or S, wherein each 38 PATENT Attorney Docket No.052687-508001WO heterocycloalkyl is substituted with 0, 1, 2, or 3 R 8f3 .
  • the compound, or the pharmaceutically acceptable salt 5 thereof is the compound of Formula (I), wherein each R 8f3 is independently C1-6 alkyl, –Y 8 – C 1-6 alkyl, C 1-6 deuteroalkyl, –Y 8 –C 1-6 deuteroalkyl, –OH, –C 1-6 alkyl–OH, –Y 8 –C 1-6 alkyl– OH, –C1-6 alkyl–Y 8 –C1-6 alkyl, –(C1-2 alkyl–O)2-4–C1-2 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, –Y 8 –C 1-6 haloalkyl, cyano, –C 1-6 alkyl–cyano
  • R 8f3 can be combined with any of the embodiments 20 described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each Y 8 is independently –Y 8 –C 1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each Y 8 is independently –Y 8 –methyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each Y 8 is independently C(O).
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each Y 8 is independently C(O)O. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y 8 is 30 independently NHC(O). In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein each Y 8 is independently O. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the 39 PATENT Attorney Docket No.052687-508001WO compound of Formula (I), wherein each Y 8 is independently S.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each Y 8 is independently S(O) 2 .
  • Y 8 can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, R 8f , and R 8f3 .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f3 is independently C 1-6 alkyl, C 1-6 deuteroalky, –OH, –C1-6 alkyl–OH, halo, C1-6 haloalkyl, or oxo.
  • R 8f3 can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f . 10
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f3 is independently C 1-6 alkyl or – Y 8 –C1-6 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each Y 8 is independently a C(O) or C(O)O.
  • R 8f3 and Y 8 can be combined with any of the embodiments described 15 herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f3 is independently C3-6 cycloalkyl, – X 8f3 –C 3-6 cycloalkyl, heterocycloalkyl, or –X 8f3 –heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 heteroatoms, each independently N, O, S, or 20 S(O) 2 ; and each X 8f3 is independently C 1-6 alkylene, C(O), or S(O) 2 .
  • R 8f3 can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each X 8f3 is independently C1-6 alkylene.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each X 8f3 is independently C(O).
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each X 8f3 is independently S(O)2.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f3 is independently C3-6 cycloalkyl or heterocycloalkyl, wherein each heterocycloalkyl has 3 to 6 members and 1 to 2 40 PATENT Attorney Docket No.052687-508001WO heteroatoms, each independently N, O, S, or S(O) 2 .
  • R 8f3 can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f .
  • the compound, or the pharmaceutically acceptable salt 5 thereof is the compound of Formula (I), wherein two R 8f3 groups on adjacent ring vertices combine to form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently N, O or S.
  • R 8f3 can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f .
  • the compound, or the pharmaceutically acceptable salt 10 thereof is the compound of Formula (I), wherein each R 8f3 is independently C1-4 alkyl, C1-4 alkoxy, C 2-6 alkoxyalkyl, –S(O) 2 –C 1-4 alkyl, –C 1-4 alkyl–S(O) 2 –C 1-4 alkyl, halo, C 1-4 haloalkyl, oxo, –C(O)–C1-4 alkyl, or –C(O)O–C1-4 alkyl.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein each R 8f3 is independently C 1-4 alkyl, C 1-4 alkoxy, C2-6 alkoxyalkyl, halo, C1-4 haloalkyl, oxo, –S(O)2–C1-4 alkyl, –C1-4 alkyl–S(O)2–C1-4 alkyl,–C(O)–C 1-4 alkyl, –C(O)O–C 1-4 alkyl, C 3-6 cycloalkyl, –C(O)–C 3-6 cycloalkyl, –S(O) 2 – C3-6 cycloalkyl, heterocycloalkyl, –C1-4 alkyl
  • R 8f3 can be combined with any of the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, ring B, 25 and R 8f .
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein m8 is 2; 41 PATENT Attorney Docket No.052687-508001WO each R 8f is independently fluoro, chloro, bromo, , , 5 [0128] , , lt thereof, is the compound of Formula (I), wherein m8 is 2; each R 8f is independently fluoro, chloro, bromo, , 42 PATENT Attorney Docket No.052687-508001WO [0129] ent in any combination.
  • any of the embodiments of R 8a , R 8b , R 8d , R 8e , m8 and R 8f as described herein, can be combined with any of the embodiments described herein for R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b R 6d , L 6a , Y 6 , L 6b , R 7a , R 7b , R 7c , and ring A.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I), wherein R 3 is , 15 R 4b is R 4c and R 4a together with the carbon and nitrogen to which each is attached combine to form a pyrrolidinyl, wherein the pyrrolidinyl is substituted with 0, 1, or 2 fluoro; R 5a is H; R 5b is H; 43 PATENT Attorney Docket No.052687-508001WO R 5c is methyl or ; R 6a is H, met , opyl, or ; R 6b is H; R 6d is H or methyl; 5 the moiety s , , , 44 PATENT Attorney Docket No.052687-508001WO O , alternatively, the moiety is ; 5 alternatively, the moiety is , 45 PATENT Attorney Docket No.052687-508001WO , 5 alternatively, the moiet is ; 46
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) having the structure of any one of Examples 1-103.
  • the compound, or the pharmaceutically acceptable salt thereof is the compound of Formula (I) having the structure of any one of Examples 1-50.
  • the compound, or the pharmaceutically acceptable salt thereof is the 20 compound of Formula (I) having the structure of any one of Examples 51-103 51 PATENT Attorney Docket No.052687-508001WO [0134]
  • the present disclosure includes all tautomers and stereoisomers of the compounds described herein, either in admixture or in pure or substantially pure form.
  • the compounds of Formula (I) can have asymmetric centers at one or more carbon atoms, and therefore compounds of Formula (I) can exist in diastereomeric or enantiomeric forms or mixtures 5 thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, and tautomers are within the scope of the present disclosure. Compounds of Formula (I) can be prepared using diastereomers, enantiomers or racemic mixtures as starting materials.
  • diastereomer and enantiomer products can be 10 separated by chromatography, fractional crystallization or other methods known to those of skill in the art.
  • a stereochemical depiction it is meant that the isomer with the depicted stereochemistry is present and substantially free of the other isomer(s).
  • “Substantially free of” another isomer indicates at least an 80/20 ratio of the two isomers, more preferably 90/10, or 95/5 or more.
  • a structure includes a wavy 15 bond attached to a double bond, this indicates E, Z, or a mixture of both isomers.
  • the compounds of Formula (I) can also be in the salt forms, such as acid or base salts of the compounds of Formula (I).
  • Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, 20 quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic.
  • Pharmaceutically acceptable salts of the acidic compounds of Formula (I) are salts 25 formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
  • bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
  • acid addition salts such as of mineral acids, organic carboxylic and 30 organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.
  • a basic group such as pyridyl
  • the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the 5 compound for the purposes of the present disclosure.
  • the present disclosure also includes isotopically-labeled compounds of Formula(I), wherein one or more atoms are replaced by one or more atoms having specific atomic mass or mass numbers.
  • isotopes that can be incorporated into compounds of Formula (I) include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine,10 sulfur, and chlorine (such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl).
  • Isotopically- labeled compounds of Formula (I) can be useful in assays of the tissue distribution of the compounds and their prodrugs and metabolites; preferred isotopes for such assays include 3 H and 14 C.
  • Isotopically- labeled compounds of Formula (I) can generally be prepared according to methods known in the art.
  • IV. Compositions [0140] The compounds of Formula (I) described herein are useful in the manufacture of a 20 pharmaceutical composition or a medicament for modulating one or more cyclins (e.g. cyclin A, cyclin B, cycline E).
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable excipient.
  • compositions or medicaments comprising one or more compounds of Formula (I) can be administered to a 25 subject for the treatment of a cancer.
  • Pharmaceutical compositions or medicaments for use in the present disclosure can be formulated by standard techniques or methods well-known in the art of pharmacy using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in, e.g., “Remington’s Pharmaceutical Sciences” by E.W. 30 Martin.
  • Compounds of Formula (I) and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including, but not limited to, orally, topically, nasally, rectally, pulmonary, parenterally (e.g., intravenously, 53 PATENT Attorney Docket No.052687-508001WO subcutaneously, intramuscularly, etc.), and combinations thereof.
  • the compounds of Formula (I) is dissolved in a liquid, for example, water.
  • the most suitable route of administration for a compound of Formula (I) in any given case will depend, in part, on the nature, severity, and optionally, and the stage of the cancer.
  • compositions or medicaments of the present disclosure can include a compound of Formula (I) with as an active ingredient and a pharmaceutically acceptable carrier and/or excipient or diluent. Any carrier and/or excipient suitable for the form of preparation desired for administration is contemplated for use with the compounds of Formula (I) disclosed herein. 10 [0143]
  • the pharmaceutical compositions or medicaments described herein are suitable for systemic administration. Systemic administration includes enteral administration (e.g., absorption of the compound through the gastrointestinal tract) or parenteral administration (e.g., injection, infusion, or implantation).
  • the pharmaceutical compositions or medicaments can be administered via a syringe or 15 intravenously.
  • the pharmaceutical compositions or medicaments are injected subcutaneously.
  • a pharmaceutical composition or a medicament can take the form of, e.g., a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient.
  • tablets and gelatin capsules comprising the active 20 ingredient(s), together with (a) diluents or fillers, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates and/or calcium hydrogen phosphate, calcium sulfate, (b) lubricants, e.g., silica, anhydrous colloidal silica, talcum, stearic acid, its magnesium or calcium salt (e.g., magnesium stearate or calcium stearate), metallic stearates, colloidal silicon dioxide, 25 hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and/or polyethyleneglycol; for tablets also (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxy
  • the tablet contains a mixture of 54 PATENT Attorney Docket No.052687-508001WO hydroxypropyl methylcellulose, polyethyleneglycol 6000 and titatium dioxide. Tablets can be either film coated or enteric coated according to methods known in the art.
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution 5 with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for 10 example, methyl or propyl-p-hydroxybenzoates or sorbic acid.
  • the preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound.
  • Typical formulations for topical administration include creams, ointments, sprays, 15 lotions, and patches.
  • the pharmaceutical composition can, however, be formulated for any type of administration, e.g., intradermal, subdermal, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary or intratumoral injection, with a syringe or other devices.
  • Formulation for administration by inhalation e.g., aerosol
  • oral, rectal, or vaginal administration is 20 also contemplated.
  • compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound described herein, or a salt thereof, and the powder of a suitable carrier and/or lubricant.
  • the compositions for pulmonary administration can be inhaled from any suitable dry powder 25 inhaler device known to a person skilled in the art.
  • the compositions can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit can be determined by providing a valve to 30 deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound(s) and a suitable powder base, for example, lactose or starch.
  • a suitable powder base for example, lactose or starch.
  • the compounds of Formula (I) can also be formulated in rectal compositions, for example, suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides.
  • the compounds of Formula (I) set forth herein can be formulated for parenteral 5 administration by injection, for example by bolus injection.
  • Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative.
  • Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions.
  • the compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, 10 wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • the compound(s) can be in powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
  • a suitable vehicle for example, sterile pyrogen-free water
  • they may also contain other therapeutically valuable substances.
  • the compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain 15 about 0.1 to 75%, preferably about 1 to 50%, of the compound(s).
  • the compositions described herein are prepared with a polysaccharide such as chitosan or derivatives thereof (e.g., chitosan succinate, chitosan phthalate, etc.), pectin and derivatives thereof (e.g., amidated pectin, calcium pectinate, etc.), chondroitin and derivatives thereof (e.g., chondroitin sulfate), and alginates.
  • the compositions described herein further include a pharmaceutical surfactant.
  • the compositions further include a cryoprotectant.
  • cryoprotectants include glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, cyclodextrin, 2-hydroxypropyl-13-cyclodextrin (HPI3CD) glycerol, maltose, mannitol, saccharose, and mixtures thereof. 25 V. Methods [0152]
  • the present disclosure contemplates the use of the compounds of Formula (I) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by one or more cyclins.
  • the cyclin mediated disease is a proliferative condition or disorder, including cancer.
  • the present 30 disclosure provides a method of treating a cancer mediated at least in part by cyclin activity, the method comprising administering to a subject in need there of, a therapeutically effective 56 PATENT Attorney Docket No.052687-508001WO amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer.
  • a therapeutically effective 56 PATENT Attorney Docket No.052687-508001WO amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure thereby treating the cancer.
  • provided herein are compounds of Formula (I) for use in 5 therapy.
  • the present disclosure contemplates the use of the compounds of Formula (I) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin A.
  • the cyclin A mediated disease is a proliferative condition or disorder, including cancer.
  • the present disclosure 10 provides a method of treating a cancer mediated at least in part by cyclin A, the method comprising administering to a subject in need there of, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer.
  • provided herein are methods of treating a proliferative 15 condition or disorder mediated at least in part by cyclin A comprising administering a compound of Formula (I) described herein.
  • provided herein are compounds of Formula (I) for use in a method for treating a proliferative condition or disorder mediated at least in part by cyclin A.
  • the present disclosure contemplates the use of the compounds of Formula (I) described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin B.
  • the cyclin B mediated disease is a proliferative 25 condition or disorder, including cancer.
  • the present disclosure provides a method of treating a cancer mediated at least in part by cyclin B, the method comprising administering to a subject in need there of, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer.
  • a proliferative condition or disorder mediated at least in part by cyclin B comprising administering a compound of Formula (I) described herein.
  • provided herein are compounds of Formula (I) for use in a 5 method for treating a proliferative condition or disorder mediated at least in part by cyclin B.
  • the present disclosure contemplates the use of the compounds of Formula (I) 10 described herein in the treatment or prevention of diseases or disorders modulated, at least in part, by cyclin E.
  • the cyclin E mediated disease is a proliferative condition or disorder, including cancer.
  • the present disclosure provides a method of treating a cancer mediated at least in part by cyclin E, the method comprising administering to a subject in need there of, a therapeutically effective amount of a 15 compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, thereby treating the cancer.
  • methods of treating a proliferative condition or disorder mediated at least in part by cyclin E comprising administering a compound of Formula (I) described herein.
  • compounds of Formula (I) for use in a method for treating a proliferative condition or disorder mediated at least in part by cyclin E.
  • a cancer for example, cancer of the uterus, cervix, breast, prostate, testes, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), kidney, renal cell, bladder, bone, bone marrow, skin, head or neck, liver, gall bladder, bile ducts, heart, lung (e.g., non- 30 small-cell lung carcinoma, small cell lung cancer), pancreas, salivary gland, adrenal gland, 58 PATENT Attorney Docket No.052687-508001WO thyroid, brain, ganglia, central nervous system (
  • the present disclosure also provides methods of treating or preventing other cancer- related diseases, disorders or conditions, including, for example, virus-induced cancers (e.g., 5 epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically-induced cancers, metastasis, and angiogenesis.
  • virus-induced cancers e.g., 5 epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus
  • adenocarcinomas e.g., 5 epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus
  • adenocarcinomas e.g., 5 epithelial cell cancers
  • the tumor or cancer is small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • the use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer, and includes, e.g., angiogenesis and precancerous conditions such as dysplasia.
  • the cancer is a blood cancer (e.g., leukemia, lymphoma, multiple myeloma).
  • the leukemia is acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, or hairy cell leukemia.
  • the lymphoma is non-Hodgkin's lymphoma, Hodgkin's lymphoma, B-cell lymphoma, or Burkitt's lymphoma.
  • the cancer is an Rb mutated cancer. In some embodiments, the cancer has a mutation in the Rb/E2F pathway.
  • Administration 25 [0175] The present disclosure contemplates the administration of compounds of Formula (I) and compositions thereof, in any appropriate manner.
  • Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral 59 PATENT Attorney Docket No.052687-508001WO (intraparenchymal) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal and inhalation.
  • parenteral e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral 59 PATENT Attorney Docket No.052687-508001WO (intraparenchymal) and intracerebroventricular
  • nasal, vaginal, sublingual, intraocular, rectal topical (e.g., transdermal), buccal and inhalation.
  • the unit dosage form can be a packaged preparation, the package 5 containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Compounds of Formula (I) or pharmaceutical compositions or medicaments thereof can be administered to a subject diagnosed or suspected of having a disease or disorder 10 mediated at least in part by cyclin A in an amount sufficient to elicit an effective therapeutic response in the subject.
  • the dosage of compounds administered is dependent on a variety of factors including the subject’s body weight, age, individual condition, and/or on the form of administration.
  • a dosage of the active compounds is a dosage that is sufficient to achieve the desired effect.
  • Optimal dosing schedules can be calculated from measurements of compound accumulation in the body of a subject. In general, dosage can be given once or more daily, weekly, or monthly. Persons of ordinary skill in the art can easily determine 20 optimum dosages, dosing methodologies, and repetition rates.
  • a unit dosage for oral administration of a compound of Formula (I) described herein to a subject (e.g., a human) of about 50 to about 70 kg may contain between about 1 and about 5,000 mg, about 1 and about 3,000 mg, about 1 and about 2,000 mg, or about 1 to about 1,000 mg of the compound(s). 25 [0180] In some embodiments, a unit dosage for subcutaneous administration of a compound of Formula (I) described herein to a subject (e.g., human) of about 50 to about 70 kg may contain between about 0.1 and about 500 mg, about 0.5 and about 300 mg, about 0.5 and about 200 mg, about 0.5 and about 100 mg, or about 0.5 and about 50 mg.
  • the dose can be administered once per day or divided into sub-doses and 30 administered in multiple doses, e.g., twice, three times, or four times per day. However, as 60 PATENT Attorney Docket No.052687-508001WO will be appreciated by a skilled artisan, depending on the route of administration different amounts can be administered at different times.
  • the compounds are administered for about 1 to 31 days, or for about 1 to 12 months. In some embodiments, the compounds are administered for one or more 5 weeks, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more weeks.
  • the compounds are administered for one or more months, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months.
  • Optimum dosages, toxicity, and therapeutic efficacy of such compounds may vary depending on the relative potency of individual compounds and can be determined by standard 10 pharmaceutical procedures in experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio, LD 50 /ED 50 .
  • Compounds that exhibit large therapeutic indices are preferred.
  • compositions or medicaments can be monitored and adjusted throughout treatment, depending on severity of symptoms, frequency of recurrence, and/or the physiological response to the therapeutic 20 regimen. Those of skill in the art commonly engage in such adjustments in therapeutic regimens.
  • Single or multiple administrations of the pharmaceutical compositions or medicaments can be administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition or medicament should provide a 25 sufficient quantity of the compounds of the disclosure to effectively treat the patient.
  • the present disclosure provides intermediates useful in the 30 preparation of compounds of Formula (I). Certain intermediates useful in the preparation of a 61 PATENT Attorney Docket No.052687-508001WO compound of Formula (I) can be found, for example, in the Examples section of the current disclosure.
  • the intermediate is an External Building Block described herein.
  • the intermediate is a compound produced in one of Methods 5 A-C or Methods 1-7 for any one of the compounds exemplified herein.
  • the intermediate is one of Int.1-78.
  • kits comprising a compound of Formula (I) described herein described herein, and pharmaceutical compositions thereof.
  • the kits are generally in the form of a physical structure housing various components, as described below, and can be utilized, for example, in practicing the methods described above.
  • a kit can include one or more of the compounds disclosed herein (provided in, e.g., 15 a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject.
  • the compounds described herein can be provided in a form that is ready for use (e.g., a tablet, capsule, syringe) or in a form requiring, for example, reconstitution or dilution (e.g., a powder) prior to administration.
  • the kit may 20 also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from the compounds described herein.
  • diluents e.g., sterile water
  • buffers e.g., sterile water
  • pharmaceutically acceptable excipients e.g., sterile water
  • a kit of the present disclosure can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or 25 freezing).
  • a kit may contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.).
  • Labels or inserts can 30 include manufacturer information such as lot numbers and expiration dates.
  • Labels or inserts may be, e.g., integrated into the physical structure housing the components, 62 PATENT Attorney Docket No.052687-508001WO contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial).
  • Labels or inserts can additionally include, or be incorporated into, a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as 5 CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards.
  • the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g., via the internet, are provided.
  • 10 IX The following examples illustrate how various intermediates and exemplary compounds of Formula (I) are prepared. The following examples are offered to illustrate, but not to limit the current disclosure.
  • A. External Building Blocks 15 [0194] The compounds of Formula (I) described herein are prepared by covalently linking the external building blocks described in this section. The external building blocks of the present disclosure are identified in Table 1, below, by intermediate number (INT #), IUPAC name, and CAS number, if known. For those without a CAS number, an experimental write- up is provided herein.
  • Step 2 Int.2: [0196] t ert- uty ( -(a y oxy)- -met y propan- -y )car amate ( . g, q, .7 mmol) was dissolved in 30% TFA in DCM (50 mL). The reaction was continued until the complete 15 consumption of starting materials (monitored by LCMS). Upon completion, the reaction was concentrated. PhMe was added (50 mL) and the reaction was concentrated again to drive off excess TFA. Int.2 (2.1 g, 8.7 mmol, 100 %) was isolated as a clear liquid and used directly in the next reaction. LCMS (ESI+): m/z 130.3 (M+H + ).
  • Int.7 Preparation of (S)-2-((allyloxy)methyl)pyrrolidine: 69 PATENT Attorney Docket No.052687-508001WO [0201] Int.7 was synthesized by following the procedure for Int.6 with tert-butyl (S)-2- (hydroxymethyl)pyrrolidine-1-carboxylate as the starting alcohol.
  • Int.10 Preparation of (R)-2-((allyloxy)methyl)piperidine: [0203] Int.10 was synthesized b y o ow ng e procedure for Int.6 with tert-butyl (R)-2- (hydroxymethyl)piperidine-1-carboxylate as the starting alcohol. LCMS (ESI+): m/z 156.3 15 (M+H + ). Int.11: Preparation of 2-(allyloxy)-N-methylethan-1-amine [0204] Int.11 was synthesized by following the procedure for Int.6 with tert-butyl (2- hydroxyethyl)(methyl)carbamate as the starting alcohol.
  • Step 3 Int.12: 71 PATENT Attorney Docket No.052687-508001WO [0207] tert-butyl (R)-2-((allylthio)methyl)pyrrolidine-1-carboxylate (1.0 g, 1 Eq, 3.9 mmol) was dissolved in a mixture of 30% TFA in DCM. upon the consumption of starting material (monitored by LCMS) the volatile solvent was removed. PhMe ( ⁇ 20 mL) was added to the residue and evaporated under reduced pressure to drive off remaining TFA. (R)-2- 5 ((allylthio)methyl)pyrrolidine (0.61 g, 3.9 mmol, 100 %) was used without further purification.
  • Int.14 Preparation of 1-((allyloxy)methyl)cyclopropan-1-amine: [0209] Int.14 was synthesized us ng t e proce ure outlined in Int.4 using tert-butyl (1- 15 (hydroxymethyl)cyclopropyl)carbamate as starting material.
  • Step 2 tert-butyl (R)-(1-(allyloxy)propan-2-yl)(methyl)carbamate: [0214] To a stirred mixture of tert-butyl N-[(2R)-1-(prop-2-en-1-yloxy)propan-2- 20 yl]carbamate (3.1 g, 14.4 mmol, 1 equiv) in THF (50 mL) were added NaH (1.73 g, 72.0 mmol, 5 equiv) in portions at 0 o C under nitrogen atmosphere. The resulting mixture was stirred for an additional 1hr.
  • Step 2 Int.18: [0217] Int.18 tlined in the synthesis of Int.2 (Step 2) using tert-butyl (S)-(2-(allyloxy)propyl)carbamate as starting 5 material LCMS (ESI+): m/z 116.5 (M+H + ).
  • Int.19 Preparation of (R)-3-(allyloxy)pyrrolidine: [0218] Int.19 was synthesized by cedure for Int.6 with tert-butyl (R)-3- hydroxypyrrolidine-1-carboxylate as the starting alcohol.
  • Int.21 Preparation of N-methyl-2-((2-methylallyl)oxy)ethan-1-amine: 20 [0220] Int.21 was synthesized by following the procedure for Int.6 with tert-butyl (2- hydroxyethyl)(methyl)carbamate and 3-bromo-2-methylprop-1-ene as starting materials.
  • Int.22 Preparation of (3S,4R)-4-(allyloxy)-N-methyltetrahydrofuran-3-amine: 76 PATENT Attorney Docket No.052687-508001WO [0221] Int.22 was synthesized by cedure for Int.6 using tert-butyl ((3S,4R)-4-(allyloxy)tetrahydrofuran-3-yl)carbamate (from the synthesis of Int.15) and MeI as starting materials. The following modification was also used: the removal of the Boc group 5 was conducted using the procedure outlined in the synthesis of Int.2 – Step 2. TFA in DCM was used instead of HCl in EtOAc.
  • Step 2 (4R,5S)-3-(tert-butoxycarbonyl)-5-methyloxazolidine-4-carboxylic acid: [0223] K2CO3 (21.04 g, 152.226 mmol, 3.00 equiv) was added to a stirred solution of (4R,5S)-3-(tert-butoxycarbonyl)-5-methyl-1,3-oxazolidine-4-carboxylic acid (11.734 g, 50.742 mmol, 1.00 equiv) and CH3I (8.64 g, 60.890 mmol, 1.20 equiv) in acetone (50 mL) 10 at room temperature under nitrogen atmosphere. The reaction was stirred under nitrogen atmosphere for 16h at reflux.
  • Step 3 3-(tert-butyl) 4-methyl (4R,5S)-5-methyloxazolidine-3,4-dicarboxylate: [0224] NaBH 4 (6.26 g, 165.445 mmol, 5.00 equiv) was added in portions to o a stirred solution of 3-tert-butyl 4-methyl (4R,5S)-5-methyl-1,3-oxazolidine-3,4-dicarboxylate (8.116 g, 33.089 mmol, 1.00 equiv) in THF (50 mL) and MeOH (50 25 mL) at 0°C under nitrogen atmosphere.
  • Step 4 tert-butyl (4S,5S)-4-(hydroxymethyl)-5-methyloxazolidine-3-carboxylate: [0225] Step 4 for I . p p d in Step 1 for Int.16. LCMS (ESI+): m/z 280.0 (M+Na + ).
  • Step 5 tert-butyl (4S,5S)-4-((allyloxy)methyl)-5-methyloxazolidine-3-carboxylate: Step 6: Int.23: 20 [0226] Step 6 for Int.23 was performed with the procedure outlined in Step 2 for Int.16. The product was used directly in the next reaction.
  • Step 2 tert-butyl (S)-4-(hydroxymethyl)oxazolidine-3-carboxylate: 15 [0228] To a stir red mixture of 3-tert-butyl 4-methyl (4R)-1,3-oxazolidine-3,4-dicarboxylate (8 g, 34.595 mmol, 1 equiv) in MeOH (70 mL) and THF (70 mL) was added NaBH 4 (6.54 g, 172.975 mmol, 5 equiv) at 0°C. The resulting mixture was stirred for 5hr at 20°C. The reaction was quenched by the addition of Water (70mL) at 0°C.
  • Step 3 tert-butyl (S)-4-((allyloxy)methyl)oxazolidine-3-carboxylate: [0229] Step 3 fo in Step 1 for Int.16.
  • the resulting mixture was stirred for 16 5 h at rt under nitrogen atmosphere.
  • the above mixture was added into a solution of 1,4- dichloro-2-iodo-benzene (50 g, 183.22 mmol, 1 eq), CuI (6.96 g, 36.64 mmol, 0.2 eq) and Pd(dppf)Cl 2 .CH 2 Cl 2 (14.93 g, 18.32 mmol, 0.10 eq) at rt under nitrogen.
  • the resulting mixture was stirred for additional 16 h at 85 °C. Desired product could be detected by LCMS.
  • the reaction was quenched by the addition of water (1.5 L) at rt.
  • Step 2 Methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5- dichlorophenyl)propanoate: [0232] o a st rre so ut on o met y ( S)- -[(tert- utoxycar ony )am no]-3-( ,5- 20 dichlorophenyl)propanoate (200 mg, 0.574 mmol, 1 eq) and methyl iodide (214.00 g, 1507.67 mmol, 15 eq) in DMF (350 mL) was added (argentiooxy)silver (93.17 g, 402.04 mmol, 4 eq) in portions at 25 °C under nitrogen atmosphere.
  • the reaction mixture was stirred for 16 h at 25 °C. Desired product could be detected by LCMS.
  • the resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 100 mL).
  • the filtrate was diluted water 25 (500 mL) and extracted with EtOAc (3 x 300 mL).
  • the combined organic layers were washed with water (4 x 200 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.05% TFA), 10% to 50% gradient in 10 min; detector, UV 220 nm.
  • Step 3 (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid: 84 PATENT Attorney Docket No.052687-508001WO [0236] T oate (143 g, 466 mmol, 1.00 eq) in THF (715 mL) and EtOH (715 mL) was added LiOH . H2O (58.7 g, 1.40 mol, 3.00 eq) at 0 °C, then the reaction was stirred at 25 °C for 12 hours. TLC indicated 5 ethyl (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate was consumed completely.
  • reaction mixture was concentrated under reduced pressure at 30 °C to remove half of solvent. It was added into a saturated solution of citric acid (1.50 L) at 5-10 °C, to keep all the progress worked under acid condition. Some solid precipitated, then the suspension was filtered, the filter cake was washed with MTBE (1.00 L). The filter cake was collected and 10 dried in vacuum to give desired (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid (130 g, crude) as yellow solid which was confirmed by LCMS and SFC, then was used to the next step without further purification.
  • Step 4 (S)-3-(2-bromo-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid: 15 [0237]
  • (2S)-2-amno-3-(2-bromo-5-c oro-p eny )propano c acid 70.00 g, 251.32 mmol, 1 eq
  • THF 750 mL
  • NaOH (1 N, 750 mL
  • Boc2O 109.70 g, 502.64 mmol, 115.47 mL, 2 eq
  • the LCMS showed that the reactant 1 was consumed completely, and the desired product was detected.
  • the mixture was poured into sat. Citric acid (4 L) and extracted with EtOAc (1 L x 3). The 20 organic layer was washed with water (2 L) and brine (2 L), dried over Na 2 SO 4 , filtered, and concentrated. The mixture was suspended in PE (1 L) and stirred at 20 °C for 0.5 h.
  • Step 2 Methyl (2S)-2-[(tert-butoxycarbonyl) amino]-3-(5-chloro-2-cyclobutoxypyridin- 3-yl) propanoate: 15 [0240] To a st rred mxture o 3-bromo-5-c oro-2-cyc obutoxypyr d ne (15 g, 57.14 mmol, 1.0 eq), Pd(dppf)Cl 2 .CH 2 Cl 2 (2.33 g, 2.86 mmol, 0.05 eq) and CuI (1.09 g, 5.71 mmol, 0.1 eq) in N, N-dimethylacetamide (300 mL) was added methyl (2R)-2-[(tert-butoxycarbonyl) amino]-3-(iodozincio) propanoate (171.41 mL, 171.41 mmol, 3.00 eq) in one portion at rt 20 under nitrogen atmosphere.
  • the resulting mixture was stirred for 16 h at 80 °C under nitrogen atmosphere.
  • the resulting mixture was diluted with water (600 mL) and EtOAc (200 mL), and then filtered.
  • the filter cake was washed with EtOAc (1 x 20 mL).
  • the filtrate was separated, and the aqueous layer was extracted with EtOAc (2 x 200 mL).
  • the combined organic layers were washed with sat. NH 4 Cl(aq.) (2 x 300 mL), brine (1 x 300 mL) and dried 25 over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 3 Methyl (2S)-2-[(tert-butoxycarbonyl) (methyl)amino]-3-(5-chloro-2- cyclobutoxypyridin-3-yl) propanoate: [0241] To -3-(5-chloro-2- cyclobutoxypyridin-3-yl) propanoate (16.4 g, 42.61 mmol, 1 eq) and Ag2O (39.50 g, 170.45 10 mmol, 4.0 eq) in DMF (200 mL) was added CH3I (96.8 g, 681.81 mmol, 16.0 eq) in one portion at rt under nitrogen atmosphere.
  • CH3I 96.8 g, 681.81 mmol, 16.0 eq
  • the resulting mixture was stirred for 16 h at 50 °C under nitrogen atmosphere. The starting material was transformed completely. The resulting mixture was diluted with water (500 mL) and EtOAc (200 mL) and was then filtered. The filter cake was washed with EtOAc (1 x 20 mL). The resulting mixture was separated, and the 15 aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with sat. NH4Cl(aq.) (2 x 300 mL), brine (1 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 4 Int.35: [0242] To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl) (methyl)amino]-3-(5- chloro-2-cyclobutoxypyridin-3-yl) propanoate (17 g, 42.62 mmol, 1 eq) in THF (300 mL) 88 PATENT Attorney Docket No.052687-508001WO and H 2 O (100 mL) was added LiOH (3.06 g, 127.86 mmol, 3.00 eq) in H 2 O (100 mL) dropwise at 0 °C. The resulting mixture was stirred for 16 h at rt.
  • Step 1 3-Bromo-5-chloro-2-c yc op opoxypy e: [0243] Into a 1000 mL round-bottom flask were added 3-bromo-5-chloro-2-fluoropyridine (50 g, 237.61 mmol, 1 eq) in DMF (400 mL), Cs 2 CO 3 (232.97 g, 712.83 mmol, 3 eq) was 20 added at rt under nitrogen atmosphere.
  • Step 3 Methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2- cyclopropoxypyridin-3-yl)propanoate: 90 PATENT Attorney Docket No.052687-508001WO [0245] Into a 10 -[(tert- butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3-yl)propanoate (25 g, 67.42 mmol, 1 eq) in DMF (400 mL), Ag2O (78.11 g, 337.08 mmol, 5 eq) was added at 0 °C under 5 nitrogen atmosphere.
  • Step 4 Int.39: [0246] Into a 1000 mL round-bottom flask were added methyl (2S)-2-[(tert- butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclopropoxypyridin-3-yl)propanoate (20 g, 20 51.97 mmol, 1 eq) in THF (250 ml) and NaOH (10.39 g, 259.84 mmol, 5 eq) in water (50 ml) was added dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at rt for 2 h.
  • the mixture was slowly warmed up to rt and stirred overnight at rt.
  • the mixture was concentrated under vacuum at 28 o C and diluted with EtOAc (900 mL) and washed with HCl (0.5N,1400 mL x 1).
  • the aqueous layer was extracted again with EtOAc (1x500 mL).
  • the combined organic 20 layers were washed with saturated NaHCO 3 (1000 mL x1).
  • the aqueous layer was extracted 93 PATENT Attorney Docket No.052687-508001WO with EtOAc (300mL x1) again.
  • the combined organic layers were washed with brine and dried over anhydrous Na2SO4.
  • Step 3 Int.50: [0251] To a s , 10 (trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (180 g, 82.15 mmol, 1 eq, 90%) in MeOH (1400 mL) was added dropwise NaOH (58.33 g, 246.45 mmol, 3 eq) in H2O (400 mL) in 30 min at 0-20 o C. The mixture was stirred for 2 h at rt. MeOH was evaporated out under vacuum. The residue was diluted with water (2500 mL) and acidified with HCl (3N,400 mL) at 0-20 o C.
  • Step 2 Methyl (2S,4R)-1-(3-(1,1-difluoroethyl)oxetane-3-carbonyl)-4-fluoropyrrolidine- 2-carboxylate 5
  • boxylate 1.2 g, 8.155 mmol, 1 equiv
  • 3-(1,1-difluoroethyl)oxetane-3-carboxylic acid (1.35g, 8.16 mmol, 1 equiv) in MeCN (25 mL, 475.61 mmol) were added TCFH (4.58g, 16.31 mmol, 2 equiv) and NMI (2.01g, 24.4 mmol, 3 equiv) in portions at room temperature.
  • Step 3 Int.54 [0258] To a stirred solution of methyl (2S,4R)-1-[3-(1,1-difluoroethyl)oxetane-3-carbonyl]- 20 4-fluoropyrrolidine-2-carboxylate (2.1 g, 7.11 mmol, 1 equiv) in THF (4 mL) was added NaOH (0.85 g, 21.34 mmol, 3 equiv) in H2O (15 mL) at room temperature. The resulting mixture was stirred for an additional 2hr at room temperature. The reaction was acidified to 97 PATENT Attorney Docket No.052687-508001WO pH 4 with conc. HCl.
  • Step 3 Int.56: 99 PATENT Attorney Docket No.052687-508001WO [0262] To a soluti methyl)tetrahydro-2H- pyran-2-carbonyl)pyrrolidine-2-carboxylate (10.7 g, 31.66 mmol, 96.83% purity, 1 eq) in THF (100 mL) and H2O (100 mL) was added LiOH.H2O (2.66 g, 63.32 mmol, 2 eq). Then 5 the mixture was stirred at 25 °C for 1 hr.
  • Step 2 Int.57 and Int.58: [0264] To a stirred solution of methyl (2S,4R)-4-fluoro-1-[(cis-1,3)-3-methoxy-1- (trifluoromethyl)cyclopentanecarbonyl]pyrrolidine-2-carboxylate (2.2 g, 6.446 mmol, 1 15 equiv) in THF (10 mL) was added LiOH (0.77 g, 32.230 mmol, 5 equiv) in H 2 O (10 mL) at 0°C . The resulting mixture was stirred for 6 hr at room temperature. The mixture was then acidified with 1N HCl to pH ⁇ 3.
  • Step 2 Isopropyl 3-((tert-butyldiphenylsilyl)oxy)-1-formylcyclobutane-1-carboxylate: 5 [0267] To a stir lyl)oxy]cyclobutane- 1,1-dicarboxylate (17.7 g, 36.67 mmol, 1 equiv) in DCM (400 mL) was added DIBAl-H (1M in DCM, 73.34 mL, 73.338 mmol, 2 equiv) dropwise at -60°C under an atmosphere of Ar. The resulting mixture was stirred for 3hr at -60°C.
  • Step 3 Isopropyl 3-((tert-butyldiphenylsilyl)oxy)-1-(difluoromethyl)cyclobutane-1- carboxylate: O O D AST, DCM F F [0268] To a stirred solution of isopropyl 3-[(tert-butyldiphenylsilyl)oxy]-1- formylcyclobutane-1-carboxylate (12.8 g, 30.145 mmol, 1 equiv) in DCM (400 mL) was 20 added DAST (14.58 g, 90.435 mmol, 3 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred overnight at room temperature.
  • Step 5 Methyl (2S,4R)-1-(3-((tert-butyldiphenylsilyl)oxy)-1- (difluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxylate: [0270] To a stirred solution of 3-[(tert-butyldiphenylsilyl)oxy]-1- 20 (difluoromethyl)cyclobutane-1-carboxylic acid (3.7 g, 9.146 mmol, 1 equiv) and methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (1.48 g, 10.061 mmol, 1.1 equiv) in MeCN (68 mL) were added TCFH (3.85 g, 13.719 mmol, 1.5 equiv) and NMI (5.63 g, 68.595 mmol, 7.5 equiv) dropwise at 0°C under argon atmosphere.
  • Step 6 Methyl (2S,4R)-1-(1-(difluoromethyl)-3-hydroxycyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxylate: [0271] To a stirred so , phenylsilyl)oxy]-1- (difluoromethyl)cyclobutanecarbonyl ⁇ -4-fluoropyrrolidine-2-carboxylate (4.5 g, 8.43 mmol, 10 1 equiv) in THF (45 mL) was added TBAF (8.43 mL, 32.242 mmol, 3.82 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred overnight at room temperature.
  • Step 7 Methyl (2S,4R)-1-(1-(difluoromethyl)-3-fluorocyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxylate: 20 [0272] To a stirred solution of methyl (2S,4R)-1-[1-(difluoromethyl)-3- hydroxycyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (3.2 g, 8.13 mmol, 1 equiv, 105 PATENT Attorney Docket No.052687-508001WO 75%) in DCM (60 mL) was added DAST (3.93 g, 24.384 mmol, 3 equiv) dropwise at -78°C under argon atmosphere.
  • Step 8 Int.59: 10 [0273] (2S,4R)-1 y y y -4-fluoropyrrolidine-2- carboxylate (1.4 g, 3.768 mmol, 1 equiv) in THF (15 mL) /H2O (15 mL) was added LiOH (0.27 g, 11.304 mmol, 3 equiv) in portions at 0°C.The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water (15mL) and was 15 concentrated under reduced pressure to remove MeOH. The aqueous layer was extracted with EtOAc (2x30 mL). The mixture was acidified to pH 4 with HCl (aq.).
  • Step 3 methyl (S)-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pent-4-enoate: 5 [0276] To a mi 4-enoate (28 g, 152 mmol) in DCM (300 mL) was added TEA (23.19 g, 229 mmol, 31.9 mL) and Boc 2 O (35.0 g, 160 mmol, 36.9 mL) at 25°C. Then the mixture was stirred for 1 hour. Upon the consumption of starting material (TLC, 20% EtOAc in pet. ether) The mixture was concentrated under reduced pressure and was purified by column chromatography (SiO2, EtOAc in pet.
  • the aqueous 10 phase was washed with hexanes (2 x 50 mL) and then acidified with citric acid.
  • the aqueous phase was extracted EtOAc (3 x 50mL).
  • the combined organics were washed with brine, dried over MgSO 4 , filtered, and concentrated by rotary evaporation.
  • the crude product was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to yield Int.65 (5.01 grams, 19 mmol, 61%).
  • Step 2 Int.66: [0279] S-allyl-N-(tert-butoxycarbonyl)-L-cysteine (5.0 g, 1 Eq, 19 mmol) was dissolved in THF (30 mL). The solution was degassed for 10 minutes, followed by the addition of NaH (0.92 g, 2 Eq, 38 mmol) in small portions. MeI (16 g, 7.2 mL, 6 Eq, 0.11 mol) was added and 20 the reaction stirred overnight. The reaction was quenched with water (50 mL) and washed with hexanes (2 x 50 mL).
  • reaction was concentrated by rotary evaporation and the residue was diluted in water (50 mL).
  • Na 2 CO 3 (10.5 g, 2 Eq, 100 mmol) was added.
  • Boc 2 O (13.1 g, 1.2 Eq, 60 mmol) was dissolved in THF and the solution was added to the reaction mixture and the reaction was 15 stirred for 4 hr.
  • the reaction was acidified with 1M HCl and extracted EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated by rotary evaporation.
  • Step 2 Cis-1-(tert-butyl) 2-methyl-3-vinylpiperidine-1,2-dicarboxylate: 115 PATENT Attorney Docket No.052687-508001WO [0292] To a mixture of bromocopper;methylsulfanylmethane (1.02 g, 4.97 mmol, 0.2 eq) in THF (60 mL) was added vinylmagnesiumbromide (1 M, 49.73 mL, 2 eq) at -35 °C under argon, then the mixture was stirred at -35 °C for 15 min, 1-(tert-butyl) 2-methyl 5,6- dihydropyridine-1,2(4H)-dicarboxylate (6 g, 24.87 mmol, 1 eq) in THF (30 mL) was slowly 5 added to the above mixture.
  • Step 3 Int.72: [0293] To a solution of cis-1-(tert-butyl) 2-methyl-3-vinylpiperidine-1,2-dicarboxylate carboxylate (400 mg, 1.49 mmol, 1 eq) in MeOH (1.5 mL) and THF (4.5 mL) was added LiOH in H2O (2 M, 1.49 mL, 2 eq). Then the mixture was stirred at 50 °C for 3 hr. The 25 reaction mixture was next cooled to room temperature. The aqueous phase was washed with MTBE (5 mL) and acidified with 1M HCl.
  • Step 2 methyl 4,4-difluoropyrrolidine-2-carboxylate: 20 [0295] Into a 250 mL flask were added 1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine- 1,2-dicarboxylate (14.6 g, 55.0 mmol, 1.0 equiv) and 4M HCl in 1,4-dioxane (146 mL) at 117 PATENT Attorney Docket No.052687-508001WO 15 ⁇ 25 o C. The resulting mixture was stirred for 2.5 hr at 25 o C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure.
  • Step 3 methyl (S)-4,4-difluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2- methylpropanoyl)pyrrolidine-2-carboxylate: [0296] To a s rre mx ure o me y - , - uoropyrro ne- -car oxylate (6 g, 36.3 mmol, 1.00 equiv) and (2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (8.62 g, 54.5 10 mmol, 1.50 equiv) in DMF (60 mL) were added HATU (27.63 g, 72.7 mmol, 2 equiv) and DIPEA (23.48 g, 181.7 mmol, 5 equiv) dropwise at 0 o C under nitrogen atmosphere.
  • Step 4 Int.74: [0297] To a stirred mixture of methyl (2S)-4,4-difluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy- 2-methyl propanoyl] pyrrolidine-2-carboxylate (6.9 g, 12.7 mmol, 1.00 equiv) in MeOH (56 118 PATENT Attorney Docket No.052687-508001WO mL, 1383.14 mmol, 109 equiv), THF (56 mL) and H 2 O (56 mL) was added LiOH (0.61 g, 25.3 mmol, 2 equiv) at 0 o C under nitrogen atmosphere.
  • Step 2 Int.75: [0299] Dissolve (S -4-enoic acid (10 g, 1 Eq, 28 mmol) in DCM (20 mL), bring to 0 °C under argon. Add DCC (6.5 g, 1.1 Eq, 31 mmol) and DMAP (0.35 g, 0.1 Eq, 2.8 mmol) as solids. Add tert-butanol (8.4 g, 11 10 mL, 4 Eq, 0.11 mol) by syringe. Stir at rt overnight. Dilute in water and DCM, extract 3X DCM. Wash combined organic layers with water and brine, dry over MgSO 4 , filter, concentrate.
  • Step 2 tert-butyl (R)-(3-oxohept-6-en-2-yl)carbamate: [0301] To a sti o)-1-oxopropan-2- yl)carbamate (30 g, 129.154 mmol, 1 equiv) in THF (600 mL) was added bromo (but-3-en-1- 10 yl) magnesium (645.77 mL, 645.770 mmol, 5 equiv) dropwise at 0°C under nitrogen atmosphere. Then the mixture was stirred for 16 hr at ambient temperature. The reaction was quenched with sat. NH 4 Cl (aq.)/ NH 4 .OH (9:1) at -10 °C.
  • Step 3 (R)-2-methylhept-6-enoic acid: 15 [0306]
  • (R) -4-benzyl-3-((R)-2-methylhept-6-enoyl)oxazolidin-2-one (19 g, 63.042 mmol, 1 equiv) was dissolved in tetrahydrofuran (700 mL) and cooled in an ice-water bath.
  • Hydrogen peroxide 60 mL, 1763.980 mmol, 30%
  • LiOH 4.53 g, 189.126 mmol, 3 equiv
  • Step 4 tert-butyl (R)-hept-6-en-2-ylcarbamate: 123 PATENT Attorney Docket No.052687-508001WO [0307] To a 27 mmol, 1 equiv) in anhydrous tBuOH (100 mL) was added TEA (9.96 g, 98.454 mmol, 2 equiv) and DPPA (14.90 g, 54.150 mmol, 1.1 equiv). The reaction mixture was stirred at 5 90°C overnight. The reaction mixture was quenched by addition of water (200 mL). The aqueous layer was extracted with EtOAc (300 mL).
  • Step 5 tert-butyl (R)-hept-6-en-2-yl(methyl)carbamate: [0308] To a so u o e - u y - ep - -e - -y ca a a e . g, . 7 mmol, 1 equiv) in THF (80 mL) was added NaH (1.61 g, 40.314 mmol, 2 equiv, 60%) in portions. The 15 reaction was stirred at 0°C for 30 min. Then, MeI (28.61 g, 201.570 mmol, 10 equiv) was added dropwise. The reaction was warmed to room temperature and stirred overnight under an atmosphere of nitrogen.
  • Step 6 Int.77 124 PATENT Attorney Docket No.052687-508001WO [0309] Step 6 for Int.77 was performed with the procedure outlined in Step 2 for Int.16.
  • Boc 2 O (9.01 g, 41.264 mmol, 1.5equiv) was added in portions and the reaction was 5 stirred at room temperature for 5 hr. The resulting mixture was concentrated under reduced pressure and was directly purified by column chromatography (SiO 2 , 20% EtOAc in pet. ether) to afford tert-butyl (2,2-dimethylhex-5-en-1-yl)carbamate (3.7 g, 59.15%) as a yellow oil.
  • Step 4 tert-butyl (2,2-dimethylhex-5-en-1-yl)(methyl)carbamate: [0313] To a sol u on o er - u y , - me y ex- -en- -y car amate (5.4 g, 23.752 mmol, 1 equiv) in DMF (80 mL) was added NaH (1.43 g, 35.628 mmol, 1.5 equiv, 60%) at 0 15 °C under a nitrogen atmosphere. After 15 min, MeI (6.74 g, 47.504 mmol, 2 equiv) was added and the mixture was warmed to room temperature and continued overnight. The resulting mixture was quenched with sat.
  • the macrocyclic synthesis procedures described herein include Methods A, B, and C.
  • the final synthesis 10 procedures described herein include Methods 1-7.
  • Macrocycle Synthesis Procedures a. Method A Generic Procedure for Method A: 127 PATENT Attorney Docket No.052687-508001WO Representative Procedure for Method A: 1) TFA/DCM 1) TFA/DCM O 2) O Cl O O Cl Cl Cl 2) Boc-Leu-OH O N O N HO O HN O N HATU, DIPEA O B ocN DMF OH O Br
  • Step 1 tert-butyl ((S)-1-((R)-2-((allyloxy)methyl)pyrrolidin-1-yl)-3-(2-bromo-5- 5 chlorophenyl)-1-oxopropan-2-yl)(methyl)carbamate (500): [0316] To a so ut on o nt.
  • reaction mixture 15 was quenched by addition water (3000 mL) at 0°C, and then extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (1000 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by FCC (0 to 25% EtOAc in pet. ether) to afford 502 (130 g, 206.67 mmol, 64.40%) as a yellow oil.
  • Step 4-5 tert-butyl ((S)-1-(((S)-1-(((S)-1-(((S)-1-((R)-2-((allyloxy)methyl)pyrrolidin-1-yl)-3-(2-25 bromo-5-chlorophenyl)-1-oxopropan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)amino)-1- oxopent-4-en-2-yl)(methyl)carbamate (504): 129 PATENT Attorney Docket No.052687-508001WO [ A (100 mL). The mixture was stirred at ambient temperature for 1 hr. The LCMS trace showed that the starting material was consumed.
  • reaction mixture 15 was quenched by the addition of water (2000 mL) at 0°C, then extracted with EtOAc (2000 mL x 2). The combined organic layers were washed with brine (2000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by FCC (0 ⁇ 20% EtOAc/Pet. ether) give 504 (60 g, 81.06 mmol, 64.34%) as a yellow oil.
  • Step 8 tert-butyl ((S)-2-(((7S,10S,13S,18aR)-13-(2-bromo-5-chlorobenzyl)-10-isobutyl-25 12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a-tetradecahydro-1H- pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-1-cyclopropyl-2- oxoethyl)carbamate (507) 131 PATENT Attorney Docket No.052687-508001WO h Ar for 20 min.
  • Method B Generic Procedure for Method B: epese a ve oce ue o e o 5 133 PATENT Attorney Docket No.052687-508001WO Representative Experimental for Method B: Steps 1-3: 502: Steps 1-3 for Method B, the syn ed in Method A.
  • Step 4 tert-butyl (S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-6-(((R)- 1-((S)-3-(2-bromo-5-chlorophenyl)-2-((S)-2-((tert-butoxycarbonyl)amino)-N,4- dimethylpentanamido)propanoyl)pyrrolidin-2-yl)methoxy)hex-4-enoate (508): [ 0324] 502 (2.33 g, 1 Eq, 3.71 mmo ) and Int.75 (4.9 g, 3.2 Eq, 12 mmo ) were d sso ved10 in DCE (25 mL).
  • Step 5 (S,Z)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-6-(((R)-1-((S)-2- ((S)-2-amino-N,4-dimethylpentanamido)-3-(2-bromo-5- chlorophenyl)propanoyl)pyrrolidin-2-yl)methoxy)hex-4-enoic acid (509): 134 PATENT Attorney Docket No.052687-508001WO [032 olution was allowed to sit for 2 hours and concentrated by rotary evaporation. Excess TFA was removed by co-evaporation with Toluene.
  • Step 8 tert-butyl ((S)-2-(((7S,10S,13S,18aR,Z)-13-(2-bromo-5-chlorobenzyl)-10- isobutyl-12-methyl-8,11,14-trioxo-3,6,7,8,9,10,11,12,13,14,16,17,18,18a-tetradecahydro- 1H-pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)carbamate (512): O BocHN O Cl Br 15 [0328] 511 (569 mg, 1 Eq, 930 ⁇ mol), Int.62 (400 mg, 2 Eq, 1.86 mmol), and HATU (707 mg, 2 Eq, 1.86 mmol) were dissolved in DMF (4.0 mL).
  • Step 5 tert-butyl ((S)-2-(((1S,2R)-1-(((S)-1-(((S)-1-((R)-2-((allyloxy)methyl)pyrrolidin-1- 5 yl)-3-(2-bromo-5-chlorophenyl)-1-oxopropan-2-yl)(methyl)amino)-4-methyl-1- oxopentan-2-yl)carbamoyl)-2-vinylcyclopropyl)(methyl)amino)-1-cyclopropyl-2- oxoethyl)carbamate (513): [03 30] To a solution of 503 (1.5 g, 1 eq, TFA) and Int.70 (0.98 g, 1.3 Eq, 2.9 mmol) in 10 DMF (20 mL) was added HATU (1.1 g, 1.3 Eq, 2.9 mmol) and DIPEA (0.86 g, 1.2
  • Step 6 tert-butyl ((S)-2-(((1aS,4S,7S,12aR,17aR)-7-(2-bromo-5-chlorobenzyl)-4-isobutyl- 6-methyl-2,5,8-trioxo-3,4,5,6,7,8,11,12,12a,13,15,17a-dodecahydro-1H,10H- 138 PATENT Attorney Docket No.052687-508001WO cyclopropa[l]pyrrolo[2,1-c][1]oxa[4,7,10]triazacyclohexadecin-1a(2H)- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (514): , , , Ar 5 for 20 min.
  • Method 2 141 PATENT Attorney Docket No.052687-508001WO Generic Procedure for Method 2 5 Representative Experimental for Method 2: Example 54 Tert-butyl ((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-4,7,15-trimethyl- 5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadec-14-en-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)carbamate (517): 142 PATENT Attorney Docket No.052687-508001WO [0335] The macrocycle as synthesized using Method A with Int.21, Int.26, and Int.61.
  • Step 2-3 (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-(5-chloro-2-(1-methyl-1H-pyrazol-4- yl)benzyl)-9-isobutyl-4,7,15-trimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadec-14- en-12-yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 20 54): 143 PATENT Attorney Docket No.052687-508001WO ed until the deprotection was complete (monitored by LCMS).
  • Method 3 15 Generic Procedure for Method 3 144 PATENT Attorney Docket No.052687-508001WO Representative Procedure for Method 3:
  • Example 46 (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-(5-chloro-2-(2-methylthiazol-5-yl)benzyl)-9-isobutyl- 5 4,7-dimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadecan-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxamide (520): [0339] The macrocycle starting material for method 4 (520), was synthesized using Method 10 A with Int.11, Int.26, and Int.61 as starting materials.
  • Step 1 tert-butyl ((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-4,7- dimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadecan-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)carbamate (521): 145 PATENT Attorney Docket No.052687-508001WO ent temperature.
  • Step 2 tert-butyl ((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-4,7- dimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadecan-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)carbamate (522): [ 0341] 521 (110 mg, 1.0 Eq, 144.0 ⁇ mol), Na2CO3 (44.5 mg, 3 Eq, 420 ⁇ mol), Int.34 15 (63.0 mg, 2.0 Eq, 280 ⁇ mol) and PdCl2(dppf) •CH2Cl2 adduct (11.4 mg, 0.1 Eq, 14.0 ⁇ mol) were dissolved in 4:1 Dioxane/Water (4 mL).
  • Step 3-4 (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-(5-chloro-2-(2-methylthiazol-5-yl)benzyl)-9- isobutyl-4,7-dimethyl-5,8,11-trioxo-1-oxa-4,7,10-triazacyclohexadecan-12- 146
  • Step 1 tert-butyl ((S)-2-(((1S,4S,7S,16S)-7-((5-chloro-2-cyclopropoxypyridin-3- 5 yl)methyl)-4-isobutyl-6,9-dimethyl-2,5,8-trioxo-3,6,9-triazabicyclo[14.1.0]heptadecan-1- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (525): [ ] ( mg, q, .
  • Step 2-3 ((2S,4R)-N-((S)-2-(((1S,4S ,7S,16S)-7-((5-chloro-2-cyclopropoxypyridin-3- yl)methyl)-4-isobutyl-6,9-dimethyl-2,5,8-trioxo-3,6,9-triazabicyclo[14.1.0]heptadecan-1- yl)(methyl)amino)-1-cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1- (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 77): 149 PATENT Attorney Docket No.052687-508001WO reaction was stirred at ambient temperature until the complete consumption of starting material (monitored by LCMS).
  • Step 1 tert-butyl ((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-7-methyl- 5,8,11-trioxo-17-oxa-4,7,10-triazaspiro[2.15]octadecan-12-yl)(methyl)amino)-1- 5 cyclopropyl-2-oxoethyl)carbamate (528): , , added PtO 2 (14.3 mg, 0.1 Eq, 62.9 ⁇ mol). The reaction was vigorously stirred under an atmosphere of hydrogen until the complete consumption of starting material (monitored by 10 LCMS).
  • Steps 2-3 (2S,4R)-N-((S)-2-(((6S,9S,12S)-6-(2-bromo-5-chlorobenzyl)-9-isobutyl-7-15 methyl-5,8,11-trioxo-17-oxa-4,7,10-triazaspiro[2.15]octadecan-12-yl)(methyl)amino)-1- cyclopropyl-2-oxoethyl)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4- fluoropyrrolidine-2-carboxamide (528): [0350] 528 (380 mg, 1 Eq, 417 ⁇ mol) was dissolved in 30% TFA in DCM (25 mL).
  • Example 96 (9.8 153 PATENT Attorney Docket No.052687-508001WO mg, 9.0 ⁇ mol, 7.2 %) was isolated as a white solid after lyophilization.
  • Step 1 tert-butyl ((S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- 5 isobutyl-12-methyl-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)carbamate (532): [ ] mg, q, ⁇ mo was sso ve n c .
  • Step 3 (2S,4R)-N-((1S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- isobutyl-12-methyl-2-oxido-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)-1-(3,3-difluoro-1- 10 (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 67): [ 0356] 533 (26 mg, 1 Eq, 32.0 ⁇ mol) was dissolved in 6 mL DCM/TFA (3:1) and stirred until the deprotection was complete (monitored by LCMS).
  • Step 2 tert-butyl ((S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- isobutyl-12-methyl-2,2-dioxido-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- 5 c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)carbamate (535): [ g, . q, ⁇ o was sso ve e .
  • Step 3 (2S,4R)-N-((S)-1-cyclopropyl-2-(((7S,10S,13S,18aR)-13-(2,5-dichlorobenzyl)-10- isobutyl-12-methyl-2,2-dioxido-8,11,14-trioxohexadecahydro-1H-pyrrolo[2,1- c][1]thia[4,7,10]triazacyclohexadecin-7-yl)(methyl)amino)-2-oxoethyl)-1-(3,3-difluoro-1- 15 (trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxamide (Example 56): 158 PATENT Attorney Docket No.052687-508001WO until the deprotection was complete (monitored by LCMS).
  • Example 56 (1.17 mg, 1.15 ⁇ mol, 1.3 %) was recovered as a white solid after lyophilization.
  • Table 2 provides information on the methods used to prepare the exemplified compounds in the current application. This table includes a column listing the 20 Example Number, Macrocyclic Synthesis procedure, and Final Synthesis procedure. Chemical structures for the exemplified compounds are shown in Table 4, while analytical data for these compounds are shown in Table 3.
  • Table 2 Summary Table Procedures for Compound Preparation 159 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 160 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 161 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 162 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 163 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis 164 PATENT Attorney Docket No.052687-508001WO Example Number Macrocycle Synthesis Final Synthesis [0363] Table 3, below, provides the expected (Exact Mass) and observed molecular weight for each exemplary compound listed in Table 2.
  • Table 3 Analytical Data for Exemplary Compounds of Table 2 E x. Number Exact Mass Observed m/z 1 9103 91144 165 PATENT Attorney Docket No.052687-508001WO E x. Number Exact Mass Observed m/z 24 1024.44 1025.51 166 PATENT Attorney Docket No.052687-508001WO E x. Number Exact Mass Observed m/z 60 964.35 965.42 167 PATENT Attorney Docket No.052687-508001WO E x. Number Exact Mass Observed m/z 96 1092.5 1093.89 [0364] Table 4, below, provides the full chemical structure for each exemplified compound in Table 2.
  • Table 4 Chemical Structure for Exemplary 5 Compounds Described in Table 2 Ex. Chemical Structure Ex. Chemical Structure No. No. Cl Cl 168 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 169 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 170 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 171 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No. 172 PATENT Attorney Docket No.052687-508001WO Ex. Chemical Structure Ex. Chemical Structure No. No.
  • Cyclin/CDK protein complexes were sourced as follows: CyclinA2/CDK2 (CRELUX Protein Services), CyclinB1/CDK1 (Eurofins, discovery. Cat. No.14-450) and CyclinE1/CDK2 (Eurofins, discovery. Cat. No. 10 14-475).
  • CyclinA2/CDK2 CRELUX Protein Services
  • CyclinB1/CDK1 Eurofins, discovery. Cat. No.14-450
  • CyclinE1/CDK2 Eurofins, discovery. Cat. No. 10 14-475
  • 176 PATENT Attorney Docket No.052687-508001WO [0366] FP binding assays were performed in 25 mM HEPES pH 7.5, 100 mM NaCl, 1mM DTT, 0.01% NP-40 and 1 mg/mL BSA for all 3 protein complexes in black 96-well plates.
  • the protein concentration used for the competitive FP assays were 8 nM for Cyclin A2/Cdk2 and 10 nM for Cyclin B1/Cdk1 and Cyclin E1/Cdk2 with 2 nM of FAM probe FAM probe. Under these conditions, the dynamic range was about 120 mP 100% binding of 15 FAM probe and complete inhibition of binding by excess of an unlabeled competitor compound, with all experiment showing a Z’ factor > 0.80.
  • IC50 for test compounds were determined in eight-point serial dilution dose response curves. Reported IC 50 are the average of 2-3 independent experiments. Data from these assays are reported in Table 5.
  • Fmoc-Glycine (G), CAS#29022- 11-5, (4 equiv.) was dissolved in 1.0 mL of anhydrous NMP.
  • Neat DIEA (8 equiv.) was 5 added to the Fmoc-amino acid solution.
  • the solution was dispensed in a peptide reactor vessel containing 50 mg of 2-chlorotrityl chloride (CTC) resin and was agitated for 2 hours at rt. The amino acid solution was drained then the resin was washed with 1.0 mL DMF three times.
  • CTC 2-chlorotrityl chloride
  • Unreacted CTC resin was capped with 1.0 mL solution of methanol:DMF (50:50), and DIEA (8 equiv.) for 10 min at rt. The methanol solution was drained then the resin was 10 washed with 1.0 mL DMF three times.
  • a mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 10 to 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times.
  • Fmoc-L-Leucine-OH (L), CAS# 35661-60-0 (12 equiv.), HATU (4 equiv.), and DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times. To 5 remove Fmoc, A mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt.
  • the mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. 25 The mixture was drained then the resin was washed with 1.0 mL of DMF three times.
  • a mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt. The piperidine solution was drained and then the resin was washed with 1.0 mL DMF three times.
  • Fmoc-L-Alanine-OH (A), CAS#35661-39-3, (4 equiv.), HATU (4 equiv.), and 30 DIEA (8 equiv.) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times.
  • the mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained then the resin was washed with 1.0 mL of DMF three times.
  • a mixture of piperidine:DMF (20:80, 1 mL) was added to the resin and agitated for 15 min at rt. The piperidine solution was drained and then the resin was 10 washed with 1.0 mL DMF three times.
  • Fmoc-6-aminohexanoic acid (Ahx), CAS#88574-06-5, (4 equiv.), HATU (4 equiv.), and DIEA (8 equiv) in 1.0 mL of anhydrous NMP was prepared. The mixture was allowed to pre-activate at rt for 5 min, and then was added to the resin and agitated at 35°C for 30 min. The mixture was drained and then the resin was washed with 1.0 mL of DMF three times.
  • 183 PATENT Attorney Docket No.052687-508001WO [0381]
  • the linear intermediate X ( ⁇ 15 mg) was cyclized using a medium volume, T3P solution cyclization method.
  • the deprotected and purified linear product was transferred to a 50 mL conical vial and dissolved in 1 mL NMP followed by the addition of DIEA (0.5 mL) and DCM (35 mL).
  • T3P (3 eqv) was added to the solution and the reaction pH was adjusted 5 to pH 9 via dropwise addition of DIEA.
  • the closed conical vial was agitated at rt for 2 hours at 150 rotations per minute.
  • the solution was concentrated at 45°C under reduced pressure in a Genevac system.
  • the Fmoc group was then removed with the addition of a 10% of KOH/Water solution (5 mL) heated at 70°C for 30 min.
  • the resulting LCMS trace revealed that the trityl group had been unexpectedly removed during the cyclization and Fmoc- 10 deprotection steps.
  • the cyclic peptide was then purified via reverse phase HPLC using an Acetonitrile/Water gradient with 0.05% formic acid.
  • 15 [0382] The probe was fluorescently labeled via a peptide coupling in solution.
  • MTT Proliferation Assay was used to determine the 50% growth inhibition (GI50) of disclosed compounds.5 x 10 3 cells were seeded into 96 well plates.24 hours later, cells were dosed with compound in an 8- or 10-point 1:3 serial dilution starting at 10 ⁇ M. Cells were exposed to compound for a sufficient time to allow 3-4 cell doublings (3 days (WI-38); 5 15 days (NCI-H1048 and OVCAR3)).

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Abstract

L'invention concerne des composés de formule (I), des intermédiaires de ceux-ci, et des procédés de fabrication de ceux-ci. L'invention concerne également l'utilisation de tels composés et compositions pour le traitement de maladies et de troubles qui sont médiés, au moins en partie, par une ou plusieurs cyclines, y compris le cancer.
PCT/US2025/026045 2024-04-24 2025-04-23 Inhibiteurs de cycline Pending WO2025226861A1 (fr)

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